A Prospective Observational Registry Study to Characterise Normal Conditions of Use, Dosing and Safety Following Administration of Vernakalant IV Sterile Concentrate
Conditions: Atrial Fibrillation
Sponsor: Correvio International Sarl

Vernakalant IV Sterile Concentrate Prospective Safety Registry Study 
Sponsor Protocol Identifier: 6621-049-00 
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CONFIDENTIAL AND PROPRIETARY 
 
  
 
 
A Prospective Observational Registry Study to Characterise Normal Conditions of Use, Dosing 
and Safety Following Administration of Vernakalant IV Sterile Concentrate 
 
Post-Authorisation Safety Study (PASS) 
Study Protocol Incorporating Amendments 1 and 2 
 
 
 
Sponsor:  Cardiome Pharma Corp. 
 
Sponsor Protocol Identifier: 6621 049-00 
 
Document Date: 3 August 2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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CONFIDENTIAL AND PROPRIETARY 
 
  
 
TABLE OF CONTENTS 
 
TABLE OF CONTENTS.......................................................................................................2 
 
1 
ABBREVIATIONS................................................................................................................8 
 
2 
SYNOPSIS .............................................................................................................................9 
 
3 
BACKGROUND INFORMATION AND RATIONALE ...................................................12 
 
4 
OBJECTIVES ......................................................................................................................15 
 
5 
STUDY DESIGN .................................................................................................................17 
 
5.1 
Description..................................................................................................................17 
 
5.2 
Duration of Study .......................................................................................................19 
 
5.3 
Study Population.........................................................................................................19 
 
5.4 
Number of Patients .....................................................................................................19 
 
6 
SELECTION OF PATIENTS ..............................................................................................19 
 
6.1 
Inclusion Criteria ........................................................................................................19 
 
6.2 
Exclusion Criteria .......................................................................................................20 
 
6.3 
Study Enrolment .........................................................................................................20 
 
6.3.1 
Site Enrolment and Country Selection .........................................................20 
 
6.3.2 
Patient Enrolment .........................................................................................21 
 
6.4 
Patient Withdrawal .....................................................................................................21 
 
7 
DATA COLLECTION.........................................................................................................21 
 
7.1 
Collection of Required Data Elements .......................................................................21 
 
7.1.1 
Description of Key Data Elements ...............................................................22 
 
7.1.2 
Schedule of Assessments .............................................................................26 
 
 
7.2 
Collection of Data Retrospectively ………………………………………………...28 
 
 
 
7.2.1 Required Key Data Elements for Retrospective Data Collection…………..31 
 
8 
SAFETY MEASUREMENTS .............................................................................................32 
 
8.1 
Definitions of AEs ......................................................................................................32 
 
8.2 
Definition of SAEs .....................................................................................................32 
 
8.3 
Definition of Experiences of Clinical Interest ............................................................33 
 
8.4 
Reporting by Investigators..........................................................................................33 
 
8.5 
Confirmation of SAEs and HOIs ................................................................................33 
 
8.6 
Safety Reporting to Competent Authorities ...............................................................34 
 
8.7 
SPONSOR Responsibility for Reporting Adverse Experiences.................................35 
 
 

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CONFIDENTIAL AND PROPRIETARY 
 
9 
EFFECTIVENESS ...............................................................................................................36 
 
9.1 
Definition of Effectiveness Endpoint .........................................................................36 
 
10 
STATISTICAL METHODS AND ANALYSES.................................................................36 
 
10.1  Analysis Population ....................................................................................................36 
 
10.2  Primary analyses .........................................................................................................36 
 
10.3  Secondary Analyses ....................................................................................................38 
 
10.4  Subgroups ...................................................................................................................39 
 
10.5  Statistical Analysis Plan .............................................................................................40 
 
10.6  Analysis Software and Coding ...................................................................................40 
 
10.7  Sample Size ................................................................................................................40 
 
10.8  Missing data ................................................................................................................42 
 
10.9  Interim and Final Analyses and Reporting .................................................................42 
 
11 
MANAGEMENT OF THE STUDY ....................................................................................43 
 
11.1 Data Entry ...................................................................................................................43 
11.2 Source Documents ......................................................................................................43 
11.3 File Retention and Archiving......................................................................................44 
11.4 Quality Assurance.......................................................................................................44 
11.5 Data Management .......................................................................................................44 
11.6 Monitoring ..................................................................................................................44 
11.7 External Safety Review Committee (SRC) ................................................................45 
11.8 Changes to Protocol ....................................................................................................45 
11.9 Publication Policy .......................................................................................................46 
12 
ETH ICAL AND REGULATORY CONSIDERATIONS ...................................................47 
12.1 Patient Information and Informed Consent/Assent ....................................................47 
12.2 Patient Identification and Privacy...............................................................................47 
12.3 Independent Ethics Committees .................................................................................48 
REFERENCES………………..…………………………………………………………………49 
ANNEX TO THE PROTOCOL FOR GERMAN SITES – 29 OCTOBER 2015……….……...51 
APPENDIX I...…………………………………………………………………………………..54 
APPENDIX II……………………………………………………………………………………55

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CONFIDENTIAL AND PROPRIETARY 
 
 
 
 
INFORMATIONAL CONTACTS 
SPONSOR (hereafter referred to as the Sponsor) 
Cardiome Pharma Corp 
1441 Creekside Drive 
6th Floor 
Vancouver, BC 
Canada V6J 4S7 
 
SPONSOR Contacts: 
Lucy Brindle 
SPECTRUM Study Manager 
Phone: +44 7971 421119 
Email: lbrindle@cardiome.com 
 
Sheila Grant 
Chief Operating Officer 
Phone: + 1 604 677 6905 
Email: sgrant@cardiome.com 
 
Dr Kiran Bhirangi 
Head of Medical Affairs 
Phone: + 41 79 196 86 10 
Email: K.Bhirangi@correvio.com 
 
 
 
 
 
 
 
Clinical Research Organisation responsible for the management of the study (hereafter 
referred to as the CRO): 
 
Quintiles Switzerland Sárl, formerly operating as Outcome Europe Sárl:  
Route de Pallatex 29 
1162 St-Prex 
Switzerland 
Phone: +41 21 321 3560 
Fax: +41 21 321 3562 

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CONFIDENTIAL AND PROPRIETARY 
 
 
SPONSOR SIGNATURE PAGE 
 
Reviewed and Approved by: 
 
 
Name and Title 
 
Signature 
Date 
Lucy Brindle 
SPECTRUM Study Manager 
Cardiome Pharma Corp 
 
 
 
Dr Steen Juul-Moller 
Medical Director 
Cardiome Pharma Corp 
 
 
 
Dr Kiran Bhirangi 
Head of Medical Affairs 
Cardiome Pharma Corp 
 
 
 

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CONFIDENTIAL AND PROPRIETARY 
 
 
INVESTIGATOR SIGNATURE PAGE 
 
 
 
STUDY TITLE: 
A Prospective Observational Registry Study to Characterise Normal Conditions of Use, Dosing, 
and Safety Following Administration of Vernakalant IV 
 
 
Sponsor Protocol Identifier: 6621-049-00 
Dated: 3 August 2016 
 
I have read and understand the protocol and agree that it contains the ethical, legal, and scientific 
information necessary to participate in this Study.  I will personally oversee conduct of the Study 
as described herein and in the participating site agreement. 
 
