Clinical trial NCT04582409
Conditions: Atrial Fibrillation
Keywords: atrial fibrillation arrhythmia pharmacological cardioversion
Sponsor: Novartis Pharmaceuticals
Start date: 2020-11-30; Completion date: 2022-07-11
Enrollment: 13 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a randomized, placebo-controlled, investigator- and participant-blinded study to evaluate the efficacy, safety, tolerability, and pharmacokinetics (PK) of HSY244 in participants with atrial fibrillation (AF), with and without heart failure (HF).

Detailed description:
A screening period of up to 3 days (72 hours) was used to assess eligibility. After eligibility was confirmed, patients were randomized to either HSY244 or placebo. Prior to study drug administration, pre-dose assessments were completed. After the start of study drug administration, the participant was monitored for cardioversion to sinus rhythm. If a participant was still in AF at 90 minutes after the start of study drug administration, direct current cardioversion was planned to be applied at a time deemed appropriate by the investigator.

Arms: arm 1: HSY244 150 mg concentrate solution for injection via intravenous infusion arm 2: Placebo concentrate solution for injection via intravenous infusion
Interventions: intervention 1: HSY244 intervention 2: Placebo
Intervention descriptions: intervention 1: HSY244 concentrate solution for injection via intravenous infusion intervention 2: Placebo concentrate solution for injection via intravenous infusion

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development
HSY244
Clinical Trial Protocol CHSY244X2201
A randomized, placebo-controlled, investigator- and 
participant-blinded study to evaluate the efficacy, safety, 
tolerability, and pharmacokinetics of HSY244 in 
participants with atrial fibrillation
Document type:
Amended Clinical Trial Protocol
EUDRACT number:
2020-004327-17
Version number:
v04 (Clean)
Clinical Trial Phase:
II
Release date:
07-Feb-2022
Property of Novartis Institutes for BioMedical Research
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 3.0 dated 31-Jan-2020
ClinicalTrials.gov Identifier: NCT04582409


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Table of contents
Table of contents..................................................................................................................2
List of tables.........................................................................................................................5
List of figures.......................................................................................................................6
List of abbreviations ............................................................................................................7
Glossary of terms.................................................................................................................9
Protocol summary..............................................................................................................23
1
Introduction........................................................................................................................26
1.1
Background............................................................................................................26
1.2
Purpose...................................................................................................................28
2
Objectives and endpoints...................................................................................................28
3
Study design.......................................................................................................................29
4
Rationale ............................................................................................................................31
4.1
Rationale for study design......................................................................................31
4.2
Rationale for dose/regimen and duration of treatment...........................................32
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs.......................................................................................................................32
4.4
Purpose and timing of interim analyses.................................................................32
4.5
Risks and benefits ..................................................................................................33
4.5.1
Effects on the central nervous system ...................................................34
4.5.2
Effects on the cardiovascular system ....................................................35
4.5.7
Potential risk associated with the COVID-19 pandemic.......................37
4.6
Rationale for Public Health Emergency mitigation procedures.............................37
5
Study Population................................................................................................................38
5.1
Inclusion criteria ....................................................................................................38
5.2
Exclusion criteria ...................................................................................................39
6
Treatment...........................................................................................................................41
6.1
Study treatment ......................................................................................................41
6.1.1
Investigational and control drugs ..........................................................41
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6.1.2
Additional study treatments...................................................................42
6.1.3
Treatment arms/group ...........................................................................42
6.2
Other treatment(s) ..................................................................................................42
6.2.1
Concomitant therapy .............................................................................42
6.2.3
Rescue medication.................................................................................44
6.2.4
Restriction for study participants...........................................................44
6.3
Participant numbering, treatment assignment, randomization...............................45
6.3.1
Participant numbering ...........................................................................45
6.3.2
Treatment assignment, randomization...................................................45
6.4
Treatment blinding.................................................................................................45
6.5
Dose escalation and dose modification..................................................................47
6.6
Additional treatment guidance...............................................................................47
6.6.1
Treatment compliance ...........................................................................47
6.6.2
Recommended treatment of adverse events ..........................................47
6.6.3
Emergency breaking of assigned treatment code ..................................47
6.7
Preparation and dispensation .................................................................................48
6.7.1
Handling of study treatment and additional treatment ..........................48
6.7.2
Instruction for prescribing and taking study treatment..........................49
7
Informed consent procedures.............................................................................................49
8
Visit schedule and assessments..........................................................................................50
8.1
Screening................................................................................................................55
8.1.1
Eligibility screening...............................................................................55
8.1.2
Information to be collected on screening failures .................................55
8.2
Participant demographics/other baseline characteristics........................................56
8.3
Efficacy..................................................................................................................56
8.3.1
Continuous digital 12-lead Holter .........................................................56
8.3.2
Appropriateness of efficacy assessments ..............................................57
8.4
Safety .....................................................................................................................57
8.4.1
Laboratory evaluations..........................................................................58
8.4.2
Electrocardiogram (ECG)......................................................................59
8.4.3
Pregnancy and assessments of fertility..................................................60
8.4.4
Appropriateness of safety measurements ..............................................60
8.4.5
Injection/Infusion site reaction..............................................................60
8.5
Additional assessments ..........................................................................................61
8.5.1
Pharmacokinetics...................................................................................61
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9
Study discontinuation and completion...............................................................................63
9.1
Discontinuation and completion ............................................................................63
9.1.1
Study treatment discontinuation and study discontinuation..................63
9.1.2
Replacement policy ...............................................................................64
9.2
Withdrawal of informed consent............................................................................64
9.2.1
Lost to follow-up...................................................................................65
9.2.2
Study stopping rules ..............................................................................65
9.2.3
Early study termination by the sponsor.................................................65
9.3
Study completion and post-study treatment...........................................................66
10 Safety monitoring and reporting........................................................................................66
10.1
Definition of adverse events and reporting requirements......................................66
10.1.1
Adverse events.......................................................................................66
10.1.2
Serious adverse events...........................................................................68
10.1.3
SAE reporting........................................................................................69
10.1.4
Pregnancy reporting...............................................................................70
10.1.5
Reporting of study treatment errors including misuse/abuse ................70
10.2
Additional Safety Monitoring................................................................................71
10.2.1
Liver safety monitoring.........................................................................71
10.2.2
Renal safety monitoring ........................................................................71
11 Data Collection and Database management ......................................................................72
11.1
Data collection .......................................................................................................72
11.2
Database management and quality control ............................................................72
11.3
Site monitoring.......................................................................................................73
12 Data analysis and statistical methods.................................................................................74
12.1
Analysis sets...........................................................................................................74
12.2
Participant demographics and other baseline characteristics.................................74
12.3
Treatments..............................................................................................................74
12.4
Analysis of the primary endpoint(s)/estimand(s)...................................................74
12.4.1
Definition of primary endpoint(s)/estimand(s)......................................74
12.4.2
Statistical model, hypothesis, and method of analysis ..........................74
12.4.3
Handling of remaining intercurrent events of primary estimand ..........75
12.4.4
Handling of missing values not related to intercurrent event................75
12.4.5
Sensitivity analyses for primary endpoint/estimand..............................75
12.4.6
Not applicable Supplementary analysis.................................................75
12.5
Analysis of secondary endpoints/estimands ..........................................................75
12.5.1
Safety endpoints ....................................................................................75
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12.5.2
Pharmacokinetics...................................................................................76
12.5.3
PK/PD relationships ..............................................................................77
12.6
Analysis of exploratory endpoints .........................................................................77
12.7
Interim analyses .....................................................................................................78
12.8
Sample size calculation..........................................................................................78
12.8.1
Primary endpoint(s)...............................................................................78
13 Ethical considerations and administrative procedures.......................................................79
13.1
Regulatory and ethical compliance........................................................................79
13.2
Responsibilities of the investigator and IRB/IEC..................................................79
13.3
Publication of study protocol and results...............................................................79
13.4
Quality Control and Quality Assurance.................................................................79
13.5
Participant Engagement .........................................................................................80
14 Protocol adherence.............................................................................................................80
14.1
Protocol amendments.............................................................................................80
15 References..........................................................................................................................81
16 Appendices.........................................................................................................................82
16.1
Appendix 1: Liver event and laboratory trigger definitions & follow-up 
requirements...........................................................................................................82
16.2
Appendix 2: Specific Renal Alert Criteria and Actions and Event Follow-up......86
List of tables
Table 2-1
Objectives and related endpoints...........................................................28
Table 4-1
Rationale for study design.....................................................................31
Table 6-1
Investigational and control drug............................................................41
Table 6-3
Blinding levels.......................................................................................46
Table 8-1
Assessment Schedule.............................................................................52
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse..........................................................................................70
Table 12-1
Non-compartmental pharmacokinetic parameters.................................77
Table 16-1
Liver event and laboratory trigger definitions.......................................82
Table 16-2
Follow up requirements for liver laboratory triggers with liver 
symptoms...............................................................................................83
Table 16-3
Follow up requirements for liver laboratory triggers ............................85
Table 16-4
Specific Renal Alert Criteria and Actions.............................................86
Table 16-5
Renal Event Follow Up .........................................................................86
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List of figures
Figure 3-1
Study Design .........................................................................................29


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List of abbreviations
AE
Adverse Event
AERP
Atrial effective refractory period
AF
Atrial fibrillation
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
ANCOVA
Analysis of covariance
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical
AUC
Area under the curve
AV
Atrioventricular
BMI
Body Mass Index
BUN
Blood Urea Nitrogen
CK
Creatine Kinase
Cmax
Maximum concentration
CMO&PS 
Chief Medical Office and Patient Safety
CNS
Central nervous system
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CSR
Clinical study report
DBP
Diastolic Blood Pressure
EC90
90% Effective concentration
ECG
Electrocardiogram
EDC
Electronic Data Capture
EMA
European Medicines Agency
EOS
End of Study
FIH
First-in-human
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GCS
Global Clinical Supply
GGT
Gamma-glutamyl transferase
GLDH
Glutamate Dehydrogenase
GLP
Good Laboratory Practices
h
Hour
HBcAg
Hepatitis B core antigen
HBsAg
Hepatitis B virus surface antigen
HCV
Hepatitis C Virus
HF
Heart failure
HIV
Human immunodeficiency virus
i.v.
Intravenous
IB
Investigator’s Brochure
ICF
Informed Consent Form


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ICH
International Council for Harmonization of Technical Requirements for Pharmaceuticals 
for Human Use
IEC
Independent Ethics Committee
IN
Investigator Notification
INR
International Normalized Ratio
IRB
Institutional Review Board
IUD
Intrauterine device
IUS
Intrauterine system
LDH
lactate dehydrogenase
LFT
Liver function test 
LLOQ
lower limit of quantification
MedDRA
Medical dictionary for regulatory activities 
mg
milligram(s)
mL
milliliter(s)
NIRT
Novartis Interactive Response Technology
NOAC
Novel oral anticoagulant
P-gp
P-glycoprotein
PACU
Post-anesthesia care unit
PCR
Protein-creatinine ratio
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PoC
Proof of Concept
PT
prothrombin time
QMS 
Quality Management System
QTcF
QT interval corrected by Fridericia’s formula
SA
Sinoatrial
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
sCR
serum creatinine
SD
standard deviation
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic Pyruvic Transaminase
SMQ
Standardized MedDRA Query
SUSAR
Suspected Unexpected Serious Adverse Reaction
TdP
Torsades de Pointes
TIA
Transient ischemic attack
ULN
upper limit of normal
UTI
Urinary Tract Infection
WHO
World Health Organization 
WPW
Wolff-Parkinson-White


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Glossary of terms
Additional 
treatment
Medicinal products that may be used during the clinical trial as described in 
the protocol, but not as an investigational medicinal product (e.g. any 
background therapy)
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study participant 
Coded data
Personal Data which has been de-identified by the investigative center team 
by replacing personal identifiers with a code. 
Cohort
A specific group of participants fulfilling certain criteria and generally treated at 
the same time
Control drug
A study drug (active or placebo) 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
Discontinuation 
from study 
treatment
Point/time when the participant permanently stops receiving the study 
treatment for any reason (prior to the planned completion of study drug 
administration, if any). Participant agrees to the other protocol required 
assessments including follow-up. No specific request is made to stop the use 
of their samples or data. 
Dosage
Dose of the study treatment given to the participant in a time unit (e.g., 100 
mg once a day, 75 mg twice a day)
Electronic Data 
Capture (EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical study 
data using data collection systems, such as Web-based applications, 
interactive voice response systems and clinical laboratory interfaces. EDC 
includes the use of Electronic Case Report Forms (eCRFs) which are used to 
capture data transcribed from source data/documents used at the point of 
care
End of the clinical 
trial
The end of the clinical trial is defined as the last visit of the last participant. 
Enrollment
Point/time of participant entry into the study at which informed consent must 
be obtained. The action of enrolling one or more participants. 
Healthy volunteer
A person with no known significant health problems who volunteers to be a 
study participant 
Intercurrent events
Events occurring after treatment initiation that affect either the interpretation or 
the existence of the measurements associated with the clinical question of 
interest.
Investigational 
drug/ treatment
The drug whose properties are being tested in the study
Medication number
A unique identifier on the label of medication kits
Mis-randomized 
participants
Mis-randomized participants are those who were not qualified for 
randomization and who did not take study treatment, but have been 
inadvertently randomized into the study 
Other treatment
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy)
Participant
A trial participant (can be a healthy volunteer or a patient). “Participant” 
terminology is used in the protocol whereas term “Subject” is used in data 
collection. 


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Participant number
A unique number assigned to each participant upon signing the informed 
consent. This number is the definitive, unique identifier for the participant and 
should be used to identify the participant throughout the study for all data 
collected, sample labels, etc.
Period
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) 
which are described in the Protocol. Periods define the study phases and will 
be used in clinical trial database setup and eventually in analysis
Personal data
Participant information collected by the Investigator that is coded and 
transferred to Novartis for the purpose of the clinical trial. This data includes 
participant identifier information, study information and biological samples.
Premature 
participant 
withdrawal
Point/time when the participant exits from the study prior to the planned 
completion of all study drug administration and/or assessments; at this time all 
study drug administration is discontinued and no further assessments are 
planned
Randomization
The process of assigning trial participants to investigational drug or 
control/comparator drug using an element of chance to determine the 
assignments in order to reduce bias. 
Randomization 
number
A unique identifier assigned to each randomized participant
Re-screening
If a participant fails the initial screening and is considered as a Screen Failure, 
he/she can be invited once for a new Screening visit after medical judgment 
and as specified by the protocol. 
Screen Failure
A participant who did not meet one or more criteria that were required for 
participation in the study
Source 
Data/Document
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource
Start of the clinical 
trial
The start of the clinical trial is defined as the signature of the informed consent 
by the first participant
Study treatment
Any drug or combination of drugs   or intervention administered to the study 
participants as part of the required study procedures; includes investigational 
drug(s), control(s) or background therapy
Study treatment 
discontinuation
When the participant permanently stops taking any of the study drug(s) prior 
to the defined study treatment completion date (if any) for any reason; may or 
may not also be the point/time of study discontinuation 
Treatment 
arm/group 
A treatment arm/group defines the dose and regimen or the combination, and 
may consist of 1 or more cohorts.
Variable (or 
endpoint)
The variable (or endpoint) to be obtained for each participant that is required 
to address the clinical question. The specification of the variable might include 
whether the participant experiences an intercurrent event.