 
I agree to conduct this clinical study in accordance with the design outlined in this protocol and 
to abide by all provisions of this protocol (including other manuals and documents referenced 
from this protocol); deviations from the protocol are acceptable only with a mutually agreed 
upon protocol amendment.  I agree to conduct the study in accordance with generally accepted 
standards of Good Clinical Practice.  I also agree to report all information or data in accordance 
with the protocol and, in particular, I agree to report any serious adverse experiences (SAEs) as 
defined in the SAFETY MEASUREMENTS section of this protocol.  I understand that 
information that identifies me will be used and disclosed as described in the protocol, and that 
such information may be transferred to countries that do not have laws protecting such 
information.  Since the information in this protocol is confidential, I understand that its 
disclosure to any third parties, other than those involved in approval, supervision, or conduct of 
the study is prohibited.  I will ensure that the necessary precautions are taken to protect such 
information from loss, inadvertent disclosure, or access by third parties. 
 
 
I will provide copies of this protocol as needed to all physicians, nurses, and other healthcare 
professional personnel responsible to me who will participate in the Study.  I will discuss the 
protocol with them to assure myself that they are sufficiently informed regarding the conduct of 
the Study.  I am aware that this protocol will need to be approved by an appropriate Ethics 
Committee prior to any patients being enrolled and that I am responsible for verifying whether 

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CONFIDENTIAL AND PROPRIETARY 
 
 
that requirement is met.  I agree to adhere to the attached protocol, to the ethical principles that 
have their origin in the Declaration of Helsinki and to applicable national and regional laws.  If 
requested to provide copies of medical information for the purpose of verification of submitted 
information, I will comply. 
 
 
 
 
 
 
 
 
 
INVESTIGATOR SIGNATURE 
Date 
 
 
 
 
 
Investigator Name 
Institution Name 

Vernakalant IV Sterile Concentrate Prospective Safety Registry Study 
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CONFIDENTIAL AND PROPRIETARY 
 
 
1 
ABBREVIATIONS 
 
 
AE 
AF 
BP 
bpm 
CHF 
CHMP 
CRA 
CRO 
EC 
eCRF 
Adverse experience 
Atrial Fibrillation 
Blood pressure 
Beats per minute 
Congestive Heart Failure 
Committee for Medicinal Products for Human Use 
Clinical Research Associate 
Clinical Research Organisation 
Ethics Committee 
Electronic Case Report Form 
ECG Electrocardiogram 
EDC Electronic Data Capture 
EMA European Medicines Agency 
EU European Union 
FDA US Food and Drug Administration 
GPP Good Pharmacoepidemiology Practices 
HCP Health Care Provider
HLT 
HOI 
High Level Term 
Health Outcome of Interest 
ICH International Committee on Harmonisation 
IEC Independent Ethics Committee 
IV Intravenous 
MedDRA 
MI 
Medical Dictionary for Regulatory Activities 
Myocardial Infarction 
NSAE Non-serious adverse experience 
NYHA New York Heart Association 
PASS 
PSUR  
PT 
SADR 
SAE 
Post-Authorisation Safety Study 
Periodic Safety Update Report 
Preferred Term 
Serious Adverse Reaction 
Serious Adverse experience 
SAP      Statistical Analysis Plan  
SmPC Summary of Product Characteristics 
SRC 
Safety Review Committee 
SOC System Organ Class 
VT Ventricular tachycardia 

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CONFIDENTIAL AND PROPRIETARY 
 
 
 
 
 
2 
SYNOPSIS 
 
Study Title:  A Prospective Observational Registry Study to Characterise Normal Conditions of Use, 
Dosing and Safety Following Administration of Vernakalant IV 
Condition/Disease: Atrial fibrillation 
Number of Patients 
 
2000 
Duration of Patient Participation 
24 hours 
Number of Sites (approx.) 
45 
Duration of Study 
3rd Quarter, 2011 – 1st 
Quarter 2018 (approx.) 
Rationale: Vernakalant IV, an atrial-selective ion channel blocker, has a differing mechanism of action 
that mitigates some of the main safety concerns of other anti-arrhythmic treatments. Vernakalant IV 
(BrinavessTM) has been recently approved by the European Commission for rapid cardioversion of recent 
onset atrial fibrillation (<=3 days duration for post-cardiac surgery and <=7 days duration for non- 
surgical patients).  In view of the recognised limitations of spontaneous reporting, the Sponsor will 
conduct a post-authorisation safety study (PASS) of vernakalant IV in order to collect information about 
normal conditions of use and appropriate dosing, and to quantify possible medically significant risks 
associated with the use of vernakalant IV in real-world clinical practice. 
Study Design:  Observational, prospective PASS (no study intervention or procedures) of patients 
administered vernakalant IV within a network of clinical sites across EU member countries. Countries 
currently included are Austria, Denmark, Germany, Spain, and Sweden. Finland, and other EU and non-
EU countries may be included but selection is conditional on a number of factors, including, but not 
limited to, the actual date of product launch in each country and rate of market uptake of vernakalant IV. 
Objectives: 
The primary objectives of the study are to: 
1.   Estimate the incidence of the following medically significant health outcomes of interest (HOIs) 
reported during treatment and during the first 24 hours after last infusion of vernakalant IV or 
until discharge/end of medical encounter, whichever occurs earlier. 
• 
Significant hypotension defined as: symptomatic hypotension with systolic BP <90 mmHg, 
requiring treatment with vasopressors 
• 
Significant ventricular arrhythmia defined as: 
-  Sustained ventricular tachycardia (VT) with a ventricular heart rate > 120 beats per 
minute with duration > 30 seconds or VT that required intervention with either electrical 
shock or anti-arrhythmic drugs, or 
- Torsade de Pointes with a duration of >10 seconds, or 
- Ventricular fibrillation of any duration 
• 
Significant atrial flutter defined as: atrial flutter with 1:1 atrioventricular conduction of 
>10 seconds duration and a ventricular rate of >200 bpm 
• 
Significant bradycardia defined as: bradycardia requiring electrical pacing (temporary or 
permanent) or any other serious adverse event reports involving bradycardia 

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CONFIDENTIAL AND PROPRIETARY 
 
 
2.   In order to investigate the potential risk of overdose and medication error, describe vernakalant 
IV administration/dosing by summarising patient body weight, total dose with each intravenous 
(IV) infusion, and length of time for each IV infusion. 
 
 
3.   To evaluate the effectiveness of the risk minimisation activities by: 
 
• 
Describing the appropriateness of selection of patients for treatment with vernakalant IV, 
monitoring of patients during and after vernakalant IV administration, and use of anti- 
arrhythmics before and after vernakalant IV, as consistent with the label and risk minimization 
activities (Pre-Infusion Checklist and healthcare provider (HCP) educational card) 
• 
Monitoring for the occurrence and incidence of serious adverse events (SAEs) and HOIs to 
review with the EU Regulatory Agency with respect to risk minimization activities 
 
The secondary objective of the study are to: 
 
1.   Summarise the count and rate of all serious adverse experiences (SAEs) for HOIs that may not 
meet the definitions of medically significant HOIs as defined above, as well as all other SAEs 
reported during treatment and during the first 24 hours after the last infusion of vernakalant IV 
or until discharge/end of medical encounter, whichever occurs earlier. 
 
2.   Characterise patients administered vernakalant IV in terms of patient demographics, medical 
history, and presenting conditions.  Specific conditions to be summarised include: 
 
• 
Heart failure, New York Heart Association (NYHA) class 
• 
Prolonged QT, severe bradycardia, sinus node dysfunction, second or third degree heart 
block, clinically meaningful valvular stenosis, hypertrophic obstructive cardiomyopathy, 
restrictive cardiomyopathy, constrictive pericarditis 
• 
History of hyperthyroidism 
• 
Severe aortic stenosis, Low systolic blood pressure (BP) 
• 
Recent acute coronary syndrome (including myocardial infarction [MI]) 
• 
Presence of pacemaker/year of implantation 
• 
Hepatic impairment 
 
3.   Document the administration of concomitant treatment modalities to restore or maintain sinus 
rhythm during the hospitalisation/medical encounter (e.g., oral or IV anti-arrhythmics, electrical 
cardioversion, ablation, Maze procedure). 
 
4.   Describe the rate of successful cardioversion to sinus rhythm for at least one minute within 90 
minutes of start of first vernakalant IV administration and time (in hours) from vernakalant 
infusion until discharge/end of medical encounter. 
 
Treatment: 
 
The study will not provide or recommend any treatment. All direction for medical treatment and 
medication usage is solely at the discretion of the physician in accordance with their usual practice. 

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Inclusion Criteria: 
• 
Patients will be treated with vernakalant IV, independently of this study 
• 
Subjects and/or legal guardians willing to provide informed consent and/or informed assent 
according to local regulations 
Exclusion Criteria: 
• 
 Enrolment in an investigational drug or device clinical trial in the 30 days prior to study 
enrolment. Participation in another non-interventional drug or device study or registry is 
permitted. 
Statistical Analysis: 
Descriptive analyses including the frequency and measures of central tendency, range, and dispersion of 
the clinical characteristics of the population administered vernakalant IV, as well as details of 
administration and dosing will be conducted. Frequencies and cumulative incidence of HOIs and other 
SAEs following vernakalant IV administration will be reported for the 24-hour follow-up period, or until 
end of medical encounter, whichever occurs earlier.  Ninety-five percent confidence intervals for the 
cumulative incidence measures for HOIs will be computed.  Descriptive listings of patients with HOIs 
with relevant medical history, concomitant medications, and concurrent illnesses will also be generated. 
Ethical Considerations: 
Ethics Committee approval of study documents will be obtained, in accordance with the requirements in 
each country and at each site. The study will be conducted in compliance with local and/or national 
regulations, the European Union (EU) Directive on Data Protection, and in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki. 

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3 
BACKGROUND INFORMATION AND RATIONALE 
 
 
Atrial fibrillation (AF) contributes a considerable burden of disease, affecting 4.5 million people 
in the European Union (EU) [Ref. 5.4: 72, 431] and 2.3 million in North America. [Ref. 5.4: 
431,432]  With an overall prevalence of 6% in Europe, [Ref. 5.4: 72, 431]an even higher 
prevalence of AF can be found in the elderly, which will contribute to even greater disease 
burden as the population ages.  Causes of AF include underlying disease (e.g., myocardial 
infarction, pulmonary embolism), cardiac or thoracic surgery, heart disease, or familial cause, 
with the primary associated risk factors being obesity (elevated body mass index). [Ref. 5.4: 
345]Defined by the American College of Cardiology/American Heart Association/European 
Society of Cardiology practice guidelines as a “supraventricular tachyarrhythmia characterised 
by uncoordinated atrial activation with consequent deterioration of atrial mechanical function,” 
AF can present as paroxysmal (self-terminating within 7 days, and usually less than 24 hours), 
persistent (lasts greater than 7 days), or permanent (refractory arrhythmia with failed 
cardioversion or treatment considered inappropriate). [Ref. 5.4: 345]Considered one of the most 
common arrhythmias, AF results in cardiac rhythm disturbance hospitalisations, stroke risk, 
[Ref. 5.4: 62]reduced quality of life, [Ref. 5.4: 434]increase in CHF exacerbations and is 
associated with a tremendous cost burden. [Ref. 5.4: 430, 433]Ten to -15% of congestive heart 
failure (CHF) patients present with AF, [Ref. 5.4: 445]and co-morbidities associated with AF 
pose increased morbidity and mortality for this patient population. 
 
 
Treatment algorithms are based on a combination of patient factors (e.g., symptoms, 
haemodynamics compromise, co-morbidities) and arrhythmia characteristics (e.g., first episode 
of temporal pattern) which contribute to clinical decision-making between two basic strategies: 
heart rate control or rhythm control. [Ref. 5.4: 345, 431]  Several clinical trials have been 
performed to address the relative merits of rate control versus rhythm control, [Ref. 5.4: 
345] including the AFFIRM trial which demonstrated no statistically significant difference in 
outcomes between rate and rhythm control. [Ref. 5.4: 150]  However, severely symptomatic 
patients and those in whom adequate rate control cannot be achieved may require rhythm 
control. [Ref. 5.4: 345] Rhythm control options to restore sinus rhythm include cardioversion 
with anti-arrhythmic drugs (e.g., dofetilide, ibutilide, propafenone, amiodarone) or electrical 
cardioversion.  The primary safety concern with any cardioversion is the risk of thromboembolic 
complications.  However, with currently marketed anti-arrhythmic treatment, additional safety 
concerns involve ventricular tachycardia (VT), especially Torsade de Pointes.  Additional 
potential risks with various anti-arrhythmic therapies include QT prolongation, bradycardia, and 
hypotension.  Electrical cardioversion, while considered effective, has its own safety concerns 