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Protocol summary
Protocol number
CHSY244X2201
Full Title
A randomized, placebo-controlled, investigator- and participant-blinded study 
to evaluate the efficacy, safety, tolerability, and pharmacokinetics of HSY244 
in participants with atrial fibrillation
Brief title
A study to evaluate the efficacy, safety, tolerability, and pharmacokinetics of 
HSY244 in participants with atrial fibrillation
Sponsor and 
Clinical Phase
Novartis Institutes for BioMedical Research
Phase II
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
The purpose of this study is to evaluate the efficacy, safety, tolerability, and 
pharmacokinetics of HSY244 in participants with atrial fibrillation (AF). 
HSY244 is a potent inhibitor of GIRK1/4 channels, which are believed to play 
an important role in AF. GIRK1/4 inhibition is expected to restore sinus rhythm 
without undesirable effects on ventricular repolarization and hence, may offer 
superior properties for pharmacologic cardioversion of AF. HSY244 is planned 
to be developed as an intravenous (i.v.) infusion for the acute cardioversion of 
AF to sinus rhythm.
Primary 
Objective(s) 
The primary objective of this study is to evaluate the efficacy of HSY244 to 
restore sinus rhythm in participants with AF. 
Secondary 
Objectives
To evaluate the safety and tolerability of HSY244 in participants with AF
To evaluate the pharmacokinetics of HSY244 in participants with AF
Study design
This is a randomized, placebo-controlled, investigator- and participant-blinded 
study to evaluate the efficacy, safety, tolerability, and pharmacokinetics of 
HSY244 in participants with AF. An initial cohort (Cohort 1) of approximately 
29 participants (approximately 20 participants receiving HSY244) is planned 
to be enrolled to evaluate a single 150 mg i.v. dose of HSY244 for 
AF cardioversion to sinus rhythm.
 
 
 
 
Participants with AF that meet clinical 
criteria for direct current cardioversion will be screened, and on Day 1, after 
eligibility is confirmed, administration of a 15 minute i.v. infusion of HSY244 or 
placebo will occur. Participants will then be monitored for cardioversion to 
sinus rhythm. For those remaining in AF after 90 minutes, direct current 
cardioversion can be performed. Participants will be monitored for at least 3 
hours, although overnight observation will be available. Participants will be 
evaluated for safety and pharmacokinetic assessments during end of study 
assessments, which are to occur on Day 5 (96 hours post dose) ± 24 hours. 
An interim analysis in Cohort 1 is planned after approximately 10 participants 
have received HSY244 and completed end of study assessments. 
 
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Study population
The study population will include hemodynamically stable men and women between 
18 and 80 years of age with a clinical indication for direct current cardioversion of 
AF, with the current AF episode lasting between 6 hours and 60 days.
In Cohort 1, a total of approximately 20 participants will receive HSY244 and 
a total of approximately 29 participants with AF will be randomized. The 
randomization ratio will be a 5:1 ratio of HSY244 and placebo. 
Key Inclusion 
criteria

Hemodynamically stable men and women between 18 and 80 years of 
age with a clinical indication for direct current cardioversion of AF

Current episode of AF has been ongoing for ≥6 hours and ≤60 days

Successful initiation and achievement of therapeutic levels of national 
guideline and institution-specific anticoagulation therapy as appropriate 
for the duration of the AF episode and risk for the participant 

Completion of national guideline and institution-specific imaging 
evaluation for left atrial thrombi as appropriate for the duration of AF 
episode and risk for the participant 

Participants must weigh at least 60 kg to participate in the study, and 
must have a body mass index (BMI) within the range of 18 - 45 kg/m2. 
BMI = Body weight (kg) / [Height (m)2]

Written informed consent must be obtained before any assessment is 
performed and only participants able to provide written informed consent 
themselves will be included in this study
Key Exclusion 
criteria

Use of any class I or III anti-arrhythmic medication, or other prohibited 
medications, within 5 half-lives before randomization, including use of 
amiodarone within 3 months before randomization

History or current diagnosis of electrocardiogram (ECG) abnormalities or 
cardiac rhythm disorders indicating significant risk of safety for participant 
as determined by the Investigator's interpretation of the ECG findings

Attempted or unsuccessful cardioversion within 2 weeks prior to 
randomization

Presence of known severe mitral regurgitation and/or known severely 
dilated left atrium

Pre-existing or tachycardia-induced moderate to severe cardiac 
dysfunction (New York Heart Association class III or IV)

History within the preceding 3 months prior to randomization of either a: 
myocardial infarction, unstable angina, cardiac surgery, or a 
percutaneous coronary intervention

History of confirmed stroke or transient ischemic attack (TIA)

History or current diagnosis of any seizure disorder or major neurological 
disorder or major psychiatric disorder

Sexually active males, including those post-vasectomy, must use a 
condom during sexual intercourse for at least 96 hours after dosing to 
prevent delivery of the drug via seminal fluid and should not father a child 
during this period

Women must be either of non-childbearing potential or child-bearing 
potential using highly effective non-hormonal contraception
Study treatment
HSY244 or placebo
Efficacy 
assessments
Digital Holter (continuous ECG) monitor
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Pharmacokinetic 
assessments
PK profile as measured by Cmax, Tmax, and AUClast from the plasma 
concentration-time data
Key safety 
assessments
Adverse event monitoring, vital signs, physical examinations, monitoring of 
laboratory markers in blood and urine, ECG parameters
Other 
assessments
Data analysis
The rate of conversion to sinus rhythm for HSY244 and placebo will be 
compared using Fisher’s Exact test. The difference in the conversion rates 
between HSY244 and placebo will be reported along with the 80% confidence 
limits for the difference and the p-value from Fisher’s Exact test. Results may 
be reported for the subpopulations of participants with and without heart 
failure.
Key words
Atrial fibrillation, Arrhythmia, Pharmacological cardioversion, GIRK1/4
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1
Introduction
1.1
Background
Atrial fibrillation (AF) is a common cardiac arrhythmia that increases in prevalence with age. 
AF affects approximately 2% of people under the age of 65 and about 9% of people above the 
age of 65. In the US, AF accounts for more than 467,000 hospitalizations and contributes to 
more than 99,000 deaths a year (January et al 2014). A 2010 health survey estimated that 33 
million people worldwide had AF (Chugh et al 2014). With the aging of the population, the 
prevalence of AF is expected to rise substantially in the future adding burden to healthcare 
systems. AF is highly prevalent among individuals with heart failure (HF) with an increasing 
frequency of AF as severity of HF increases (Trulock et al 2014). Patients with AF and HF have 
worse outcomes as compared to patients with HF alone, regardless of the degree of cardiac 
dysfunction (Olsson et al 2006).
AF can lead to symptoms such as palpitations, dyspnea, chest pain, and fatigue. AF is associated 
with an increased risk of stroke, congestive heart failure, and a decreased quality of life. 
Cardioversion of AF to sinus rhythm remains an important option for patients with AF. 
The most commonly utilized method of restoring sinus rhythm is direct current cardioversion 
in which an electric shock is delivered to the heart under sedation or anesthesia. This procedure 
is generally performed under the supervision of a cardiologist and an anesthesiologist. 
Pharmacologic cardioversion is another option, but not commonly performed even though it is 
less invasive and could be initiated more rapidly as it does not require sedation or anesthesia. 
Antiarrhythmic drugs such as flecainide, propafenone, ibutilide, dofetilide, or amiodarone have 
demonstrated some efficacy as AF cardioversion agents, but they are limited by poor efficacy, 
slow onset of action, or undesired effects on ventricular repolarization leading to a prolonged 
QT interval and risk of torsades de pointes. There is an unmet need for a safe and effective drug 
that can rapidly cardiovert AF patients to sinus rhythm.
The cardiac acetylcholine-sensitive inwardly rectifying K+ current ( IKACh), is mediated by a 
channel with two subunits, GIRK1 and GIRK4, assembled as heterotetramers (Voigt et al 2014). 
In the heart, IKACh channels are primarily expressed in the sinoatrial (SA) node, atrioventricular 
(AV) node, and atrial myocytes. IKACh is believed to have a physiologic role in the regulation of 
sinus node automaticity and in the repolarization of atrial myocytes. As GIRK1/4 expression is 
largely absent in the ventricles, inhibition of GIRK1/4 is believed to represent an attractive 
antiarrhythmic drug target since such a blocker would be expected to have little to no effects on 
ventricular repolarization and thus be devoid of pro-arrhythmic ventricular side effects.
Increased activation of IKACh channels has been proposed to contribute to AF by leading to a 
shortening of the atrial action potential duration. Activation of IKACh has been observed in 
experimental models of AF induced by tachypacing, and constitutive IKACh activity has been 
observed in atrial myocytes from patients with chronic AF (Dobrev et al 2005). Mechanistically, 
by shortening the atrial action potential duration and decreasing the atrial effective refractory 
period (AERP), IKACh activity is assumed to increase vulnerability to electrical reentry 
promoting the propagation of AF. Indeed, several antiarrhythmic drugs such as amiodarone, 
flecainide, and verapamil have been shown to possess IKACh blocking effects, and tertiapin, a 
bee venom peptide that selectively blocks IKACh, has been shown to terminate AF in both dog 
and guinea pig models without affecting PR, QRS, and QT intervals (Voigt et al 2014). These 


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data suggest that a selective pharmacologic inhibitor of GIRK channels has potential as a novel 
antiarrhythmic drug for the cardioversion of patients with AF.
HSY244 is a potent inhibitor of GIRK channels. Novartis is developing HSY244 as an 
intravenous (i.v.) infusion for the acute cardioversion of patients with AF. 
 
The most relevant data for the present study are summarized in the sections below. For detailed 
information, please refer to the Investigator's Brochure.
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1.2
Purpose
The purpose of this study is to evaluate the efficacy, safety, tolerability, and pharmacokinetics 
of HSY244 in participants with AF, with and without HF. HSY244 is a potent inhibitor of 
GIRK1/4 channels, which are believed to play an important role in AF. 
 
2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

To evaluate the efficacy of HSY244 to
restore sinus rhythm in participants
with AF

Conversion to sinus rhythm for at least 1 minute
within 90 minutes from the start of study drug
administration
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To evaluate the safety and tolerability
of HSY244 in participants with AF

Results of safety assessments including adverse
events, vital signs, ECG parameters, and
laboratory assessments of blood and urine.

To evaluate the pharmacokinetics of
HSY244 in participants with AF

HSY244 plasma AUClast, Cmax, and Tmax after
i.v. administration
Exploratory objective(s)
Endpoint(s) for exploratory objective(s)
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3
Study design
This is a randomized, placebo-controlled, investigator- and participant-blinded study to 
evaluate the efficacy, safety, tolerability, and pharmacokinetics (PK) of HSY244 in participants 
with AF, with and without HF. An initial cohort (Cohort 1) evaluating a 150 mg i.v. dose of 
HSY244, administered over a 15-minute infusion, is planned to be enrolled. 
Figure 3-1
Study Design
For Cohort 1 
 the following will occur:
A screening period of up to 3 days (72 hours) will be used to assess eligibility.  After eligibility 
is confirmed, participants will be randomized to either HSY244 or placebo. Prior to study drug 
administration, pre-dose assessments will be completed (refer to Section 8 for complete details). 
Standard clinical care practices should be followed per Investigator's discretion, including but 
not limited to bedside telemetry and application of defibrillator pads. A study 12-lead Holter 
(continuous ECG) monitor will be applied for continuous heart rate and rhythm monitoring for 
24 hours and will also allow for single-timepoint ECG tracings to be captured. After the 
participant's ongoing AF episode is confirmed, study drug administration of a 15 minute 
i.v. infusion of HSY244 or placebo will begin; this is time '0' as related to all post-dose
assessments. After the start of study drug administration, the participant will be monitored for
cardioversion to sinus rhythm. If a participant is still in AF at 90 minutes after the start of study
drug administration, direct current cardioversion may be applied at a time deemed appropriate
by the investigator. Standard clinical care approaches should be followed for direct current
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cardioversion but alternatives should be considered for the medications on the prohibited 
medication list (Table 6-2) until the EOS visit has occurred.
For the first 120 minutes (2 hours) after study drug administration, the participant should 
be resting in the supine or semi-recumbent position with minimal disturbances to allow for 
assessments of heart rate 
 If direct current cardioversion is applied at 
90 minutes, there should be an additional 30 minutes afterward during which the participant 
should be resting in the supine or semi-recumbent position with minimal disturbances to allow 
for assessments of heart rate 
The participant should be monitored for at least 180 minutes (3 hours),  after study drug 
administration for safety and blood sampling; this monitoring period can be extended through 
24 hours if deemed necessary or appropriate by the Investigator and/or for convenience for the 
participant. The participant can be transferred to other locations within the study site (i.e., to a 
post-anesthesia care unit [PACU], hospital ward, or clinical trials unit given site staff is 
appropriately trained) during the 3 hour monitoring period (or for 24 hours if observation period 
is extended), at the discretion of the Investigator, as long as the participant can remain 
undisturbed (i.e., remain in supine/semi-recumbant position for the first 2 hours), and the study 
protocol requirements, assessments and appropriate standard clinical care practices are possible. 
If the participant remains on-site overnight, Day 2 (24 hours post-dose) assessments should be 
completed before the participant's release from the study site. If the participant does not remain 
at the site overnight, the site will call the participant on Day 2 (24 hours post dose ±4 hours) to 
check on AEs, as well as to guide the participant for the removal of the Holter device. The 
participant should remain resting in a supine or semi-recumbent position for at least 15 minutes 
prior to the removal of the Holter (continuous ECG) monitor to allow for the assessment of 
resting heart rate 
. The participant is required to return to the study site 
within ±24 hours of Day 5 (96 hours post dose) for end of study (EOS) assessments. 
A total of approximately 29 participants are planned to be randomized in Cohort 1, of which  
approximately 20 will receive HSY244. Participants will be randomized in a 5:1 HSY244-to-
placebo ratio. 
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4
Rationale
4.1
Rationale for study design
Table 4-1
Rationale for study design
Study Design Aspect
Rationale
Overall
This is a randomized, placebo-controlled, investigator- and 
participant-blinded study to evaluate the efficacy, safety, 
tolerability, and pharmacokinetics of HSY244 in participants 
with AF, with or without HF. The study design was chosen to 
minimize bias. An initial cohort (Cohort 1) evaluating a 
150 mg i.v. dose of HSY244 or placebo given over a 15-
minute infusion is planned to determine if this dose will 
restore sinus rhythm to participants with AF. 
Randomization (strata, allocation 
ratio)
Randomizing participants 5:1 to receive HSY244 or placebo 
will maintain the blind and enable detection of possible 
differences in each group. 
Participant and investigator 
blinding
Blinding of participants and the investigator allows for an 
unbiased assessment of study endpoints, particularly for 
subjective readouts, such as adverse events. Limited 
unblinding of the Sponsor as detailed in Table 6-3 will 
improve the accuracy of safety-related decisions.
Duration of study
The study duration minimizes the burden to the participants 
and allows the Sponsor to collect the data required for 
efficacy, safety, tolerability, and PK readouts. 
Placebo comparator
The use of placebo as a comparator is to provide a 
comparison 
group 
for 
an 
unbiased 
collection 
and 
assessment of efficacy, safety and tolerability.
Observation period
This allows for close observation of safety and tolerability 
during the time of the highest exposure to HSY244. At 180 
minutes (3 hours), the time of planned discharge, exposure 
is predicted to be below the threshold for physiological effect 
for both Cohort 1 
increased if deemed necessary or appropriate by the 
Investigator and/or for the convenience for the participant.
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4.2
Rationale for dose/regimen and duration of treatment
In Cohort 1, a single 150 mg dose of HSY244 will be administered via a 15-minute i.v. infusion. 
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
The use of placebo as a comparator is to provide a comparison group for an unbiased collection 
and assessment of efficacy, safety and tolerability.
A placebo and not an active arm comparator will be used as a control for this study because 
marketed drugs that are used for pharmacological cardioversion are either contraindicated in 
patients with AF and HF (e.g., dofetilide) or induce cardioversion much slower than 90 minutes 
(e.g., amiodarone). 
Due to the lack of appropriate drugs for cardioversion, in particular among patients with AF 
and HF, direct current cardioversion is the standard of care and may be applied at 90 minutes 
(or later) after HSY244 or placebo administration if sinus rhythm has not already been restored, 
unless deemed inappropriate by the Investigator. 
4.4
Purpose and timing of interim analyses
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4.5
Risks and benefits
Participants will receive either HSY244 or placebo in the current study. Participants receiving 
HSY244 may benefit from cardioversion to sinus rhythm without the need for direct current 
cardioversion and concomitant sedation.
Risks to participants in this trial will be minimized by adherence to the eligibility criteria, close 
clinical monitoring, and study stopping rules.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4.5.1
Effects on the central nervous system
GIRK1/4 is closely related to GIRK1/2, which is predominantly expressed in the brain but not 
the heart. Mice engineered with a knockout of the GIRK2 gene have been reported to be 
susceptible to stress induced seizures (Signorini et al 1997). Furthermore, at high doses of BMS 
914392, an oral inhibitor of GIRK1/4, subjects reported reversible symptoms of euphoria, ataxia 
and impaired motor skills (Podd et al 2016). 
 