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unique to this technique, including skin burns, complications of sedation and malfunctions of a 
pacemaker or internal defibrillator.  [Ref. 5.4: 104] 
The potential adverse events of both electrical and pharmacological cardioversion and the limited 
efficacy of pharmacological cardioversion have warranted the development of novel therapeutic 
options.  [Ref. 5.4: 371, 441] 
 
 
Vernakalant, a medicine that acts preferentially in the atria, has a novel and unique mechanism of 
action.  Controlled clinical trials [Ref. 5.4: 441] of vernakalant IV have been conducted to define 
the efficacy and safety profile of vernakalant IV.  Two phase III randomised trials demonstrated 
that the conversion rate of recent onset (≤7 days) AF to sinus rhythm was significantly better for 
Vernakalant compared to placebo (51.1% versus 3.8%, respectively; p<0.0001) with an open-
label trial demonstrating a conversion rate of 50.9%. [Ref. 5.4: 442] Another phase III 
randomised trial of post-cardiac surgery patients (CAD and/or VHD) demonstrated that 
Vernakalant was significantly better compared to placebo in the conversion of recent onset (≤3 
days) AF to sinus rhythm (47% versus 14%, respectively; p<0.001). [Ref. 5.4: 210]  In patients 
who converted to sinus rhythm, the median time to conversion was 11-13 minutes in those 
studies. 
 
Clinically significant adverse reactions occurred infrequently.  Clinically significant adverse 
reactions observed in the clinical program and described in detail in the Summary of Product 
Characteristics (SmPC) included:  hypotension, ventricular arrhythmia, atrial flutter and 
bradycardia.  Incidence rates for these adverse reactions are presented below, using pooled data 
from the placebo-controlled phase 2 and phase 3 clinical trials (773 patients received 
vernakalant, 335 received placebo).  Because vernakalant IV is rapidly cleared from the 
circulation, adverse events from the start of infusion through the first 2 hours after infusion are 
considered, as these occur during the period of peak vernakalant exposure. 
 
Adverse Reaction 
Vernakalant 
Placebo 
 (95%CI) 
Hypotension 
CHF subpopulation 
7.6% 
16.1% 
5.1% 
4.7% 
2.5 (-0.6, 5.6) 
11.4 (3.3, 19.4) 
Clinically meaningful hypotension* 
CHF subpopulation 
1.2% 
2.9% 
0% 
0% 
--- 
--- 
Ventricular arrhythmia 
CHF subpopulation 
3.9% 
7.3% 
3.2% 
1.6% 
0.8 (-1.6, 3.2) 
5.7 (0.4, 11.0) 
Clinically meaningful ventricular 
arrhythmia* 
CHF subpopulation 
0.6% 
2.2% 
0% 
0% 
--- 
--- 
Atrial flutter 
10.0% 
2.5% 
7.5 (4.7, 10.3) 
Clinically meaningful atrial flutter* 
0.1% 
0% 
--- 
Bradycardia 
5.4% 
3.8% 
1.6 (-1.1, 4.3) 
Clinically meaningful bradycardia 
1.3% 
0% 
--- 

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* “Clinically meaningful” events included serious adverse events (SAEs) and events leading to discontinuation of 
therapy. 
In these studies, hypotension typically occurred early, either during the infusion or early after the 
end of the infusion, and could usually be corrected by standard supportive measures.  Ventricular 
arrhythmias typically presented as asymptomatic, monomorphic, non-sustained (average 3-4 
beats) ventricular tachycardias. Bradycardia was observed predominantly at the time of 
conversion to sinus rhythm.  In general, bradycardia responded well to discontinuation of 
vernakalant and/or administration of atropine. 
 
 
Due to the higher incidence of hypotension and ventricular arrhythmia in patients with CHF, 
vernakalant should be used cautiously in haemodynamically stable patients with CHF functional 
classes NYHA I to II. There is limited experience with the use of vernakalant in patients with 
previously documented LVEF ≤ 35% and its use in these patients is not recommended. The use 
of vernakalant IV in CHF patients corresponding to NYHA III or NYHA IV is contraindicated. 
 
 
These clinically significant adverse reactions are being monitored as identified and potential 
risks in the vernakalant Risk Management Plan (RMP).  In addition, although there were no 
examples of vernakalant IV overdosing in the clinical trials, in consideration of the logistical 
complexity of weight-based dosing regimens such as that used for vernakalant, potential risk of 
overdose is also being monitored through the RMP. 
 
Vernakalant IV was approved 1 September 2010 by the European Commission for rapid 
cardioversion of recent onset AF (<=3 days duration for post-cardiac surgery and <=7 days 
duration for non-surgical patients).   
 
The clinically significant adverse reactions discussed above are being monitored and have 
been identified as potential risks in the vernakalant IV Risk Management Plan (RMP).  In 
addition, specific contraindications such as heart failure (NYHA III and IV), severe aortic 
stenosis, myocardial infarction (MI) or acute coronary syndrome (ACS) in 30 days prior to 
administration, prolonged QT at baseline (uncorrected > 440 msec), severe bradycardia, 
sinus node dysfunction, second degree and third degree heart block in the absence of a 
pacemaker, and use of intravenous rhythm control antiarrhythmics (class I and class III) 
within 4 hours prior to vernakalant IV administration are also being monitored. 
 
Key prescribing information from the SmPC are included as part of the package leaflet in 
the BrinavessTM packaging, and distributed with the product directly to the point-of care 
site.  Additionally, the SmPC accompanies the HCP education card packs that are 
distributed to all anticipated prescribers and users of the product.  In addition to this, 
SmPCs are handed out at the occasion of each customer contact, at national and 
international conferences, as well as in local educational events.  The SmPC is accessible 
on Cardiome's BrinavessTM website through hyperlinks to the EMA website.  The SmPC is 

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CONFIDENTIAL AND PROPRIETARY 
 
also attached to each written answer from the Medical Information Service to healthcare 
professionals' (HCPs) questions on the use of vernakalant IV. 
 
The risk minimization measure to incorporate a Pre-Infusion Checklist with drug 
packaging was initiated in 2012.  The checklist provides specific instructions on how to 
determine the eligibility and potential risks of a patient (including contraindications) to be 
administered vernakalant IV, and for monitoring of the patient for the duration of the 
infusion and for at least 15 minutes after the completion of the infusion for signs and 
symptoms of a sudden decrease in blood pressure or heart rate.  Within the SmPC, an HCP 
is reminded to use the Pre-Infusion Checklist before administering vernakalant IV. 
 
The risk minimization plan requires information gathering on whether the risk minimisation 
tools (Pre-Infusion Checklist and HCP Educational Card) are reaching the target audience and 
whether they are being used. 
 
The Sponsor, in collaboration with the designated CRO, will conduct a post-authorisation safety 
study (PASS) of vernakalant IV in order to collect information about normal conditions of use 
and dosing of vernakalant IV, and to quantify possible medically significant risks of 
hypotension, ventricular arrhythmia, bradycardia, and atrial flutter in real-world clinical practice. 
Due to expected limitations of existing registries and electronic healthcare records systems in EU 
countries (e.g., AFNET, THIN, GPRD, Nordic Country Hospital Registries) for obtaining all 
data elements necessary to address the study's research objectives, the PASS will employ 
prospective data collection using a network of clinical sites across multiple countries in the EU. 
 
 
4 
OBJECTIVES 
 
The research objectives of the study are to describe patients receiving vernakalant IV, to 
characterise the normal use and dosing of the product, and to better estimate the incidence of 
medically significant HOIs.  Collection of information on dosing/administration and patient 
selection for vernakalant IV will help characterise prescribing in the context of the product 
label. The proportion of subjects in whom successful cardioversion to sinus rhythm following 
vernakalant IV administration is achieved will also be reported. 
 
Specifically, the primary  objectives of the PASS are to: 
 
 
1.   Estimate the incidence of the following medically significant health outcomes of 
interest (HOIs) reported during treatment and during the first 24 hours after last 
infusion of vernakalant IV or until discharge/end of medical encounter, whichever 
occurs earlier. 
 
• Significant hypotension defined as: symptomatic hypotension with BP <90 
mmHg, requiring treatment with vasopressors 

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• Significant ventricular arrhythmia defined as: 
- Sustained ventricular tachycardia (VT) with a ventricular heart rate > 120 
beats per minute with duration > 30 seconds or VT that required 
intervention with either electrical shock or anti-arrhythmic drugs, or 
- Torsade de Pointes with a duration of >10 seconds, or 
- Ventricular fibrillation of any duration 
• Significant atrial flutter defined as: atrial flutter with 1:1 atrioventricular 
conduction of >10 seconds duration and a ventricular rate of >200 bpm 
 
• Significant bradycardia defined as: bradycardia requiring electrical pacing 
(temporary or permanent) or any other serious adverse event reports involving 
bradycardia 
 
2.   In order to investigate the potential risk of overdose and medication error, describe 
vernakalant IV administration/dosing by summarising patient body weight, total dose 
with each intravenous (IV) infusion, and length of time for each IV infusion. 
 
3.   To evaluate the effectiveness of the risk minimisation activities by: 
• Describing the appropriateness of selection of patients for treatment with vernakalant 
IV, monitoring of patients during and after vernakalant IV administration, and use of 
anti-arrhythmics before and after vernakalant IV, as consistent with the label and risk 
minimization activities (Pre-Infusion Checklist and (HCP) healthcare provider 
educational card) 
 
• Monitoring for the occurrence and incidence of SAEs and HOIs to review with the 
EU Regulatory Agency with respect to risk minimization activities 
 
 
The secondary  objectives of the PASS are to: 
 
1.   Summarise the count and rate of all serious adverse experiences (SAEs) for HOIs that 
may not meet the definitions of medically significant HOIs as defined above, as well as 
all other SAEs reported during treatment and during the first 24 hours after the last 
infusion of vernakalant IV or until discharge/end of medical encounter, whichever occurs 
earlier. 
 
2.   Characterise patients administered vernakalant IV in terms of patient demographics, 
medical history, and presenting conditions.  Specific conditions to be summarised 
include: 
 
• Heart failure, New York Heart Association (NYHA) class 
• Prolonged QT, severe bradycardia, sinus node dysfunction, second or third degree 
heart block, clinically meaningful valvular stenosis, hypertrophic obstructive 

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cardiomyopathy, restrictive cardiomyopathy, constrictive pericarditis 
• History of hyperthyroidism 
• Severe aortic stenosis, Low systolic BP 
• Recent acute coronary syndrome (including MI) 
• Pacemaker implantation 
• Presence of pacemaker/year of implantation 
• Hepatic impairment 
 
 
3.   Document the administration of concomitant treatment modalities to restore or maintain 
sinus rhythm during the index hospitalization/medical encounter (e.g., oral or IV anti- 
arrhythmics, electrical cardioversion, ablation, Maze procedure). 
 
4.   Describe the rate of successful cardioversion to sinus rhythm for at least one minute 
within 90 minutes of start of first vernakalant IV administration and time (in hours) from 
vernakalant infusion until discharge/end of medical encounter. 
 
5 
STUDY DESIGN 
 
5.1 
Description 
 
This prospective, observational, PASS will be conducted in compliance with the Guideline on 
good pharmacovigilance practices (GVP), Module VIII [Ref. 5.4: 436] and Volume 9A of The 
Rules Governing Medicinal Products in the EU Guidelines on Pharmacovigilance of Medicinal 
Products for Human Use. [Ref. 5.4: 435]. 
 
The study will not provide or recommend any medication use or other treatment.  All direction 
for medication usage and treatment is at the discretion of the physician in accordance with their 
usual practice; participation in this study will not change or influence a patient’s treatment in any 
way.  The study will include a network of clinical sites in inpatient and acute care settings 
appropriate for IV pharmacologic treatment of AF. Patients being given vernakalant IV will be 
enrolled and followed for 24 hours after the last vernakalant IV infusion or until end of medical 
encounter, whichever occurs first, for medically significant HOIs and SAEs.  Data collection will 
be performed prospectively during and shortly following vernakalant IV administration, with 
abstraction of required data elements from patient medical charts as well as supplemental, 
prospective data collection of study-specific data elements. 
 
 
 
Baseline 
Follow-up time 
Total period of 
follow up 

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Day 1 
Start date of 
vernakalant 
IV 
administration 
From start of first infusion through the  24- 
hour period following last infusion of 
vernakalant IV or until discharge/end of 
medical encounter (whichever occurs earlier) 
24 hours 

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5.2 
Duration of Study 
 
The study is anticipated to be launched by Q3 2011. The study is expected to take approximately 6-
7 years to complete, dependent on the timing of vernakalant IV commercial availability in each 
country, local EU member regulatory approval of the PASS, and the rate of market uptake of 
vernakalant IV.  Site recruitment for the study will begin in third-quarter 2010 and will continue 
through study launch or as needed. Interim reports will be provided with each periodic safety 
update report (PSUR/PBRER) for Vernakalant Sterile concentrate (BrinavessTM) and submitted to 
CHMP after the study is launched.  Assuming an estimated 74 months of active enrolment into the 
study, the final PASS report would be targeted for submission to CHMP by Q1 2018. 
 
5.3 
Study Population 
 
The study population will include patients) who are treated with vernakalant IV in acute care and 
inpatient hospital settings. The decision to treat with vernakalant IV will be made by the treating 
physician independently of this study. The epidemiology of atrial fibrillation suggests that 
prospective patients are more likely to be elderly, and somewhat more likely to be male than 
female. At each site, consecutive patients will be enrolled into the PASS, to the extent possible. 
 