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4.5.2
Effects on the cardiovascular system
IKACh is primarily found in the SA node, atrioventricular (AV) node, and atria. IKACh is believed 
to play an important role in the regulation of sinus node automaticity, in particular, 
parasympathetically mediated changes in beat-to-beat heart rate and heart rate variability. 
Compared to control mice, mice that are deficient in the gene for GIRK4 have slightly higher 
resting heart rates and exhibit a delayed heart rate recovery after sympathetic stimulation via 
exercise or injection of the beta-agonist isoproterenol (Mesirca et al 2013, Wickman et al 1998).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4.5.7
Potential risk associated with the COVID-19 pandemic
Novartis is committed to supporting the safety and well-being of our study participants, 
investigators, and site staff. All local regulations and site requirements are being applied in the 
countries that are affected by the COVID-19 pandemic, including COVID-19 testing of 
participants if applicable. The Novartis clinical trial team will review the situation in each 
participating country and work with investigators to continue to ensure the safety of participants 
during the conduct of the trial. A benefit/risk assessment has been made and has been 
determined to be positive for the participants to be enrolled. As the COVID-19 situation evolves, 
investigators must use their best judgement to minimize risk to participants during the conduct 
of the study. 
 
4.6
Rationale for Public Health Emergency mitigation procedures
During a Public Health emergency as declared by Local or Regional authorities, i.e., pandemic, 
epidemic or natural disaster, mitigation procedures to ensure participant safety and trial integrity 
are listed in relevant sections. Notification of the Public Health emergency should be discussed 
with Novartis prior to implementation of mitigation procedures, and permitted/approved by 
Local or Regional Health authorities and Ethics Committees as appropriate. 
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5
Study Population
The study population will include hemodynamically stable men and women between 18 and 
80 years of age with a clinical indication for direct current cardioversion of AF, with the current 
AF episode lasting between 6 hours and 60 days. In Cohort 1, a total of approximately 29 
participants with AF will be randomized, of which approximately 20 will receive HSY244.   
Replacement participants will be allowed for those participants who discontinue study drug 
administration before completion if those participants have not discontinued due to adverse 
drug reactions or adverse events from study procedures. A maximum of 4 replacement 
participants will be allowed per Cohort. Please refer to Section 9.2 for additional details. 
Rescreening of screen failures will be allowed. Please refer to Section 8.1 for additional details. 
5.1
Inclusion criteria
Participants must meet ALL of the following criteria for inclusion in this study:
1. At screening, written informed consent must be obtained before any assessment is 
performed. Only participants able to provide written informed consent themselves will be 
included in this study.
2. Hemodynamically stable men and women (either of non-child-bearing potential or 
child-bearing potential with highly effective contraception) between 18 and 80 years of 
age (inclusive) at screening with a clinical indication for direct current cardioversion of 
AF.
3. At screening, current episode of AF has been ongoing for ≥6 hours and ≤60 days
4. Successful initiation and achievement of therapeutic levels of national guideline and 
institution-specific anticoagulation therapy as appropriate for the duration of the AF 
episode and risk for the participant. 
5. Completion of national guideline and institution-specific imaging evaluation for left atrial 
thrombi as appropriate for the duration of AF episode and risk for the participant.
6. At screening, participants must weigh at least 60 kg to participate in the study, and must 
have a body mass index (BMI) within the range of 18 - 45 kg/m2. BMI = Body weight 
(kg) / [Height (m)]2
7. At screening, vital signs (systolic blood pressure and pulse rate) will be assessed in the 
sitting position. Sitting vital signs should be within the following ranges (exclusive):

systolic blood pressure between 100-160 mmHg and diastolic blood pressure 
60-100 mmHg  

pulse rate (ventricular rate) between 60-120 bpm
If vital signs are outside these ranges, the Investigator may obtain up to two additional 
readings, so that up to three consecutive assessments are made.
At least the last set of readings must be within the ranges provided above in order for the 
participant to qualify.
The investigator should consider whether to not enroll participants with a known history 
of symptomatic postural hypotension.
8. Able to communicate well with the investigator, to understand and comply with the 
requirements of the study.
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5.2
Exclusion criteria
Participants meeting any of the following criteria are not eligible for inclusion in this study:
1. Use of other investigational drugs within 5 half-lives of randomization or within 30 days, 
whichever is longer; or longer if required by local regulations.
2. 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 and for 4 days after stopping of investigational drug. Highly effective 
contraception methods include:

Total abstinence from heterosexual intercourse (when this is in line with the preferred 
and usual lifestyle of the participant). 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), total hysterectomy or bilateral tubal ligation at least six weeks before 
taking investigational drug. 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 participants in the 
study, the vasectomized male partner should be the sole partner for that participant.

Placement of non-hormonal intrauterine device (IUD) or intrauterine system (IUS)
If local regulations deviate from the contraception methods listed above and require more 
extensive measures to prevent pregnancy, local regulations apply and will be described in 
the ICF.
Women are considered post-menopausal if they have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, 
history of vasomotor symptoms). Women are considered not of childbearing potential if 
they are post-menopausal or have had surgical bilateral oophorectomy (with or without 
hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks ago. In the 
case of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment is she considered not of childbearing 
potential. Refer to Section 8.4.3 (Pregnancy and Assessments of Fertility).
3. Pregnant or nursing (lactating) women.
4. Sexually active males unwilling to use a condom during intercourse while taking 
investigational drug and for 96 hours after study drug administration. A condom is 
required for all sexually active male participants to prevent them from fathering a child 
AND to prevent delivery of the investigational drug via seminal fluid to their partner. In 
addition, male participants should not donate sperm for the time period specified above.
5. History of hypersensitivity to HSY244 or excipients of the formulation (
) or to drugs of similar chemical classes. 
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6. Use of any anti-arrhythmic class I or III drug (including Ranolazine [Ranexa]) within 
5 half-lives before randomization; including use of amiodarone within 3 months before 
randomization.
7. Use of a QT prolonging drug (as reported on crediblemeds.org in the "known risk" of 
QT prolongation category or other reliable source) within 5 half-lives before 
randomization. 
8.
9. Use of drugs that are known to substantially affect GIRK channels (inhaled volatile 
anesthetics: desflurane, sevoflurane, isoflurane) 
 
10. At screening, history or current diagnosis of ECG abnormalities or cardiac rhythm 
disorders as determined by the Investigator's interpretation of the ECG findings indicating 
a significant safety risk for participating in the study such as:

History of Torsades de Pointes (TdP), any other polymorphic ventricular tachycardia, 
sustained monomorphic ventricular tachycardia, long QT syndrome, or Brugada 
syndrome

Wolff-Parkinson-White (WPW) syndrome

In the absence of a complete bundle branch block, a resting QTcF > 460 msec for men 
and > 470 msec for women (mean of ≥ 5 consecutive QT intervals)

In the presence of a complete bundle branch block, a prolonged QTcF or JTc that in 
the opinion of the Investigator may pose a risk to patient safety

Third-degree (complete) heart block, or second-degree Mobitz type II heart block 
11.  (This exclusion criterion was intentionally removed in amendment 04)
12. Attempted or unsuccessful cardioversion within 2 weeks prior to randomization
13.  (This exclusion criterion was intentionally removed in amendment 04)
14. Presence of a left atrial thrombus that may pose a risk of embolization with cardioversion
15. Presence of known severe mitral regurgitation and/or known severely dilated left atrium. 
16. Pre-existing or tachycardia-induced moderate to severe cardiac dysfunction (New York 
Heart Association Class III and IV). 
17. History within the preceding 3 months prior to randomization of: myocardial infarction, 
unstable angina, cardiac surgery, or a percutaneous coronary intervention.
18. History of a confirmed stroke or transient ischemic attack (TIA). 
19. History or current diagnosis of any seizure disorder, epilepsy, significant head trauma, or 
other disorders increasing the risk for seizures.
20. History or current diagnosis of a major neurologic or psychiatric disorder that in the 
opinion of the Investigator poses a risk to patient safety to participate.
21. At screening, moderately or greater impaired renal function as indicated by an eGFR <60 
mL/min or abnormalities that in the opinion of the Investigator pose a risk to patient safety 
to participate. 
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22. At screening, liver disease or liver injury as indicated by abnormal liver function tests. 
ALT (SGPT), AST (SGOT), GGT, alkaline phosphatase must not exceed 2 x upper limit 
of normal (ULN) and serum bilirubin must not exceed 1.5 x ULN 
23. Donation or loss of 450 mL or more of blood within eight weeks prior to randomization, 
or longer if required by local regulation.
24. Have any other conditions, which, in the opinion of the Investigator, would make the 
patient unsuitable for inclusion or could interfere with the patient participating in or 
completing the study including any surgical or medical condition which might 
significantly alter the metabolism or excretion of drugs, or which may jeopardize the 
participant in case of participation in the study. The Investigator should make this 
determination in consideration of the participant's medical history and/or clinical or 
laboratory evidence of any of the following:

At screening, anemia (hemoglobin concentration < 9 g/dL)

At screening, evidence of urinary obstruction or difficulty in voiding at screening

At screening, hypo- or hyperkalemia as indicated by a potassium <3.5 or >5.2 
mmol/L

At screening, pancreatic injury or pancreatitis
25. Significant illness and/or infection, which has not resolved within two (2) weeks prior to 
randomization
26. Known difficult venous access, in which it would be difficult to obtain venous access in a 
large vein (i.e., antecubital) for study drug administration.
6
Treatment
6.1
Study treatment
Details on the requirements for storage and management of study treatment, and instructions to 
be followed for participant numbering, prescribing/dispensing, and administering study 
treatment are outlined in the Pharmacy Manual.
6.1.1
Investigational and control drugs
Table 6-1
Investigational and control drug
Investigational/ 
Control Drug 
(Name and 
Strength)
Pharmaceutical 
Dosage Form
Route of 
Administration
Supply Type
Sponsor (global 
or local)
HSY244 80 
mg/2mL
Concentrate 
solution for 
injection
Intravenous use
Open label bulk 
supply
Global
HSY244 
0mg/2mL
Concentrate 
solution for 
injection
Intravenous use
Open label bulk 
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The investigational drug, HSY244 active and placebo, will be prepared by Novartis and supplied to the 
Investigator as an open labeled bulk supply to be dispensed by the unblinded pharmacist at the 
Investigator site according to the randomization scheme. HSY244 active and placebo is provided as a 
concentrate for solution for injection. HSY244 active and placebo are packed in a glass vial with 
stopper and seal and should be stored at 2C to 8C (35.6-46.4F), protected from light. Please refer to 
the Pharmacy Manual for additional information. 
6.1.2
Additional study treatments
No other treatment beyond investigational drug and control drug are included in this trial.
6.1.3
Treatment arms/group
Participants will be assigned at Day 1 (Visit 101) to one of the following 2 treatment 
arms/groups in a ratio of 5:1.
Cohort 1:

HSY244 150 mg i.v. infusion over 15 minutes

Placebo
6.2
Other treatment(s)
6.2.1
Concomitant therapy
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6.2.3
Rescue medication
In the case that a participant should still be in AF at 90 minutes after study drug administration, 
direct current cardioversion may be applied unless deemed inappropriate by the Investigator. 
If the participant develops a new clinically or hemodynamically significant arrhythmia, 
medically appropriate direct current cardioversion, defibrillation, or anti-arrhythmic 
pharmacotherapy should be initiated at the Investigator's discretion. Alternatives should be 
considered for the medications on the prohibited medication list (Table 6-2) within the study 
treatment period.
If the participant develops a seizure or other neurological symptom, medically appropriate 
therapy should be initiated at the Investigator's discretion. Alternatives should be considered 
for the medications on the prohibited medication list (Table 6-2) within the study treatment 
period
6.2.4
Restriction for study participants
For the duration of the study, participants should be informed and reminded of the restrictions 
outlined in this section.
6.2.4.1
Dietary restrictions and smoking
1. No alcohol from randomization through EOS visit.
2. No cannabis use from randomization through EOS visit.
3. No cigarettes/use of nicotine products from randomization through EOS visit.
4. Intake of xanthine (e.g., caffeine) containing food or beverages should be discontinued 
upon enrollment until at least 180 minutes (3 hours) post-dose. If a deviation occurs, it 
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must be noted. After 3 hours post dose through the EOS visit, caffeinated beverages will 
be restricted to no more than 4 cups/day.
6.2.4.2
Other restrictions