5.4 
Number of Patients 
 
The study will enrol a total of 2,000 patients across participating EU member and other European 
countries, subject to adequate uptake and use of vernakalant IV within the 6-7 year study period 
to provide timely data regarding product safety.  Based on the results of a pilot-test of procedures 
completed by the Sponsor in preparation for this study, it is recognized that enrolment of patients 
in hospital and urgent care setting may be challenging based not only on the estimated product 
uptake during the planned data collection period but also on the variability in clinical practice use 
of electrical versus pharmacological cardioversion in many European countries.  If during the 
study it becomes apparent that the target patient number may not be met within the specified 
enrolment period, the Sponsor will initiate discussions with the CHMP in a timely fashion to 
ensure sample size is sufficient to provide reasonable statistical precision for the associated 95% 
confidence intervals for each HOI, as discussed in Section 10.7. A sufficient number of sites to 
meet enrolment requirements will be recruited to participate in the PASS. 
 
 
 
6 
SELECTION OF PATIENTS 
 
6.1 
Inclusion Criteria 
 
The inclusion criteria for enrolment are: 
 
• Patients treated with vernakalant IV, independently of this study 

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• Subjects and/or legal guardians willing to provide informed consent and/or informed 
assent according to local regulations 
 
6.2 
Exclusion Criteria 
 
The exclusion criteria for enrolment are: 
 
• Enrolment in an investigational drug or device clinical trial in the 30 days prior to study 
enrolment. Participation in another non-interventional drug or device study or registry is 
permitted. 
 
6.3 
Study Enrolment 
 
6.3.1 Site Enrolment and Country Selection 
 
The PASS will target clinical sites in multiple EU member countries to set up infrastructure for 
prospective data collection on vernakalant IV. Countries currently included are Austria, Denmark, 
Germany, Spain, and Sweden. Finland, and other EU and non-EU countries may be included but 
selection is conditional on a number of factors, including, but not limited to, the actual date of 
product launch in each country and rate of market uptake of vernakalant IV.  In addition, country 
selection was based on the following considerations: (1) the desire for the study to reflect 
geographic variation of patients across the EU member countries; (2) the ability to capture 
expected variation in use of different treatment modalities and clinical settings for cardioversion of 
recent onset AF across EU member countries; and (3) the Sponsor's expectation that in several of 
these countries, vernakalant IV will be commercially available for use within the first 1-2 months 
following the expected Commission Decision on the CHMP marketing authorization approval 
(MAA).  The latter consideration was adopted in order to ensure that the study will collect the 
most timely data on real-world use of vernakalant IV. 
 
Site enrolment progress will be monitored closely following the marketing launch of vernakalant 
IV across Europe.  Any substantial delays in a country with clinical sites will trigger a 
reevaluation of this country's appropriateness for inclusion in the PASS.  Under such 
circumstances, the Sponsor will inform the CHMP of this development and will consider 
inclusion of additional countries if needed. 
 
 
Clinical sites in each country reflecting both academic and community hospitals in which acute 
cardioversion is routinely performed (IV pharmacologic or electrical) will be targeted for 
participation in the study.  Centres with adequate prescription, hospital encounter, discharge and 
diagnostic data will be targeted in order to obtain good quality data about administration and 
expected safety profile of vernakalant IV in the context of normal clinical usage. All efforts will 

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be made to enrol sites that can recruit an adequate number of AF patients during the study 
enrolment period.  Regional variation within countries may also be considered in site selection. 
 
6.3.2 Patient Enrolment 
 
Patients who meet all the inclusion criteria and none of the exclusion criteria may be included in 
the PASS.  Patients will be selected for enrolment in the PASS after the decision has been made 
to administer vernakalant IV.  PASS participation will not influence their course of treatment in 
any way. 
 
 
Sites will be required to maintain a screening log of eligible patients, including their gender and 
age.  The log will document all patients that may be included or excluded from the PASS, in 
order to assess the potential study population.  To the extent possible, consecutive eligible 
patients will be included and reasons for non-participation will be documented. 
 
6.4 
Patient Withdrawal 
 
Patients may withdraw consent at any time. If a patient is withdrawn prior to completing the 
PASS follow-up period, the reason for withdrawal is to be documented.  All information already 
collected as part of the study will be retained for analysis unless the patient requests otherwise. 
 
 
7 
DATA COLLECTION 
 
7.1 
Collection of Required Data Elements 
 
Scheduled assessments for the study are presented in the Registry Assessment Flow Chart 
provided in this section.  All data elements will be collected from information routinely recorded 
in the medical record, or will be prospectively recorded by the investigator for the purposes of 
the study. 
 
Data will be collected via an electronic case report form (eCRF).  Data describing vernakalant IV 
administration and dosing at baseline, and observations during study follow-up (from start of 
first infusion through the 24-hour period following last infusion of vernakalant IV or 
discharge/end of medical encounter, whichever is earlier) will be collected; site personnel will 
enter (or transfer if collected on a paper case report form) the collected data in the appropriate 
eCRFs.  Information on concomitant medications and administration of other therapies to 
restore/maintain sinus rhythm during the index hospitalization for stays exceeding 24 hours 
following last infusion of vernakalant IV will be collected, up to a maximum of 7 days following 
last infusion of vernakalant IV.  For prospectively recorded data elements, expected to include 
NYHA class  [Ref. 5.4: 443] and elements of medical history at presentation which may not be 
available in the medical record, the investigator will record the data in the eCRF and add any 

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source documentation (described further in Section 11.2) such as paper worksheets, or printed 
ECG tracings to the medical record. Baseline ECG tracings recorded as part of standard of care 
during the index hospitalization and prior to vernakalant administration and ECGs corresponding 
to arrhythmic HOIs and SAEs during the follow-up period may also be requested. 
No follow-up visits or examinations, laboratory tests, or procedures are mandated as part of this 
study. 
 
7.1.1 Description of Key Data Elements 
 
The list of key data elements to be collected is described below. 
 
The main data elements that will be collected as part of the registry protocol will include: 
 
• Patient demographics (date of birth or age, gender, race, body weight [kg], BMI) 
 
• Hospital admission/medical encounter in which Vernakalant IV was administered 
- Setting (intensive care unit [ICU], coronary care unit [CCU], surgical unit, medical 
ward, emergency department [ED]) 
- Date/time of admission and discharge 
- Primary complaint (reason for admission) 
- Medical condition for which vernakalant IV is prescribed (indication for use) 
 
• Characterisation of AF episode for which Vernakalant IV was administered 
- AF type (surgery vs. non-surgery) 
- Duration of current AF episode (hours), date of onset 
- AF symptoms at presentation 
 
• Presenting medical conditions 
- NYHA heart failure class  [Ref. 5.4: 443] 
▪ Class I.  Patients with cardiac disease but without resulting limitation of physical 
activity.  Ordinary physical activity does not cause undue fatigue, palpitation, 
dyspnea, or anginal pain. 
▪ Class II.  Patients with cardiac disease resulting in slight limitation of physical 
activity.  They are comfortable at rest.  Ordinary physical activity results in 
fatigue, palpitation, dyspnea, or anginal pain. 
▪ Class III.  Patients with cardiac disease resulting in marked limitation of physical 
activity.  They are comfortable at rest.  Less than ordinary activity causes fatigue, 
palpitation, dyspnea, or anginal pain. 
▪ Class IV.  Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort.  Symptoms of heart failure or the anginal 

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syndrome may be present even at rest.  If any physical activity is undertaken, 
discomfort is increased. 
 