No strenuous physical exercise (e.g., weight training, aerobics, football) from screening 
until after EOS visit.
6.3
Participant numbering, treatment assignment, randomization
6.3.1
Participant numbering
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is enrolled for screening and is retained for the participant 
throughout his/her participation in the trial. A new Participant No. will be assigned at every 
subsequent enrollment if the participant is re-screened. The Participant No. consists of the 
Center Number (Center No.) (as assigned by Novartis Institutes for BioMedical Research to the 
investigative site) with a sequential participant number suffixed to it, so that each participant’s 
participation is numbered uniquely across the entire database. Upon signing the informed 
consent form, the participant is assigned to the next sequential Participant No. available.
A new ICF will need to be signed if the investigator chooses to re-screen the participant after a 
participant has screen failed, and the participant will be assigned a new Participant No.
6.3.2
Treatment assignment, randomization
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from participants and investigator staff.
A participant randomization list will be produced by the Novartis Interactive Response 
Technology (NIRT) provider, or by a delegate under Novartis supervision, using a validated 
system that automates the random assignment of participant numbers to randomization numbers. 
These randomization numbers are linked to the different treatment arms.
The randomization scheme for participants will be reviewed and approved by a member of the 
Randomization Office.
6.4
Treatment blinding
This is a participant and investigator-blinded study. Participants and investigators will remain 
blinded to study treatment throughout the study, except where indicated below.
The identity of the treatments will be concealed by the use of study drugs that are all identical 
in packaging, labeling, schedule of administration, appearance, and odor.
Site staff
With the exception of any unblinded site staff identified below, all site staff (including study 
investigator and study nurse) will be blinded to study treatment throughout the study.
Unblinding a single participant at site for safety reasons (necessary for participant management) 
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Drug product will be supplied in bulk, so an unblinded pharmacist who is independent of the 
study team will be required in order to maintain the blind. Treatment will be assigned via the 
NIRT system. Appropriate measures must be taken by the unblinded pharmacist to ensure that 
the treatment assignments are concealed from the rest of the site staff.
Sponsor staff or delegate
The following unblinded sponsor roles are required for this study:

Unblinded field monitor(s)

Unblinded clinical staff managing drug re-supply to site

Unblinded sample analyst(s) (PK)
The unblinded field monitors are required to review drug accountability and allocation at site. 
The unblinded monitors are not provided with a randomization list directly but will be unblinded 
through review of source documentation compiled by the unblinded pharmacist, which details 
treatment allocation to individual participants. 
Sponsor clinical staff are required to assist in the management and re-supply of investigational 
drug product. These individuals are not provided with randomization lists directly, but may be 
unblinded through communication of drug re-supply needs via the unblinded site pharmacists.
The sample analysts will receive a copy of the randomization schedule (via request to the 
Randomization Office), to facilitate analysis of the samples. The sample analysts will provide 
the sample data to the study team under blinded conditions unless otherwise allowed.
The study statistician will be able to access the randomization list for interim analyses and is 
allowed to share unblinded information with the rest of the clinical team as appropriate for 
internal decision purposes, as outlined in Table 6-3. For example, unblinded summaries and 
unblinded individual data can be shared with the team for interim analyses.
Study programmers and other personnel involved in study data analysis (e.g., biomarker expert) 
are allowed to access treatment assignment information for the purpose of conducting interim 
analyses.
The clinical trial team, unblinded at the time of analysis, is allowed to share unblinded results 
with other sponsor staff (e.g., decision boards) as required for internal decision making on the 
study or the project at the time of interim analyses while the study is ongoing.
All unblinded personnel will otherwise keep randomization lists and data or information that 
could unblind other study team members confidential and secure except as described above.
Following final database lock all roles may be considered unblinded.
Table 6-3
Blinding levels
Time or Event
Role
Randomization 
list generated
Treatment 
allocation & 
dosing
Safety event 
(single subject 
unblinded)
Interim 
Analysis 
Subjects/Patients
B
B
UI
Site staff
B
B
UI
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Role
Time or Event
Unblinded site staff (see text 
for details) 
B
UI
UI
Drug Supply and 
Randomization Office
UI
UI
UI
Unblinded sponsor staff (see 
text for details)
B
UI
UI
Statistician/statistical 
programmer/data analysts
B
B
UI
Independent committees used 
for assessing interim results
B
UI
UI
All other sponsor staff not 
identified above
B
B
UI
B Remains blinded
UI Allowed to be unblinded on individual patient level
6.5
Dose escalation and dose modification
Not applicable
6.6
Additional treatment guidance
6.6.1
Treatment compliance
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all 
participants treated with HSY244, as detailed in pharmacokinetics section (Section 8.5.1).
6.6.2
Recommended treatment of adverse events
If a participant experiences mild injection site discomfort, the Investigator may attempt 
applying an arm massage or a cold compress.
If a participant develops a new clinically or hemodynamically significant arrhythmia, medically 
appropriate electrical cardioversion, defibrillation, or anti-arrhythmic pharmacotherapy should 
be initiated at the Investigator's discretion. Alternatives should be considered for medications 
on the prohibited medication list (Table 6-2) within the study treatment period.
If the participant develops a seizure or other neurological symptom, medically appropriate 
therapy should be initiated at the Investigator's discretion. Alternatives should be considered 
for the medications on the prohibited medication list (Table 6-2) within the study treatment 
period.
In the case of a development of an AE, which requires additional monitoring, the minimum 
3 hour observation period can be extended at the discretion of the Investigator.
Medication used to treat adverse events (AEs) must be recorded on the appropriate CRF.
6.6.3
Emergency breaking of assigned treatment code
Emergency code breaks must only be undertaken when it is required to in order to treat the 
participant safely. Most often, discontinuation from study treatment and knowledge of the 
possible treatment assignments are sufficient to treat a study participant who presents with an 
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emergency condition. Emergency treatment code breaks are performed using the NIRT. When 
the investigator contacts the system to break a treatment code for a participant, he/she must 
provide the requested participant identifying information and confirm the necessity to break the 
treatment code for the participant. The investigator will then receive details of the 
investigational drug treatment for the specified participant and a fax or email confirming this 
information. The system will automatically inform the Novartis monitor for the site and the 
study team that the code has been broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the NIRT at any time in case of emergency. The investigator will provide:

protocol number

participant number
In addition, oral and written information to the participant must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time.
6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section (Section 6.1.1). Please refer to the Pharmacy Manual for detailed 
instructions.
A unique medication number is printed on the study medication label.
Investigator staff will identify the treatment to dispense to the participant by contacting NIRT 
and obtaining the randomization number and treatment assignment. As per the treatment 
assigned to the participant, investigator staff will select the study treatment to dispense to the 
participant and record the batch number on the accountability logs accordingly.
6.7.1
Handling of study treatment and additional treatment
6.7.1.1
Handling of study treatment
Study 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 designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels.
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis Institutes for BioMedical Research CO Quality 
Assurance.
Study treatment must be prepared by an unblinded pharmacist to ensure treatment masking. 
Please refer to the Pharmacy Manual for complete preparation instructions.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
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The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely 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 study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis Institutes for BioMedical Research monitor or to the Novartis 
Institutes for BioMedical Research address provided in the investigator folder at each site.
6.7.2
Instruction for prescribing and taking study treatment
HSY244 or placebo will be administered to the participant via i.v. injection route of 
administration for a 15-minute infusion at the study site. Please refer to the Pharmacy Manual 
for detailed instructions. 
7
Informed consent procedures
Eligible participants may only be included in the study after providing, IRB/IEC-approved 
informed consent.
Informed consent must be obtained before conducting any study-specific procedures (e.g., all 
of the procedures described in the protocol). The process of obtaining informed consent must 
be documented in the participant source documents. Only participants able to provide written 
informed consent themselves will be included in this study.
Novartis Institutes for BioMedical Research will provide to investigators in a separate 
document a proposed informed consent form that complies with the ICH GCP guidelines and 
regulatory requirements and is considered appropriate for this study. Any changes to the 
proposed consent form suggested by the investigator must be agreed by Novartis Institutes for 
BioMedical Research before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the 
participant informed consent and should be discussed with the participant during the study as 
needed. Any new information regarding the safety profile of the investigational drug that is 
identified between IB updates will be communicated as appropriate, for example, via an 
investigator notification or an aggregate safety finding. New information might require an 
update to the informed consent and then must be discussed with the participant.
The following informed consents are included in this study:

Main study consent, which also included: 

A subsection that requires a separate signature for the ‘Optional Consent for 
Additional Research’ to allow future research on data/samples collected during this 
study

As applicable, Pregnancy Outcomes Reporting Consent for female participants or the 
female partners of any male participants who took study treatment
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Women of child-bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements.
Male participants are required to agree to not father a child, donate sperm, and wear a condom 
from time of randomization through 96 hours after treatment. Male participants must be 
informed that if a female partner becomes pregnant while he is enrolled in the study, contact 
with the female partner will be attempted to request her consent to collect pregnancy outcome 
information.
A copy of the approved version of all consent forms must be provided to Novartis Institutes for 
BioMedical Research after IRB/IEC approval.
8
Visit schedule and assessments
The Assessment Schedule (Table 8-1) lists all of the assessments when they are performed. 
All data obtained from these assessments must be supported in the participant’s source 
documentation.
Participants should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 8-1) or as close to the designated day/time as possible. Missed or rescheduled visits 
should not lead to automatic discontinuation. Participants who prematurely discontinue the 
study for any reason should be scheduled for a visit as soon as possible, at which time all of the 
assessments listed for the final visit will be performed as indicated in the Assessment Schedule. 
At this final visit, any adverse events and concomitant medications not previously reported must 
be recorded on the eCRF.
The “X” in the table denotes the assessments to be recorded in the clinical database or received 
electronically from a vendor. The “S” in the table denotes the assessments that are only in the 
participant’s source documentation and do not need to be recorded in the clinical database. 
When the following assessments are scheduled to be performed at the same time point, the 
recommended order of priority will be as follows:

For Day 1, 0 min: 1) assess concomitant medications and therapies, 2) assess pre-existing 
injection/infusion site reaction (i.e., bruising from i.v. placement), 3) attach pads and leads 
for study Holter monitor, and for any standard clinical care devices and practices, 4) 
assess vital signs, 5) short physical exam, 6) blood draw per assessment schedule, 7) 
obtain ECG tracing, 8) after confirmation of AF episode, initiate study drug 
administration, and 9) monitor for adverse events and AF conversion to sinus rhythm.
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
For Day 1, 30 min: 1) assess injection/infusion site, 2) assess vital signs, 3) short physical 
exam, 4) blood draw per assessment schedule, 5) obtain ECG tracing, and 6) monitor for 
adverse events and AF conversion to sinus rhythm.

For Day 1, 90 min: 1) assess injection/infusion site, 2) assess vital signs, 3) short physical 
exam, 4) blood draw per assessment schedule, 5) obtain ECG tracing, and 6) after 
confirmation of persistent AF, initiate direct current cardioversion under appropriate 
sedation/anesthesia, unless deemed inappropriate by the Investigator. Alternatives to 
medications listed in the prohibited medication list (Table 6-2) should be used for 
sedation/anesthesia, as deemed appropriate by the Investigator.

For Day 1, 180 min: 1) assess injection/infusion site, 2) assess vital signs, 3) short 
physical exam, 4) blood draw per assessment schedule, 5) obtain ECG tracing, 6) 
 
 7) monitor for adverse events. At this point, the participant can leave the 
study site to return for assessments at the EOS visit.The observation period can be 
extended through 24 hours if deemed necessary or appropriate by the Investigator and/or 
for the convenience of the participant.

For assessments during other Day 1 time points: 1) assess concomitant medications and 
therapies, 2) assess injection/infusion site reaction, 3) assess vital signs, 4) blood draw per 
assessment schedule, and 5) monitor for adverse events.
Blood draws should be obtained at the protocol specified time and within the assessment 
window as specified in Table 8-1. Every effort should be made for the other assessments (e.g., 
ECG, vital signs, etc.) to be obtained at the specified assessment time either before or after the 
blood draw, as described by the order of assessments above.
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities, i.e., pandemic, epidemic or natural disaster that limits or prevents on-site study visits, 
alternative methods of providing continuing care may be implemented by the investigator as 
the situation dictates. If allowable by a local Health Authority and depending on operational 
capabilities, phone calls, virtual contacts (e.g., tele consult) or visits by site staff/home nursing 
staff to the participant’s home, can replace on-site study visits, for the duration of the disruption 
until it is safe for the participant to visit the site again. 
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Table 8-1
Assessment Schedule
Epoch Screening
Treatment
Visit Name Screening2
Day 1
Day 
210
End of Study
Post Study Safety 
Contact
Visit Numbers1
1
101
102
199
Days
-3 to 1
1
2
5
Last treatment +30
Time (post-dose)
-
0min 5min 10min 15min
±59
30min
±59
60min
±59
90min
±53,9
180min
±59
24h
±4
96h
±24
-
Informed consent
X
 
 
 
 
 
 
 
 
 
 
 
Inclusion / 
Exclusion criteria
S
S
 
 
 
 
 
 
 
 
 
 
Medical 
history/current 
medical conditions
X
 
 
 
 
 
 
 
 
 
 
 
Study drug 
administration
 
X
 
 
 
 
 
 
 
 
 
 
Injection/Infusion 
site reaction
 
X
X
X
X
X
X
X
X
X
X
 
Demography
X
 
 
 
 
 
 
 
 
 
 
 
Vital Signs
X
X4
X
X
X
X
X
X
X
X
 
Body Height
X
 
 
 
 
 
 
 
 
 
 
 
Body Weight
X
 
 
 
 
 
 
 
 
 
X
 
Physical 
Examination
S5
S
 
 
 
S
 
S
S
S5
 
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Epoch Screening
Treatment
Visit Name Screening2
Day 1
Day 
210
End of Study
Post Study Safety 
Contact
Visit Numbers1
1
101
102
199
Days
-3 to 1
1
2
5
Last treatment +30
Time (post-dose)
-
0min 5min 10min 15min
±59
30min
±59
60min
±59
90min
±53,9
180min
±59
24h
±4
96h
±24
-
Hepatitis screen
S
 
 
 
 
 
 
 
 
 
 
 
HIV screen
S
 
 
 
 
 
 
 
 
 
 
 
Alcohol Test and 
Drug Screen 
S
 
 
 
 
 
 
 
 
 
 
 
Pregnancy and 
assessments of 
fertility6
S6
 
 
 
 
 
 
 
 
 
S6
 
Hematology
X
X4
 
 
 
 
 
 
 
X
 
Clinical Chemistry
X
X4
 
 
 
 
 
 
 
X
 
Urinalysis
X
 
 
 
 
 
 
 
 
 X
 
PK blood 
collection
 
X4
 
 
X7
X
X
X
X
X
 
Electrocardiogram 
(ECG)
X
X4
 
 
 
X
 
X
X
X
 
Continuous digital 
12-lead Holter
 
X4
 
 
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Epoch Screening
Treatment
Visit Name Screening2
Day 1
Day 
210
End of Study
Post Study Safety 
Contact
Visit Numbers1
1
101
102
199
Days
-3 to 1
1
2
5
Last treatment +30
Time (post-dose)
-
0min 5min 10min 15min
±59
30min
±59
60min
±59
90min
±53,9
180min
±59
24h
±4
96h
±24
-
Adverse Events
 
X
 
Concomitant 
medications
 
X
 
Concomitant 
therapies
 
X
 
Study completion 
information
 
 
 
 
 
 
 
 
 
 
X
 
Safety Follow up 
Call
 
 
 
 
 
 
 
 
 
 
 
S
X Assessment to be recorded in the clinical database or received electronically from a vendor
S Assessment to be recorded in the source documentation only
1 Visit structure given for internal programming purpose only
2 Allowed screening period is 72 hours; Screening and Day 1 activities are allowed to occur on the same day
3 All assessments should be completed prior to direct current cardioversion (if deemed necessary by the Investigator)
4 Assessment to be done pre-dose
5 Complete physical examination to be done
6 All pre-menopausal women who are not surgically sterile will have pregnancy testing
7 Sample drawn at end of infusion
8 
9 Assessment windows as specified apply only to blood draw assessments
10 Can occur on site or via phone call 
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8.1
Screening
Screening
It is permissible to re-screen a participant if s/he fails the initial screening; however, each case 
must be discussed and agreed with the Sponsor on a case-by-case basis.
In the case where a safety laboratory assessment at screening is outside of the range specified 
in the exclusion criteria, the assessment may be repeated once prior to randomization. If the 
repeat value remains outside of the specified ranges, the participant must be excluded from the 
study.
8.1.1
Eligibility screening
8.1.1.1
Hepatitis screen, HIV screen
All participants will be screened for Hepatitis B surface antigen (HBsAg) and, if standard local 
practice, Hepatitis B core antigen (HBcAg). Screening for Hepatitis C will be based in HCV 
antibodies and if positive, HCV RNA levels should be determined.
Evaluation for HIV seropositivity will be performed, and, if positive, confirmation by a second 
technique available at the laboratory site, e.g., Western blot. Appropriate counseling will be 
made available by the Investigator in the event of a positive confirmatory test. Notification of 
state and federal authorities, as required by law, will be the responsibility of the Investigator.
Hepatitis and HIV results will not be required to determine eligibility. 
8.1.1.2
Alcohol test and Drug screen
Participants will be tested for substances of abuse (e.g., alcohol, amphetamines, barbituates, 
benzodiazepines, cannabinoids, cocaine and opiates).
8.1.2
Information to be collected on screening failures
Participants who sign an informed consent form and subsequently found to be ineligible prior 
to randomization will be considered a screen failure. The reason for screen failure should be 
recorded on the appropriate Case Report Form. The demographic information and informed 
consent must also be completed for screen failure participants. No other data will be entered 
into the clinical database for participants who are screen failures, unless the participant 
experienced a serious adverse event during the screening phase (see Section 10.1.3 for reporting 
details). If the participant fails to be randomized, NIRT should be notified within 2 days of the 
screen fail that the participant was not randomized.
Participants who are randomized and fail to start treatment, e.g., participants randomized in 
error, will be considered an early terminator. The reason for early termination should be 
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8.2
Participant demographics/other baseline characteristics
Participant demographics: date or year of birth, sex, race, predominant ethnicity (if permitted) 
and relevant medical history/current medical conditions, including heart failure disease status, 
(until date of signature of informed consent) will be recorded in the eCRF. If available, the most 
recent echocardiogram results should be provided as part of medical history. Where possible, 
the diagnosis and not symptoms should be recorded. Participant race and ethnicity are collected 
and analyzed to identify variations in safety or efficacy due to these factors as well as to assess 
the diversity of the study population as required by Health Authorities. 
All prescription medications, over-the-counter drugs and significant non-drug therapies prior to 
the start of the study must be documented. See Section 6.2.1 for further details on what 
information must be recorded on the appropriate page of the eCRF.
8.3
Efficacy
The primary efficacy measure is defined as conversion from AF to sinus rhythm, sustained for 
at least 1 minute during the 90 minutes after the start of the study drug administration, as 
assessed on the study Holter monitor. After 90 minutes, all participants may undergo direct 
current cardioversion if they remain in persistent AF, unless deemed inappropriate by the 
Investigator. 
The Investigator should record periods in AF or sinus rhythm during the first 90 minutes after 
study drug administration, 
 and time of direct current 
cardioversion (if occurs, unless deemed inappropriate by the Investigator).
Blood and urine samples will be collected at the time points defined in the Assessment Schedule 
(Table 8-1). Follow instructions outlined in the manual provided by the designated CRO 
regarding collection, numbering, and processing.
Results need to remain blinded during the study. 
8.3.1
Continuous digital 12-lead Holter
All study Holter monitor data will be collected using a standard continuous 12-lead ECG digital 
recorder (e.g., the Global Instrumentation [Manlius, NY, USA] M12R). The continuous 12-lead 
digital ECG data will be stored on SD memory cards. AF detection by both automated 
algorithms and manual confirmation by trained technicians will be employed to evaluate 
cardioversion to sinus rhythm and burden of AF with central reading by a designated CRO. 
Please refer to the device's Instruction Manual for additional details. 
In addition to continuous monitoring, the device can also obtain and output single time point 
12-lead ECG tracings. Details regarding the single time point 12-lead ECGs are provided in 
Section 8.4.2.
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8.3.2
Appropriateness of efficacy assessments
Assessment of an individual's heart rhythm by a Holter monitor is standard practice in clinical 
care (January et al 2014). AF detection by both automated algorithms and manual confirmation 
by trained technicians will be employed.
8.4
Safety
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed.
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities, i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits, regular phone or virtual calls can occur for safety monitoring and discussion of the 
participant’s health status until it is safe for the participant to return to the site again. 
For details on AE collection and reporting, refer to AE section (Section 10.1.1).
Assessment
Specification
Physical examination
At Screening and  EOS, a complete physical examination will include 
the examination of the participant's general appearance, skin, neck 
(including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, 
back, lymph nodes, extremities, vascular, and neurological system 
(including assessment of euphoria symptoms and seizure-related 
adverse events).
A short physical exam will include the examination of the participant's 
general appearance, vital signs (blood pressure [SBP and DBP] and 
pulse), and a limited neurologic exam. The abbreviated neurological 
exam should include, but is not limited to, a brief assessment of: 
1) mental status (level of alertness, orientation, and euphoria 
symptoms), 2) motor exam (observe for tremors/twitches/involuntary 
muscle movements), and 3) coordination (finger-nose-finger test, heel-
shin test). Any abnormalities or concerns can warrant a full physical 
examination at the discretion of the Site Investigator. The short physical 
exam will be completed at designated time points, as outlined in Table 
8-1.
Information for all physical examinations must be included in the source 
documentation at the study site. Clinically relevant findings that are 
present prior to signing informed consent must be recorded on the 
appropriate eCRF that captures medical history. Significant findings 
made after signing informed consent which meet the definition of an 
Adverse Event must be recorded as an adverse event. Seizure-related 
AEs must be reported to the Sponsor within 24 hours.
Vital signs
Vital signs will include the collection of body temperature (recorded 
in °C), blood pressure (BP) and pulse measurements.
For screening, systolic and diastolic blood pressure and pulse rate will 
be assessed after the participant has been sitting for 3 minutes, with 
back supported and both feet placed on the floor.
An automated validated device, with an appropriately sized arm cuff will 
be used, and in case the cuff sizes available are not large enough for the 
participant's arm circumference, a sphygmomanometer with an appropriately 
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Assessment
Specification
If vital signs are out-of-range at screening, two additional readings can 
be obtained, so that a total three consecutive assessments are made, 
with the participant seated quietly for approximately five minutes 
preceding each repeat assessment. The last reading must be within the 
ranges provided in the eligibility criteria in order for the participant to qualify.
In case of repeated vital assessments, the eCRF should contain the 
qualifying results.
Starting on Day 1, systolic and diastolic BP will be measured using an 
automated validated device, e.g., OMRON with an appropriately sized 
cuff used on the arm, which does not have the i.v. line placed. In case 
the cuff sizes available are not large enough for the subject's arm 
circumference, a sphygmomanometer with an appropriately sized cuff 
may be used.
Vital signs may be repeated if unexpected results arise, as clinically 
appropriate. 
Height and weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram 
(kg) in indoor clothing, but without shoes) will be measured as specified 
in Table 8-1.
Body mass index (BMI) will be calculated using the following formula:

BMI = Body weight (kg) / [Height (m)]2
Rounding should be done to the nearest whole number.
Phone call on Day 2
If the participant does not remain at the site overnight from Day 1 to Day 
2, the participant will be called on Day 2 (24 hours post dose ±4 hours) 
to perform the assessments as defined in the assessment schedule. The 
participant will also be instructed how to remove, and store the Holter 
device. The Holter device should be returned by the time of the EOS 
visit. 
8.4.1
Laboratory evaluations
All safety laboratory evaluations will be evaluated locally.
In the case where a laboratory range is not specified by the protocol, but a value is outside the 
reference range for the laboratory at screening, a decision regarding whether the result is of 
clinical significance or not shall be made by the Investigator (in consultation with the sponsor 
as needed) and shall be based, in part, upon the nature and degree of the observed abnormality. 
If needed, the assessment may be repeated once prior to randomization.
In all cases, the Investigator must document in the source documents, the clinical considerations 
(i.e., result was/was not clinically significant and/or medically relevant) in allowing or 
disallowing the participant to continue in the study.
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities, i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits, if participants cannot visit the site for protocol-specified safety lab assessments, an 
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Urinalysis
A midstream urine sample (approx. 30 mL) will be obtained, in order to avoid contamination 
with epithelial cells and sediments, and allow proper assessments.
All abnormal lab results must be evaluated for criteria defining an adverse event and reported 
as such if the criteria are met. For those lab adverse events, repeated evaluations are mandatory 
until normalization of the result(s) or until the result is no longer considered to be clinically 
significant.
Test Category
Test Name
Hematology
Hemoglobin, 
Platelets, White 
blood 
cells, Differential 
(Basophils, 
Eosinophils, Lymphocytes, Monocytes, Neutrophils, Other) 
Chemistry
Albumin, Alkaline phosphatase, ALT , AST, GGT, Lactate dehydrogenase 
(LDH), Bicarbonate, Calcium, Chloride, Magnesium, Phosphorus, Sodium, 
Potassium, Creatinine, Direct Bilirubin, Total Bilirubin, Blood Urea Nitrogen 
(BUN) or Urea, Uric Acid, Amylase, Lipase, Glucose (non-fasting)
Urinalysis
Macroscopic Panel (Dipstick) (Color, Bilirubin, Blood, Glucose, Ketones, 
Leukocytes esterase, Nitrite, pH, Protein, Specific Gravity, Urobilinogen)
Pregnancy Test
Serum / Urine pregnancy test (refer to Section 8.4.3 'Pregnancy and 
assessments of fertility' section)
8.4.2
Electrocardiogram (ECG)
ECGs must be recorded after a few minutes rest in the supine or semi-recumbent position to 
ensure a stable baseline. In addition to any ECGs obtained for clinical care, single time point 
12-lead ECG tracings will be captured using the same 12-lead Holter monitor that captures the 
continuous recording. These safety assessment ECGs should be interpreted by a qualified 
physician to ensure participant safety. Clinically significant abnormalities must be reported on 
the AE eCRF.
ECGs to be used in the analyses will be selected by pre-determined time points as defined 
in Table 8-1 and may be read centrally in addition to local interpretation by the Investigator.
If ECGs are read centrally, the following principals will be followed at the designated CRO:
1. ECG analysts are blinded to the participant, visit and treatment allocation
2. Baseline and on-treatment ECGs for a particular participant will be over-read on the same 
lead and will be analyzed by the same reader.
3. The primary analysis lead is lead II. If lead II is not analyzable, then primary lead 
of analysis will be changed to another lead for the entire participant data set.
The Fridericia QT correction formula (QTcF) must be used for clinical decisions.
Unless auto-calculated by the ECG machine, the Investigator must calculate QTcF at the 
Screening visit (as applicable) to assess eligibility according to the following formula:


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Each ECG tracing must be labeled with study number, participant initials, participant number, 
date and time, and filed in the study site source documents. Investigator should document 
clinical evaluation in source. For any ECGs with participant safety concerns, two additional 
ECGs must be performed to confirm the safety finding. Clinically significant ECG findings that 
pose a risk to participant safety at Day 1 Time 0 must be discussed with the sponsor before 
administration of study treatment.
Clinically significant abnormalities must be recorded on the relevant section of the medical 
history/Current medical conditions/AE eCRF as appropriate.
8.4.3
Pregnancy and assessments of fertility
A condom is required for all sexually active male participants to prevent them from fathering a 
child AND to prevent delivery of study treatment via seminal fluid to their partner. In addition, 
male participants should not donate sperm for 96 hours after study drug administration.
Pregnancy Test
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Additional pregnancy testing might be performed if requested by local requirements.
If participants cannot visit the site to have local serum pregnancy tests during a Public Health 
emergency as declared by Local or Regional authorities, i.e., pandemic, epidemic or natural 
disaster, that limits or prevents on-site study visits, urine pregnancy test kits may be used, if and 
where permitted by the local regulations and agreed with the local Health Authorities (in 
Germany only serum pregnancy tests are permitted at screening and EOS visits). Relevant 
participants can perform the urine pregnancy test at home and report the result to the site. A 
communication process should be established with the participant so that the site is informed 
and can verify the pregnancy test result (e.g., following country specific measures). 
Assessments of fertility
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of 
childbearing potential must also be available as source documentation in the following cases:
1. Surgical bilateral oophorectomy without a hysterectomy
2. Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile.
In the absence of the above medical documentation, FSH testing is required of any female 
participant regardless of reported reproductive/menopausal status at screening.
8.4.4
Appropriateness of safety measurements
The safety assessments selected are standard for this indication/participant population.
8.4.5
Injection/Infusion site reaction
Any local tolerability symptoms/signs related to injection will be reported as adverse events 
and followed until resolution. 