- Myocardial infarction (MI) or acute coronary syndrome (ACS) within 30 days 
- Haemodynamic stability 
- Systolic/diastolic blood pressure 
- Heart rate 
- Severe aortic stenosis 
- Severe bradycardia (without pacemaker) 
- Sinus node dysfunction 
- Heart block (2nd or 3rd degree) 
- Left atrial clot (if known) - for those receiving routine echocardiogram 
- Left ventricular hypertrophy (size of the left atrium), thickness of septum, left 
ventricular ejection fraction (if ascertained as part of usual care) 
- Baseline electrocardiogram (rhythm, ventricular rate, QRS duration, QT interval) 
- Hepatic impairment as determined by results of liver function testing performed as 
part of usual care 
 
• Concomitant Medications: All prescription and non-prescription medications taken 
within 24 hours prior to, and during, the index hospitalisation, including (but not limited 
to) 
- Rate control 
- Rhythm control 
- Blood pressure regulation 
- Anti-thrombotics 
- Anti-coagulants 
- Hypercholesterolemia / hyperlipidemia 
 
Information on concomitant medications administered during the index hospitalisation 
for stays exceeding 24 hours following last infusion of vernakalant IV will be collected, 
up to a maximum of 7 days following last vernakalant infusion. 
 
• Selected blood chemistries (with lab reference ranges) collected as part of usual care, 
including, but not limited to: 
- Serum potassium 
- Magnesium 
- Troponin 
- Creatinine 

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- Liver function tests and other analytes (e.g., platelets)  required for estimation of liver 
function using established algorithms 
 
• Medical history 
- History of heart failure (year of diagnosis) 
▪ Prior hospitalisations for acute heart failure (most recent, number in last 6 
months) 
▪ Previously documented left ventricular ejection fraction (most recent) 
- History of AF 
▪ Year of initial diagnosis 
▪ Classification (first onset, paroxysmal, persistent, permanent, post-operative, 
Wolff-Parkinson-White, other?) 
- Pacemaker (yes/no, year implanted) 
- Implantable cardioverter defibrillator (ICD) (yes/no, year implanted) 
- History of cardiovascular disease 
▪ Valvular heart disease 
▪ Clinically meaningful valvular stenosis 
▪ Hypertrophic obstructive myopathy 
▪ Restrictive cardiomyopathy 
▪ Constrictive pericarditis 
▪ MI, angina, stroke, ACS, vascular surgery (stent, coronary artery bypass graft, etc.) 
▪ Hypertension 
- Other medical and lifestyle history 
▪ Diabetes 
▪ Smoking 
▪ Hyperlipidemia/ hypercholesterolemia 
 
• Dosing/Administration of vernakalant IV 
- Total number of infusions during treatment episode 
- Total dose with each infusion 
- Start/stop times for each infusion 
- Amount of time between each infusion 
- Time to successful conversion 
 
 
• Methods of site monitoring of patients during and following each vernakalant 
infusion per SmPC guidance 

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- Duration and frequency of blood pressure measurements during each infusion, during 
15 minute post-infusion and up to two hours post-infusion, and type of healthcare 
provider performing such monitoring 
- Type and duration of cardiac rhythm monitoring during and up to two hours post- 
infusion, and type of healthcare provider performing such monitoring 
 
 
 
• Administration of other therapies for restoration/maintenance of sinus rhythm 
during the index hospitalisation or medical encounter 
- IV and oral rhythm control pharmacologic agents (drug class, administration time 
relative to any infusion of Vernakalant IV) 
- Electrical cardioversion (type [external, transvenous, or transesophageal] and 
administration time relative to any infusion of vernakalant IV) 
- Maze ablation pacemaker or ICD implantation or any other surgical procedures to 
restore sinus rhythm 
 
Information on other therapies to restore/maintain sinus rhythm administered during the 
index hospitalization for stays exceeding 24 hours following last infusion of vernakalant 
IV will be collected, up to a maximum of 7 days following last infusion of vernakalant IV 
 
• Pre-specified medically significant HOIs 
- Significant hypotension (symptomatic hypotension with systolic BP <90 mmHg, 
requiring treatment with vasopressors) 
- Sustained ventricular tachycardia (VT) with a ventricular heart rate > 120 beats per 
minute with duration > 30 seconds or VT that required intervention with either 
electrical shock or anti-arrhythmic drugs, or 
- Torsade de Pointes with a duration of >10 seconds 
- Ventricular fibrillation of any duration 
- Significant atrial flutter defined as: atrial flutter with 1:1 atrioventricular conduction 
of >10 seconds duration and ventricular rate >200 bpm 
- Significant bradycardia defined as: bradycardia requiring electrical pacing (temporary 
or permanent) or any other serious adverse event reports involving bradycardia 
 
• Risk minimization materials 
Collection of data regarding use of risk minimization materials began in August 2014. 
- 
Use of Pre-Infusion Checklist by HCP 
- 
Health Care Provider/Appropriate Use of Brinavess™ card 
▪ Receipt and date of receipt by site 
▪ Read by HCP 

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7.1.2 Schedule of Assessments 
 
 
Follow-up from start of first infusion through earlier of 24 hours after last infusion or 
hospital discharge/end of medical encounter) 
Assessment 
Source 
Baseline 
Follow-up from start 
of first infusion 
through earlier of 24 
hours after last 
infusion or until 
discharge/end of 
medical encounter 
Informed consent/assent obtained 
(may be prior to or following 
administration of vernakalant IV, see 
further detail in Section 12.1) 
Patient unless 
incapacitated, 
may seek proxy 
consent or 
waiver of 
consent based 
on EC approval 
X 
Inclusion/exclusion criteria 
Site staff 
X 
Patient demographics (date of birth 
or age, gender, race, body weight, 
BMI) 
Medical record 
or supplemental 
collection 
X 
Hospital admission/medical 
encounter in which vernakalant IV 
was administered (setting, date/time 
of admission and discharge, primary 
complaint/reason for admission) 
Medical record 
X 
Characterisation of atrial 
fibrillation episode for which 
vernakalant IV was administered 
(surgery or non-surgery setting, onset 
of current episode) 
Medical record 
X 
Presenting medical conditions 
(NYHA class, myocardial infarction, 
acute coronary syndrome, 
haemodynamic stability, 
systolic/diastolic blood pressure, 
severe aortic stenosis, severe 
bradycardia, sinus node dysfunction, 
2nd or 3rd degree heart block, baseline 
electrocardiogram, left ventricular 
ejection fraction, hepatic impairment) 
Medical record 
or supplemental 
collection- 
NYHA class is 
anticipated to 
require 
supplemental 
collection 
X 