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8.5
Additional assessments
8.5.1
Pharmacokinetics
PK samples will be collected at the visits defined in the Assessment Schedule (Table 8-1). 
Follow instructions outlined in the laboratory manual regarding sample collection, numbering, 
processing and shipment. See Section 8.5.2.1 regarding the potential use of residual samples 
for more information.
If participants cannot visit the site for lab assessments conducted through central labs, local lab 
collection may be used during a Public Health emergency as declared by Local or Regional 
authorities, i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits. 
For standard pharmacokinetic abbreviations and definitions see the list provided at the 
beginning of this protocol.
The following pharmacokinetic parameters will be determined using the actual recorded 
sampling times and non-compartmental method(s) with Phoenix WinNonlin (Version 6.4 or 
higher): 
Cmax, 
Tmax, 
AUClast 
from 
the 
plasma 
concentration-time 
data. 
Additional parameters may be estimated as relevant.
The linear trapezoidal rule will be used for AUC calculation.
Commercially Confidential Information
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Commercially Confidential Information


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9
Study discontinuation and completion
9.1
Discontinuation and completion
9.1.1
Study treatment discontinuation and study discontinuation
The Investigator must discontinue study treatment for a given participant if, he/she believes that 
continuation would negatively impact the participant's well-being.
Study drug administration must be discontinued under the following circumstances:

Participant withdraws consent

Development of new complete bundle branch block (QRS duration >120ms) for a 
participant with a normal QRS duration at baseline as determined by the Investigator's 
interpretation of the ECG findings or an increase in QRS duration that in the opinion of 
the Investigator may be a risk to participant safety

QTcF >500 ms for those individuals with a normal QTcF at baseline as determined by the 
Investigator's interpretation of the ECG findings, or an increase in QTcF that in the 
opinion of the Investigator may be a risk to participant safety

A change in atrioventricular conduction that in the opinion of the Investigator may be a 
risk to participant safety

An increase in the resting heart rate to >130 beats per minute sustained for >2 minutes as 
determined by the Investigator, unless there is an obvious alternative explanation other 
than administration of study drug

Hypotension, defined as >20 mmHg systolic blood pressure drop (repeat measurement) 
that is (a) symptomatic or (b) sustained to the point requiring medical intervention

Any moderate or higher CNS-related AE that in the opinion of the Investigator is 
suspected to be related to the study drug

A seizure

A severe or serious adverse event

Hypersensitivity reactions and/or injection site reactions of moderate severity or greater
If discontinuation of study drug administration occurs, the investigator should make a 
reasonable effort to understand the primary reason for the participant’s premature 
discontinuation of study drug administration and record this information.
Participants who discontinue study drug administration or who decide they do not wish to 
participate in the study further should NOT be considered withdrawn from the study UNLESS 
they withdraw their consent (see 'Withdrawal of Informed Consent' Section 9.2). 
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Where possible, they should return for the assessments indicated in the Assessment 
Schedule (Table 8-1). If they fail to return for these assessments for unknown reasons, every 
effort (e.g., telephone, e-mail, letter) should be made to contact the participant/pre-designated 
contact as specified in the lost to follow-up section (Section 9.2.1). This contact should 
preferably be done according to the study visit schedule.
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the participant. This 
telephone contact should preferably be done according to the study visit schedule.
After study drug administration discontinuation, at a minimum, in abbreviated visits, the 
following data should be collected at clinic visits or via telephone/email contact:

New / concomitant treatments

Adverse Events / Serious Adverse Events
The Investigator must also contact NIRT to register the participant's discontinuation from study 
treatment.
If discontinuation occurs because treatment code has been broken, please refer to Emergency 
breaking of treatment code section (Section 6.6.3).
9.1.2
Replacement policy
Participants who discontinue study drug administration before completion will be replaced 
except for those participants who discontinued due to adverse drug reactions or adverse events 
from study procedures. 
9.2
Withdrawal of informed consent
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a participant:

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
In this situation, the investigator should make a reasonable effort (e.g., telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw their consent and 
record this information.
Where consent to the use of Personal and Coded Data is not required, the participant therefore 
cannot withdraw consent. However, they still retain the right to object to the further use of their 
Personal Data.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up.


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All efforts should be made to complete the assessments prior to study discontinuation. If the 
participant agrees, a final evaluation at the time of the participant’s study discontinuation should 
be made as detailed in the Assessment Schedule (Table 8-1).
Novartis Institutes for BioMedical Research will continue to retain and use all research results 
(data) that have already been collected for the study evaluation.
9.2.1
Lost to follow-up
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the participant, e.g., dates of 
telephone calls, registered letters, etc. A participant should not be considered as lost to 
follow-up until due diligence has been completed or until the end of the study.
9.2.2
Study stopping rules
The study will be stopped, and no further dosing will be performed pending a full safety review, 
if any of the following criteria are met:

1 or more study treatment related serious adverse events (SAEs) are reported

At least 3 participants experience a similar AE which is assessed as either moderate or 
severe in intensity, and is related to study treatment

Any moderate adverse event that in the opinion of the investigator is indicative of a 
nervous system process of major clinical significance (such as stroke, seizure, acute 
psychosis or delirium) and is related to study drug administration

3 or more participants experience symptomatic sinus tachycardia with a resting heart rate 
>120 bpm that is sustained for >90 minutes during the observation period following study 
drug administration, unless there is an obvious alternative explanation other than 
administration of study drug

The Sponsor considers that the number and/or severity of AEs suggest that there is a 
significant safety concern.
If one of the above stopping rules is met, the Competent Authorities and IRB/IECs will be 
informed of the temporary halt of study conduct according to local regulations. In addition, PIs 
will be informed of the temporary halt and based on the outcome of the safety review, 
participants will be notified and given appropriate guidance should any safety concern be 
identified. The study may resume following the safety review, if the Investigator and Sponsor 
agree it is safe to proceed and after approval to restart the study is obtained from the Competent 
Authorities and IRB/IECs.
9.2.3
Early study termination by the sponsor
The study can be terminated by Novartis Institutes for BioMedical Research at any time.
Reasons for early termination include:

Unexpected, significant, or unacceptable safety risk to participants enrolled in the study

Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data


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
Discontinuation of study drug development
In taking the decision to terminate, Novartis Institutes for BioMedical Research will always 
consider participant welfare and safety. Should early termination be necessary, participants 
must be seen as soon as possible and treated as a prematurely withdrawn participant as outlined 
in Section 9.1.1. 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 participant’s 
interests. The Investigator or Sponsor depending on local regulation will be responsible for 
informing IRBs/IECs of the early termination of the trial. 
9.3
Study completion and post-study treatment
Study completion is defined as when the last participant finishes their Study Completion visit 
and any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator or, in the event of an early study termination decision, the date 
of that decision. Each participant will be required to complete the study in its entirety and 
thereafter no further study treatment will be made available to them.
All randomized and/or treated participants should have a safety follow-up call conducted 30 
days after administration of study treatment. The information collected is kept as source 
documentation. All SAEs reported during this time period must be reported as described in 
Section 10.1.3. Documentation of attempts to contact the participant should be recorded in the 
source documentation.
10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical 
investigation participant after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The Investigator has the responsibility for managing the safety of individual participant and 
identifying adverse events.
Novartis Institutes for BioMedical Research qualified medical personnel will be readily 
available to advise on trial related medical questions or problems.
The occurrence of adverse events must be sought by non-directive questioning of the participant 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the participant during or between visits or through physical examination findings, laboratory 
test findings, or other assessments.
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2):


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1. The severity grade

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities
2.  Its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e., progression of the study indication) the assessment of causality 
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single participant
3. Its duration (start and end dates or  ongoing) and the outcome must be reported
4. Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met
5. Action taken regarding with study treatment. 
6. All adverse events must be treated appropriately. Treatment may include one or more of 
the following:

Dose not changed

Dose reduced

Drug interrupted/withdrawn
7. Its outcome
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued for at least 30 days following the study drug 
administration.
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g., continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome.
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB).
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms

they are considered clinically significant

they require therapy
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 


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baseline or the previous visit, or values which are considered to be non-typical in participant 
with the underlying disease.
10.1.1.1 AEs of special interest
Any seizure-related AEs, regardless of causality and severity, occurring after the participant has 
provided informed consent and until 30 days after study drug administration must be reported 
to the Sponsor within 24 hours of learning of its occurrence. 
Participants should be informed that the site should be contacted immediately if any 
seizure-related AEs occur after EOS  but before the 30-day safety follow-up phone contact. 
10.1.2
Serious adverse events
A serious adverse event (SAE) is defined as any adverse event [appearance of (or worsening of 
any pre-existing)] undesirable sign(s), symptom(s), or medical conditions(s) which meets any 
one of the following criteria:

fatal

life-threatening
Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines).

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 of AF

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

social reasons and respite care in the absence of any deterioration in the participant’s 
general condition

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

is medically significant, e.g. defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the 
ICH-E2D Guidelines).


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All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred.
10.1.3
SAE reporting
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 30 days following the administration of study treatment  
must be reported to Novartis Institutes for BioMedical Research safety immediately, without 
undue delay, but under no circumstances later than within 24 hours of obtaining knowledge of 
the events (Note: If more stringent, local regulations regarding reporting timelines prevail).. 
Detailed instructions regarding the submission process and requirements are to be found in the 
investigator folder provided to each site. Information about all SAEs is collected and recorded 
on the paper Serious Adverse Event Report form; all applicable sections of the form must be 
completed in order to provide a clinically thorough report. 
SAEs occurring after the participant has provided informed consent until the time the participant 
is deemed a Screen Failure must be reported to Novartis Institutes for BioMedical Research.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
immediately, without undue delay, but under no circumstances later than within 24 hours of the 
investigator receiving the follow-up information (Note: If more stringent, local regulations 
regarding reporting timelines prevail). A SAE occurring at a different time interval or otherwise 
considered completely unrelated to a previously reported one must be reported separately as a 
new event.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a CMO & PS Department 
associate may urgently require further information from the investigator for health authority 
reporting. Novartis Institutes for BioMedical Research may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study treatment 
that this SAE has been reported.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.
Any SAEs experienced after the 30 day period following the administration of study treatment 
should only be reported to Novartis Institutes for BioMedical Research Safety if the Investigator 
suspects a causal relationship to study treatment, unless otherwise specified by local 
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10.1.4
Pregnancy reporting
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
pregnancy consent form should be presented to the trial participant. The participant must be 
given adequate time to read, review, and sign the pregnancy consent form. This consent form 
is necessary to allow the Investigator to collect and report information regarding the pregnancy. 
To ensure participant safety, each pregnancy occurring after signing the informed consent must 
be reported to Novartis Institutes for BioMedical Research 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 and reported by the Investigator to the Novartis Institutes for 
BioMedical Research Chief Medical Office and Patient Safety (CMO&PS). Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment any pregnancy outcome. Any SAE experienced 
during pregnancy must be reported.
If a female partner of a male trial participant who took study treatment in this study becomes 
pregnant, pregnancy outcomes should be collected. Consent to report information regarding 
these pregnancy outcomes should be obtained from the mother.
After consent is provided, the pregnancy reporting will occur up to one year after the estimated 
date of delivery. 
10.1.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dosing 
CRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with 
an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE


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For more information on AE and SAE definition and reporting requirements, please see the 
respective sections (Section 10.1.1 and Section 10.1.2).
10.2
Additional Safety Monitoring
10.2.1
Liver safety monitoring
To ensure participant 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.
Please refer to Table 16-1 in Appendix 1 for complete definitions of liver laboratory triggers.
Once a participant is exposed to study treatment, every liver event defined in Table 16-1- should 
be followed up by the Investigator or designated personnel at the trial site, as summarized below. 
Additional details on actions required in case of liver events are outlined in Table 16-2 and 
Table 16-3. Repeat liver chemistry tests (i.e. ALT, AST, TBL, PT/INR, ALP and G-GT) to 
confirm elevation.

These liver chemistry repeats should be performed using the local laboratory used by the 
site. Repeated laboratory test results must be reported as appropriate. 

If the initial elevation is confirmed, close observation of the participant will be initiated, 
including consideration of treatment interruption if deemed appropriate.

Hospitalization of the participant if appropriate

Causality assessment of the liver event

Thorough follow-up of the liver event should include 

These investigations can include based on investigator’s discretion: serology tests, 
imaging and pathology assessments, hepatologist’s consultancy; obtaining more 
detailed history of symptoms and prior or concurrent diseases, history of concomitant 
drug use, exclusion of underlying liver disease
All follow-up information and procedures performed must be recorded as appropriate in the 
CRF.
10.2.2
Renal safety monitoring
Once a participant is exposed to study treatment, the following two categories of abnormal renal 
laboratory alert values should be assessed during the study period:

Serum creatinine increase ≥ 25% compared to baseline during normal hydration status

Any one of the following: 

Urine protein-creatinine ratio (PCR) ≥1g/g or ≥100 mg/mmol, OR

New onset dipstick proteinuria ≥ 3+, OR

New onset dipstick hematuria ≥ 3+ (after excluding menstruation, UTI, extreme 
exercise, or trauma)
Abnormal renal event findings must be confirmed within 24-48 hours after the first assessment 
.


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Once a participant is exposed to study treatment, renal laboratory alerts or renal safety events 
should be monitored and followed up by the Investigator or designated trial staff as summarized 
in Table 16-4 in Appendix 2. 
Every renal laboratory trigger or renal event as defined in Table 16-4 in Appendix 2 should be 
followed up by the Investigator or designated personnel at the trial site as summarized in 
Table 16-5 in Appendix 2.
11
Data Collection and Database management
11.1
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure 
web-enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will 
not be given access to the EDC system until they have been trained. Automatic validation 
programs check for data discrepancies in the eCRFs, allow modification and/or verification of 
the entered data by the investigator staff.
The Investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate.
After final database lock, the Investigator will receive copies of the participant data for 
archiving at the investigational site.
Laboratory samples will be processed at the designated lab (locally or centrally) and the results 
will be sent electronically to Novartis (or a designated CRO).
ECG tracings will be processed locally and may be read centrally and the results will be sent 
electronically to Novartis (or a designated CRO).
Holter monitor data will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification.
11.2
Database management and quality control
Novartis Institutes for BioMedical Research personnel (or designated CRO) will review the 
data entered by investigational staff for completeness and accuracy. Electronic data queries 
stating the nature of the problem and requesting clarification will be created for discrepancies 
and missing values and sent to the investigational site via the EDC system. 
Designated investigator site staff are required to respond promptly to queries and to make any 
necessary changes to the data.
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Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology.
Dates of screenings, randomizations, screen failures and study completion, as well as 
randomization codes will be tracked using NIRT. The system will be supplied by a vendor, who 
will also manage the database. The data will be sent electronically to Novartis (or a designated 
CRO) at specific timelines.
Each occurrence of a code break via NIRT 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.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis/moved to restricted area to be accessed by independent programmer 
and statistician. Any changes to the database after that time can only be made after written 
agreement by Novartis Institutes for BioMedical Research development management.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
Institutes for BioMedical Research representative will review the protocol and data capture 
requirements (i.e., eSource DDE or eCRFs) with the Investigators and their staff. During the 
study, Novartis Institutes for BioMedical Research employs several methods of ensuring 
protocol and GCP compliance and the quality/integrity of the sites’ data. The field monitor will 
visit the site to check the completeness of participant records, the accuracy of data capture / data 
entry, the adherence to the protocol and to Good Clinical Practice, the progress of enrollment, 
and to ensure that study treatment is being stored, dispensed, and accounted for according to 
specifications. Key study personnel must be available to assist the field monitor during these 
visits. Continuous remote monitoring of each site’s data may be performed by a centralized 
Novartis CRA organization. Additionally, a central analytics organization may analyze data & 
identify risks & trends for site operational parameters, and provide reports to Novartis Institutes 
for BioMedical Research clinical teams to assist with trial oversight.
The Investigator must maintain source documents for each participant 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 
participant's file.  The investigator must also keep the original informed consent form signed by 
the participant (a signed copy is given to the participant).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis Institutes for BioMedical 
Research 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 


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CRFs are performed according to the study-specific monitoring plan. No information in source 
documents about the identity of the participants will be disclosed.
12
Data analysis and statistical methods
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
12.1
Analysis sets
For all analysis sets, participants will be analyzed according to the study treatment(s) received.
The safety analysis set will include all participants that received any investigational product.
The PK analysis set will include all participants with at least one available valid PK 
concentration measurement, who received any investigational product and with no protocol 
deviations that impact on PK data.
 
12.2
Participant demographics and other baseline characteristics
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment group and cohort for the safety analysis set.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented.
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term by treatment group and cohort.
12.3
Treatments
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system by treatment group and cohort.
12.4
Analysis of the primary endpoint(s)/estimand(s)
12.4.1
Definition of primary endpoint(s)/estimand(s)
The primary endpoint will be conversion to sinus rhythm for at least one minute within 90 
minutes after the start of study drug administration (yes or no). 
12.4.2
Statistical model, hypothesis, and method of analysis
The conversion rates between HSY244 and placebo will be compared using  Fisher’s Exact test. 
This will test a null hypothesis that the conversion rate is the same for HSY244 and placebo. 
The difference in the conversion rates between HSY244 and placebo will be reported along 
with the 80% confidence limits for the difference, as well as the odds ratio, the 80% CI for the 
odds ratio, and the associated p-value.  
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Results will be displayed tabular and graphically, where the conversion rate (80% CI) for each 
treatment  will be displayed in dot plots and a forest plot.
The impact of duration of current atrial fibrillation episode (< 48 hours, 48 hours - 7 days, 7 - 
14 days, 14 - 30 days, and 30 - 60 days) on conversion rate will be investigated in a supporting 
analysis..
 
 
Only participants who complete study treatment will be 
included in the primary analysis.
12.4.3
Handling of remaining intercurrent events of primary estimand
Not applicable.  
12.4.4
Handling of missing values not related to intercurrent event
Given the short treatment duration in this study, missing data impacting the primary endpoint 
is expected to be minimal. All participants who complete Day 1 assessments will be included 
in the primary analysis.
12.4.5
Sensitivity analyses for primary endpoint/estimand
Not applicable.
12.4.6
Not applicable Supplementary analysis
As a supplementary analysis, the conversion rates between HSY244 and placebo will again be 
compared using a  Fisher’s Exact test. All participants that received any study drug will be 
included in this analysis (the safety analysis set).
12.5
Analysis of secondary endpoints/estimands
12.5.1
Safety endpoints
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group and cohort.
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data, which will also be summarized where appropriate (e.g., change from 
baseline summaries). In particular, tables for adverse events (AEs) will summarize only 
on-treatment events, with a start date during the on-treatment period (treatment-emergent 
AEs). The on-treatment period lasts from the date of administration of study treatment to EOS 
visit.
Adverse events
All information obtained on adverse events will be displayed by treatment group, cohort and 
participant.
The number (and percentage) of participants with treatment emergent adverse events (events 
started after the first dose of study medication or events present prior to start of double-blind 
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treatment but increased in severity based on preferred term) will be summarized in the following 
ways:

by treatment, primary system organ class and preferred term.

by treatment, primary system organ class, preferred term and maximum severity.

by treatment, Standardized MedDRA Query (SMQ) and preferred term.
A participant with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class.
Vital signs
All vital signs data will be listed by treatment group, cohort, participant, and visit/time and if 
ranges are available, abnormalities (and relevant orthostatic changes) will be flagged. Summary 
statistics will be provided by treatment, cohort and visit/time.
ECG
1. PR, QRS, QT, QTcF, and RR intervals will be obtained from 12-lead ECGs for each 
participant during the study. ECG data will be read and interpreted locally for safety. 
In addition, 12-lead ECGs may be read centrally.
2. Categorical Analysis of QT/QTc interval data based on the number of participants meeting 
or exceeding predefined limits in terms of absolute QT/QTc intervals or changes from 
baseline will be presented. In addition, a listing of these participants will be produced 
(by treatment group).
QTcF and QRS duration will be examined separately between individuals with and without a 
complete bundle branch block.
All ECG data will be listed by treatment group, cohort, participant, and visit/time, and 
abnormalities will be flagged. Summary statistics will be provided by treatment, cohort and 
visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by treatment group, cohort, participant, and visit/time and if 
normal ranges are available abnormalities will be flagged. Summary statistics will be provided 
by treatment, cohort and visit/time. Shift tables using the low/normal/high/ (low and high) 
classification will be used to compare baseline to the worst on-treatment value.
12.5.2
Pharmacokinetics
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Table 12-1
Non-compartmental pharmacokinetic parameters
AUClast
The AUC from time zero to the last measurable concentration sampling time (tlast) 
(mass x time x volume-1)
Cmax
The maximum (peak) observed plasma drug concentration after single dose 
administration (mass x volume-1)
Tmax
The time to reach maximum (peak) plasma drug concentration after single dose 
administration (time)
12.5.3
PK/PD relationships
12.6
Analysis of exploratory endpoints
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12.7
Interim analyses
12.8
Sample size calculation
12.8.1
Primary endpoint(s)
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13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki.
13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the Investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, participant recruitment procedures (e.g., 
advertisements) and any other written information to be provided to participants. 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 
Institutes for BioMedical Research monitors, auditors, Novartis Institutes for BioMedical 
Research Quality Assurance representatives, designated agents of Novartis Institutes for 
BioMedical Research, 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 
Institutes for BioMedical Research immediately that this request has been made.
13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g., Clinicaltrials.gov, EudraCT 
etc.).
For details on the Novartis Institutes for BioMedical Research publication policy including 
authorship criteria, please refer to the Novartis Institutes for BioMedical Research publication 
policy training materials.
13.4
Quality Control and Quality Assurance
Novartis Institutes for BioMedical Research maintains a robust Quality Management System 
(QMS) that includes all activities involved in quality assurance and quality control, to ensure 
compliance with written Standard Operating Procedures as well as applicable global/local GCP 
regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Novartis Institutes for BioMedical Research systems 
are performed by auditors, independent from those involved in conducting, monitoring or 
performing quality control of the clinical trial. The clinical audit process uses a knowledge/risk 
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Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis Institutes for 
BioMedical Research processes.
13.5
Participant Engagement
The following participant engagement initiatives are included in this study and will be provided, 
as available, for distribution to study participants at the timepoints indicated. If compliance is 
impacted by cultural norms or local laws and regulations, sites may discuss modifications to 
these requirements with Novartis. 

Thank You letter – at beginning and end of study participation

Plain language trial summary – after CSR publication

Individual treatment information – after CSR publication
14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an Investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
Investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
Institutes for BioMedical Research and approved by the IRB/IEC and Health Authorities, where 
required, it cannot be implemented.
14.1
Protocol amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis Institutes for BioMedical Research, health authorities where 
required, and the IRB/IEC prior to implementation.
Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the Investigator is 
expected to take any immediate action required for the safety of any participant 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 according to 
local regulations.


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15
References
References are available upon request
Akel T, Lafferty J. Efficacy and safety of intravenous vernakalant for the rapid conversion of 
recent-onset atrial fibrillation: A meta-analysis. Ann Noninvasive Electrocardiol. 2018 
May;23(3):e12508
Chugh SS, Havmoeller R, Narayanan K, et al (2014) Worldwide epidemiology of atrial 
fibrillation: a Global Burden of Disease 2010 Study. Circulation; p. 837-47.
Dobrev D, Friedrich A, Voigt N, et al (2005) The G protein-gated potassium current I(K,ACh) 
is constitutively active in patients with chronic atrial fibrillation. Circulation; p. 3697-706.
January CT, Wann LS, Alpert JS, et al (2014) 2014 AHA/ACC/HRS guideline for the 
management of patients with atrial fibrillation: a report of the American College of 
Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart 
Rhythm Society. J Am Coll Cardiol; p. e1-76.
Mesirca P, Marger L, Toyoda F, et al (2013) The G-protein-gated K+ channel, IKACh, is 
required for regulation of pacemaker activity and recovery of resting heart rate after 
sympathetic stimulation. J Gen Physiol; p. 142(2):113-26.
Olsson LG, Swedberg K, Ducharme A, et al (2006) Atrial fibrillation and risk of clinical 
events in chronic heart failure with and without left ventricular systolic dysfunction: results 
from the Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity 
(CHARM) program. J Am Coll Cardiol; p. 1997-2004.
Podd SJ, Freemantle N, Furniss SS, et al (2016) First clinical trial of specific IKACh blocker 
shows no reduction in atrial fibrillation burden in patients with paroxysmal atrial fibrillation: 
pacemaker assessmet of BMS 914392 in patients with paroxysmal atrial fibrillation. 
Europace; p. 340-6.Signorini S, Liao YJ, Duncan SA et al (1997) Normal Cerebellar 
Development but Susceptibility to Seizures in Mice Lacking G Protein-Coupled, Inwardly 
Rectifying K+ Channel GIRK2. Proc Natl Acad Sci U S A; p. 94(3):923-7.
Trulock KM, Narayan SM, Piccini JP (2014) Rhythm control in heart failure patients with 
atrial fibrillation: contemporary challenges including the role of ablation. J Am Coll Cardiol; 
p. 710-21.
Voigt N, Abu-Taha I, Heijman J, et al (2014) Constitutive activity of the 
acetylcholineactivated potassium current IK,ACh in cardiomyocytes. Adv Pharmacol; p. 393-
409.
Wickman K, Nemec J, Gendler SJ, et al (1998) Abnormal heart rate regulation in GIRK4 
knockout mice. Neuron; p. 103-14.
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16
Appendices
16.1
Appendix 1: Liver event and laboratory trigger definitions & 
follow-up requirements
Table 16-1
Liver event and laboratory trigger definitions
 
Definition/ threshold
Liver laboratory triggers
If ALT, AST and total bilirubin normal 
at baseline:

ALT or AST > 5 × ULN

ALP > 2 × ULN (in the absence of known bone 
pathology)

Total bilirubin > 3 × ULN (in the absence of known 
Gilbert syndrome)

ALT or AST > 3 × ULN and INR > 1.5

Potential Hy’s Law cases (defined as ALT or AST > 3 
× ULN and Total bilirubin > 2 × ULN [mainly 
conjugated fraction] without notable increase in ALP 
to > 2 × ULN)

Any clinical event of jaundice (or equivalent term)

ALT or AST > 3 × ULN accompanied by (general) 
malaise, fatigue, abdominal pain, nausea, or vomiting, 
or rash with eosinophilia

Any adverse event potentially indicative of a liver 
toxicity*
If ALT or AST abnormal at baseline:

ALT or AST > 2x baseline or > 300 U/L (whichever 
occurs first)
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; non-infectious hepatitis; benign, malignant and unspecified liver neoplasms ULN: 
upper limit of normal


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Table 16-2
Follow up requirements for liver laboratory triggers with liver 
symptoms
 
ALT
TBL
Liver Symptoms
Action
ALT increase without bilirubin increase:
 
If normal at 
baseline:
ALT > 3 x ULN
 
If elevated at 
baseline:
ALT > 2 x 
baseline
or > 300 U/L 
(whichever 
occurs ﬁrst)
Normal
For patients with 
Gilbert’s 
syndrome: No 
change in 
baseline TBL
None

No change 
to study 
treatment

Measure 
ALT, AST, 
ALP, GGT, 
TBIL, INR, 
albumin, CK, 
and GLDH in 
48-72 hours.

Follow-up for 
symptoms.
If normal at 
baseline:
ALT > 5 x ULN 
for more than two 
weeks
 
If elevated at 
baseline:
ALT > 3 x 
baseline
or > 300 U/L 
(whichever 
occurs ﬁrst) for 
more than two 
weeks
Normal
For patients with 
Gilbert’s 
syndrome: No 
change in 
baseline TBL
None
 
If normal at 
baseline:
ALT > 8 x ULN
Normal
None

Interrupt 
study drug

Measure 
ALT, AST, 
ALP, GGT, 
TBIL, INR, 
albumin, CK, 
and GLDH in 
48-72 hours.

Follow-up for 
symptoms.

Initiate close 
monitoring 
and workup 
for competing 
etiologies.


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ALT
TBL
Liver Symptoms
Action
ALT increase with bilirubin increase:
If normal at 
baseline:
ALT > 3 x ULN
 
If elevated at 
baseline:
ALT > 2 x 
baseline
or > 300 U/L 
(whichever 
occurs ﬁrst)
TBL > 2 x ULN 
(or INR > 1.5)
For patients with 
Gilbert’s 
syndrome: 
Doubling of direct 
bilirubin
None
If normal at 
baseline:
ALT > 3 x ULN
 
If elevated at 
baseline:
ALT > 2 x 
baseline
or > 300 U/L 
(whichever 
occurs ﬁrst)
Normal or 
elevated
Severe fatigue, 
nausea, vomiting, 
right upper 
quadrant pain

Study drug 
can be 
restarted only 
if another 
etiology is 
identiﬁed and 
liver enzymes 
return to 
baseline.


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Table 16-3
Follow up requirements for liver laboratory triggers 
Criteria
Actions required
Follow-up monitoring
Total Biliruin (isolated)
 
 
>1.5 – 3.0 ULN

Maintain treatment

Repeat LFTs within 48-72 
hours
Monitor LFTs weekly until 
resolutionc to ≤ Grade 1 or to 
baseline
> 3 - 10 × ULN (in the absence 
of known Gilbert syndrome)

Interrupt treatment

Repeat LFT within 48-72 
hours

Hospitalize if clinically 
appropriate

Establish causality

Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF
Monitor LFTs weekly until 
resolutionc to ≤ Grade 1 or to 
baseline (ALT, AST, total 
bilirubin, Alb, PT/INR, ALP and 
GGT)
Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin)
> 10 x ULN

Discontinue the study 
treatment immediately

Hospitalize the participant

Establish causality

Record the AE and 
contributing factors(e.g. 
conmeds, med hx, lab)in 
the appropriate CRF
ALT, AST, total bilirubin, Alb, 
PT/INR, ALP and GGT until 
resolutionc (frequency at 
investigator discretion)
Any AE potentially indicative of 
a liver toxicity*

Consider study treatment 
interruption or 
discontinuation

Hospitalization if clinically 
appropriate

Establish causality

Record the AE and 
contributing factors(e.g., 
conmeds, med hx, lab)in 
the appropriate CRF
Investigator discretion
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable 
values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level after a 
maximum of 6 months, (4) liver transplantation, and (5) death.
Based on Investigator’s discretion investigation(s) for contributing factors for the liver event 
can include: Serology tests, imaging and pathology assessments, hepatologist’s consultancy; 
obtaining more detailed history of symptoms and prior or concurrent diseases, history of 
concomitant drug use, exclusion of underlying liver disease.


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16.2
Appendix 2: Specific Renal Alert Criteria and Actions and Event 
Follow-up
Table 16-4
Specific Renal Alert Criteria and Actions
Renal Event
Actions
Confirmed serum creatinine increase 25-
49%

Consider causes and possible interventions

Follow up within 2-5 days
Serum creatinine increase ≥50%

Consider causes and possible interventions

Repeat assessment within 24-48 h if possible

Consider drug interruption or discontinuation 
unless other causes are diagnosed and corrected

Consider patient hospitalization and specialized 
treatment
New onset dipstick proteinuria ≥3+ OR 
Protein-creatinine ratio (PCR) ≥1g/g Cr (or 
mg/mmol equivalent as converted by the 
measuring laboratory) 

Consider causes and possible interventions

Assess serum albumin & serum total protein

Repeat assessment to confirm

Consider drug interruption or discontinuation 
unless other causes are diagnosed and corrected
New onset hematuria ≥3+ on urine dipstick
Assess & document:

Repeat assessment to confirm

Distinguish hemoglobinuria from hematuria

Urine sediment microscopy

Assess sCr

Exclude infection, trauma, bleeding from the 
distal urinary tract/bladder, menstruation

Consider bleeding disorder
Table 16-5
Renal Event Follow Up
Follow-up of Renal Events
Assess, document, and record in eCRF:

Urine dipstick and sediment microscopy evidence of DIN: crystals, red blood cells 
(dysmorphic/glomerular vs. non-dsymophic/non-glomerular), white blood cells, tubular epithelial cells

Blood pressure and body weight

Serum creatinine, BUN, electrolytes (sodium, potassium, phosphate, calcium), bicarbonate, and 
uric acid

Urine output
Review and record possible contributing factors to the renal event (co-medications, other co-morbid 
conditions) and additional diagnostic procedures (MRI etc.) in the eCRF
Monitor patient regularly (frequency at investigator's discretion) until:

Event resolution (sCr within 10% of baseline or PCR <1g/g Cr, or ACR <300 mg/g Cr) or

Event stablization: sCr level with ±10% variability over last 6 months or protein-creatinine ratio 
stabilization at a new level with ±50% variability over the last 6 months. 

Analysis of urine markers in samples collected over the course of the DIN event

SAP_001.pdf: 
Biostatistics & Statistical Programming / 
Novartis Institutes for BioMedical Research
HSY244
CHSY244X2201
A randomized, placebo-controlled, investigator- and
participant-blinded study to evaluate the efficacy, safety,
tolerability, and pharmacokinetics of HSY244 in participants with 
atrial fibrillation
Statistical Analysis Plan (SAP)
Author(s):
Document type:
SAP Documentation – NIBR
Document status:
Amendment 2
Release date:
30-Nov-2022
Number of pages:
18
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
ClinicalTrials.gov Identifier: NCT04582409
Personal Protected Data


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CHSY244X2201
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CHSY244X2201
Table of contents
Table of contents .................................................................................................................3
List of tables ........................................................................................................................3
1
Introduction .........................................................................................................................4
1.1
Scope of document ..................................................................................................4
1.2
Study reference documentation ...............................................................................4
1.3
Study objectives.......................................................................................................4
1.4
Study design and treatment......................................................................................5
2
First interpretable results (FIR) ...........................................................................................6
3
Interim analyses...................................................................................................................6
4
Statistical methods: Analysis sets........................................................................................7
5
Statistical methods for Pharmacokinetic (PK) parameters..................................................8
All participants within the PK analysis set will be included in the PK data analysis. ........8
5.1
Variables..................................................................................................................8
5.2
Descriptive analyses ................................................................................................8
5.3
Statistical model, assumptions and hypotheses .......................................................8
6
Statistical methods for Pharmacodynamic (PD) parameters...............................................8
6.1
Primary objective.....................................................................................................8
6.1.1
Variables .................................................................................................8
6.1.2
Descriptive analyses................................................................................9
6.1.3
Statistical model, assumptions and hypotheses.......................................9
6.2
Secondary objectives .............................................................................................10
6.3
Exploratory objectives...........................................................................................10
6.3.1
Variables ...............................................................................................10
6.3.2
Descriptive analyses..............................................................................11
6.3.3
Statistical model, assumptions and hypotheses.....................................12
6.3.4
Graphical presentation of results...........................................................14
7
Statistical methods for safety and tolerability data............................................................14
7.1
Variables................................................................................................................14
7.2
Descriptive analyses ..............................................................................................14
7.3
Graphical presentation...........................................................................................17
List of tables
Table 4-1
Protocol deviation codes and analysis sets..............................................7
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1
Introduction
1.1
Scope of document
The RAP documents contain detailed information to aid the production of Statistics & 
Programming input into the Clinical Study Report (CSR) 
 for trial 
CHSY244X2201.
The Statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol.
1.2
Study reference documentation
The study protocol (v04) was available at the time of finalization of this Statistical Analysis 
Plan Amendment 1.
1.3
Study objectives
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

To evaluate the efficacy of HSY244 to 
restore sinus rhythm in participants with AF

Conversion to sinus rhythm for at least 1 minute 
within 90 minutes from the start of study drug 
administration
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To evaluate the safety and tolerability of 
HSY244 in participants with AF

Results of safety assessments including adverse 
events, vital signs, ECG parameters, and laboratory 
assessments of blood and urine.

To evaluate the pharmacokinetics of 
HSY244 in participants with AF

HSY244 plasma AUClast, Cmax, and Tmax after i.v. 
administration
Exploratory objective(s)
Endpoint(s) for exploratory objective(s)
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Objective(s)
Endpoint(s)
1.4
Study design and treatment
This is a randomized, placebo-controlled, investigator- and participant-blinded study to 
evaluate the efficacy, safety, tolerability, and pharmacokinetics of HSY244 in participants with 
AF. An initial cohort (Cohort 1) of approximately 29 participants (approximately 20 
participants receiving HSY244) is planned to be enrolled to evaluate a single 150 mg i.v. dose 
of HSY244 for AF cardioversion to sinus rhythm. 
 
 
 
 
Participants with AF that meet clinical criteria for direct current cardioversion will be screened, 
and on Day 1, after eligibility is confirmed, administration of a 15 minute i.v. infusion of 
HSY244 or placebo will occur. Participants will then be monitored for cardioversion to sinus 
rhythm. For those remaining in AF after 90 minutes, direct current cardioversion can be 
performed. Participants will be monitored for at least 3 hours, although overnight observation 
will be available. Participants will be evaluated for safety and pharmacokinetic assessments 
during end of study assessments, which are to occur on Day 5 (96 hours post dose) ± 24 hours.
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2
First interpretable results (FIR)
First interpretable results (FIR) will be provided for this trial.
The FIR will focus on the following analyses:
1. Participant Disposition
2. Demographics and baseline characteristics by cohort. Baseline characteristics include, 
but not limited to: age, sex, race, ethnicity, BMI, relevant medical history/current 
medical conditions (previous diagnosis of heart failure, etc.), duration of current AF 
episode, etc.
3. Safety Results
a.
Number and percentage of adverse events by body system and Cohort
b. Number and percentage of adverse events by preferred term and Cohort
4. Pharmacokinetic results for each Cohort
5. Pharmacodynamic analyses include, but are not limited to:
a.
Fisher’s exact test comparing conversion rates between HSY244 and placebo 
b. MMRM analysis of ECG and heart rate parameters comparing HSY244 and 
placebo
c.
Concentration effect analysis of QT and Heart Rate parameters
d. Time to event analysis for the time to conversion and time in sinus rhythm after 
conversion comparing HSY244 and placebo
e.
AF burden comparison between HSY244 and placebo
3
Interim analyses
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4
Statistical methods: Analysis sets
For all analysis sets, participants will be analyzed according to the study treatment(s) received.
The safety analysis set will include all participants that received any investigational product.
The PK analysis set will include all participants with at least one available valid PK
concentration measurement, who received any investigational product and with no protocol
deviations that impact on PK data.
 
The analysis sets and protocol deviation codes are related as follows:
Table 4-1
Protocol deviation codes and analysis sets
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If updates to Table 4-1 are needed, an amendment to the SAP needs to be implemented prior to
DBL.
5
Statistical methods for Pharmacokinetic (PK) parameters
All participants within the PK analysis set will be included in the PK data analysis.
5.1
Variables
The PK variables of interest are:

AUClast: the AUC from time zero to the last measurable concentration sampling time (tlast) 

Cmax: The maximum (peak) observed plasma drug concentration after single-dose 
administration 

Tmax: The time to reach maximum (peak) plasma drug concentration after single dose 
administration (time)
5.2
Descriptive analyses
HSY244 plasma concentration data will be listed by treatment, participant, and visit/sampling
time point. Descriptive summary statistics will be provided by treatment and visit/sampling
time point, including the frequency (n, %) of concentrations below the LLOQ and reported as
zero.
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and
geometric), median, minimum, and maximum. An exception to this is Tmax where median,
minimum, and maximum will be presented. Concentrations below LLOQ will be treated as zero
in summary statistics and for PK parameter calculations. A geometric mean will not be reported
if the dataset includes zero values. Pharmacokinetic parameters will be calculated as described
in Section 5.1 and will be listed by treatment and participant. Additional parameters may be
estimated as relevant. Graphical methods will be employed to show mean and individual
concentration-time profiles.
5.3
Statistical model, assumptions and hypotheses
Not applicable
6
Statistical methods for Pharmacodynamic (PD) parameters
6.1
Primary objective
The primary objective is to evaluate the efficacy of HSY244 to restore sinus rhythm in 
participants with AF.
6.1.1
Variables
The primary endpoint will be conversion to sinus rhythm for at least one minute within 90 
minutes after the start of study drug administration (yes or no). Only participants that complete 
treatment will be included in the primary analysis. If a participant has been monitored for at 
least 45 minutes and is not converted to sinus rhythm, the primary endpoint will be defined as 


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‘no’. If a participant converts to sinus rhythm at any time during the post-treatment 90 minutes 
observation period, regardless of the length of time monitored, the primary endpoint will be 
defined as ‘yes’. Participants with a non-missing primary endpoint value will be included in the 
primary analysis regardless of their study disposition e.g. loss to follow up, early termination, 
etc.
6.1.2
Descriptive analyses
The observed proportion of participants converted to sinus rhythm within the first 90mins of 
observation will be reported for each treatment and cohort. The observed proportion of 
participants that are electrcardioverted after the 90mins observation period will also be reported 
for each treatment and cohort.
6.1.3
Statistical model, assumptions and hypotheses
The conversion rates between HSY244 and placebo will be compared using Fisher’s Exact test. 
This will test a null hypothesis that the conversion rate is the same for HSY244 and placebo. 
The conversion rates for each treatment and the exact 80% confidence intervals will be reported. 
The difference in the conversion rates between HSY244 and placebo will be reported along 
with the 80% confidence limits for the difference, as well as the odds ratio, the 80% CI for the 
odds ratio, and the associated p-value.
The impact of duration of current atrial fibrillation episode (< 48 hours, 48 hours - 7 days, 7 -
14 days, 14 - 30 days, and 30-60 days) on conversion rate will be investigated in a supporting 
analysis. The impact of length of time of known atrial fibrillation diagnoses on conversion rate 
will also be explored in a supporting analysis (e.g. < 1 year, 1 – 5 years, 6 - 10 years, >10 years, 
and quartiles of length of atrial fibrillation diagnosis).
All analyses will be performed separately for Cohort 1 
Placebo participants from the two cohorts may be pooled for summaries and analyses if it is 
deemed appropriate. Only participants who complete study treatment will be included in the 
primary analysis.
6.1.3.1
Model checking procedures
Not applicable
6.1.3.2
Graphical presentation of results
Results will be displayed tabular and graphically, where the conversion rate (80% CI) for each
treatment will be displayed in dot plots and a forest plot.
6.1.3.3
Sensitivity analysis
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6.1.3.4
Supplementary analysis
6.2
Secondary objectives
There are no secondary PD objectives.
6.3
Exploratory objectives
6.3.1
Variables 
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6.3.2
Descriptive analyses
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6.3.3
Statistical model, assumptions and hypotheses
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6.3.4
Graphical presentation of results
7
Statistical methods for safety and tolerability data
The secondary safety objectives are to evaluate the safety and tolerability of HSY244 in 
participants with AF.
7.1
Variables
Adverse events, vital signs (blood pressure, pulse rate, body temperature), laboratory 
measurements, as well as participant demographics, baseline characteristics, and treatment 
information.
The values for the ECG intervals (PR interval, QRS duration, heart rate, RR, QT, QTcF). For 
these ECG parameters described, the central reader values will be used for analysis. These 
parameters will be derived from the single time point ECG data.
Heart rate will be analyzed using both the safety analysis dataset and the PD analysis dataset.
7.2
Descriptive analyses
Participant demographics and other baseline characteristics
Demographic and other baseline data including disease characteristics will be listed and
summarized descriptively by treatment group and cohort for the safety analysis set.
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Categorical data will be presented as frequencies and percentages. For continuous data, mean,
standard deviation, median, minimum, and maximum will be presented.
Relevant medical histories and current medical conditions at baseline will be summarized by
system organ class and preferred term by treatment group and cohort. For AF disease history, 
if the start month is missing, then the start month will be imputed as ‘JAN’. Similarly, if the 
start day is missing, the start day will be imputed as ‘01’.
Treatment
Data for study drug administration (rescue medication), concomitant medications and 
significant non-drug therapies prior to and after the start of the study treatment will be listed 
and summarized according to the Anatomical Therapeutic Chemical (ATC) classification 
system by treatment group and cohort.
Vital signs
All vital signs data will be listed by treatment group, cohort, participant, and visit/time and if 
ranges are available, abnormalities (and relevant orthostatic changes) will be flagged. Summary 
statistics will be provided by treatment, cohort and visit/time.
ECG evaluations
1. PR, QRS, QT, QTcF, and RR intervals will be obtained from single time point ECGs for 
each participant during the study. ECG data will be read and interpreted locally for initial 
safety readouts. The single time point ECGs will be read centrally for the parameters above 
and these will be reported in the CSR.
2. Categorical Analysis of QT/QTcF interval data based on the number of participants meeting
or exceeding predefined limits in terms of absolute QT intervals or changes from baseline 
will be presented. In addition, a listing of these participants will be produced (by treatment 
group).
QT/QTcF and QRS duration will be examined separately between individuals with and without 
a complete bundle branch block.
All ECG data will be listed by treatment group, cohort, participant, and visit/time, and
abnormalities will be flagged. 
Summary statistics will be provided by treatment, cohort and visit/time.
 
These descriptive statistics will be 
generated for all observations, observations where participants are in AF and observations 
where participants are in sinus rhythm.
The MMRM and concentration-effect analyses described in Section 6.3.3 may also be used for 
the ECG parameters described above.
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Clinical laboratory evaluations
All laboratory data will be listed by treatment, participant, and visit/time and if normal ranges 
are available abnormalities will be flagged. A separate listing is provided presenting all 
parameters in a participant with any abnormal values. Summary statistics will be provided by 
treatment, visit/time and cohort.
Adverse events
All information obtained on adverse events will be displayed by treatment, participant and 
cohort.
The number and percentage of participants with adverse events will be tabulated by body system
and preferred term with a breakdown by treatment. An adverse event starting in one period and
continuing into the next period is counted only in the onset period. A participant with multiple
adverse events within a body system and treatment period is only counted once towards the
total of this body system and treatment.
The number and percentage of participants with adverse events by maximum severity or 
severity of adverse events may be tabulated by body system and preferred term with a 
breakdown by treatment, if deemed necessary.
The number and percentage of participants with serious adverse events may be tabulated by 
body system and preferred term with a breakdown by treatment, if deemed necessary.
The number and percentage of participants with adverse events classified as related to study 
drug will be tabulated by body system and preferred term with a breakdown by treatment.
Seizure related adverse events (based on SOC and/or PT) will be listed and summarized
separately as AEs of special interest. The number and percentage of participants with such 
adverse events will be tabulated by body system and preferred term with a breakdown by 
treatment.
Only adverse events that will occur at or after first drug intake (i.e., treatment emergent AEs)
will be included in the AE summaries.
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on treatment 
emergent adverse events which are not serious adverse events with an incidence greater than 
5% and on 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 set population.
If for a same patient, 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.
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 AEs in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.


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The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.
Other safety evaluations
Not applicable
7.3
Graphical presentation 
Boxplots to visualize trends in longitudinal safety data (vitals, ECG, lab parameters) may be 
created.
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