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Concomitant Medications: 
prescription and non-prescription 
medications taken within 24 hours 
prior to, and during,  the index 
hospitalization* (to include, but not 
limited to, cardiovascular medications 
such as rate control, rhythm control, 
blood pressure regulation, anti- 
thrombosis, hypercholesterolemia) 
Medical record 
X 
X* 
Standard of care blood chemistry 
(e.g. serum potassium, magnesium, 
troponin, creatinine, liver function 
tests) 
Medical record 
X 
History of heart failure (year of 
diagnosis, recent hospitalisations, left 
ventricular ejection fraction within 
last year, current medications) 
Medical record 
or supplemental 
collection 
X 
History of atrial fibrillation (year of 
initial diagnosis, classification: first 
onset, paroxysmal, persistent, 
permanent, post-operative, Wolff- 
Parkinson-White or other) 
Medical record 
or supplemental 
collection 
X 
Pacemaker (yes/no, year implanted) 
Medical record 
or supplemental 
collection 
X 
Implantable cardioverter 
defibrillator (ICD) (yes/no, year 
implanted) 
Medical record 
or supplemental 
collection 
X 
History of cardiovascular disease 
(valvular heart disease, clinically 
meaningful valvular stenosis, 
hypertrophic obstructive myopathy, 
restrictive cardiopathy, constrictive 
pericarditis, myocardial infarction, 
angina, stroke, acute coronary 
syndrome, vascular surgery, 
hypertension) 
Medical record 
or supplemental 
collection 
X 
Other medical and lifestyle history 
(diabetes, smoking, hyperlipidemia) 
Medical record 
X 

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Dosing/Administration of 
Vernakalant IV (total number of 
infusions, total dose with each 
infusion, start/stop time for each 
infusion, amount of time between 
each infusion, time to successful 
conversion, and methods of site 
monitoring of patients during and 
following vernakalant infusion per 
SmPC guidance) 
Medical record 
X 
X 
Administration of therapies for 
restoration/maintenance of sinus 
rhythm during the index 
hospitalisation* (IV and oral rhythm 
control pharmacologic agents, 
electrical cardioversion, Maze 
ablation,  pacemaker or ICD 
implantation or any other surgical 
procedure to restore sinus rhythm, 
start/stop time for IV or electrical 
treatments) 
Medical record 
X 
X* 
Mandatory reporting of 
pre-specified medically significant 
HOIs (see section 8 for definitions 
and reporting requirements) 
Investigator/Site 
staff 
X 
X 
Mandatory reporting of SAEs (see 
section 8 for definitions and reporting 
requirements) 
Investigator/Site 
staff 
X 
X 
*Data on concomitant medications and therapies (oral, IV meds, electrical cardioversion, and/or surgical 
procedures) for restoration/maintenance of sinus rhythm during the index hospitalization for stays 
exceeding 24 hours following last infusion of vernakalant IV will be recorded up to 7 days 
following the last vernakalant IV infusion. 
 
7.2 Collection of Data Retrospectively 
To minimize further delay to completion of the study, data will be collected retrospectively from 
patients who have received BrinavessTM but were not enrolled in the study. To reflect today’s real 
world setting, retrospective data will only be collected from patients who received BrinavessTM after 
the additional risk minimization measures were implemented in April 2013. This would mean that 
data from patients would be included both retrospectively and prospectively at all new and existing 
sites.  
The inclusion of these retrospective data from patients already treated with BrinavessTM would allow 
the primary objective study to be met fully, whilst facilitating the timely completion of this trial.  

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At the completion of the study, stratified analyses will be used to present the results. Full statistical 
methods and analyses will be described in the Statistical Analysis Plan (SAP). 
Patients are consecutively enrolled into SPECTRUM based on when they present at the participating 
site.  In order to minimize any potential selection bias at the patient level, retrospective data 
collection will be conducted to include all patients already treated with  BrinavessTM  but not 
enrolled in SPECTRUM, at existing and newly qualified sites, with available key data. Specifically, 
data will be included from all patients who; 
1. Have received BrinavessTM since April 2013 but were not enrolled in SPECTRUM. 
2. Have available in their hospital records the key data variables as stipulated in section 7.2.1. 
3. Provide their informed consent or the site obtains a waiver from their IEC. 
 
Both retrospectively and prospectively included patients have to fulfill the same inclusion and 
exclusion criteria. As neither group of patients are selected randomly, this approach is not expected to 
yield selection bias. In addition, results will be reported overall and stratified by method of 
enrollment. As those who refuse to consent to participate, will not have provided their consent to use 
their data it would not be possible to compare baseline characteristics of those who refuse vs those 
who participate. To ensure the overall sample is not dominated by any one site or country by the 
inclusion of retrospective data, any site or country who reaches their limit based on the inclusion of 
retrospective data will be closed and the resources used to open other sites/countries. Enrolment will 
be capped at 10% per site (200 patients) and 40% per country (800 patients). This cap includes 
collection of patient data both prospectively and retrospectively.  
The limitations for enrolling patients prospectively include lack of available staff to discuss the study 
with the patient and ask for their consent, (this typically happens over the weekend, after hours, when 
the Investigator is on vacation or off duty for other reasons) and patients unwilling to give their 
consent to use their data. For retrospectively enrolled patients the limitations are the same. Some sites 
may not have sufficient staff to contact patients treated previously and again, the patient may be 
unwilling to give their consent to use their data. 
As stated above both retrospectively and prospectively included patients will have to fulfill the same 
inclusion and exclusion criteria, neither group of patients would be selected randomly, thus this 
approach is not expected to yield selection bias. In addition, results will be reported overall and 
stratified by method of enrollment.  
SPECTRUM is an observational study that does not use randomization to select the sample.  Treated 
patients are sequentially enrolled, based on provision of informed consent.  Inclusion of patients 
retrospectively will also not use randomization as the goal is to enroll all patients, at the selected sites, 
who were treated with Brinavess and provided their informed consent.  This will ensure that patients 

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selected retrospectively and prospectively are selected in the same manner. This will minimize the 
risk of any potential selection bias.   
Missing data is always a concern; and including patients retrospectively could increase the amount of 
missing data.  However the impact of missing data on the evaluation of the HOIs and other rare 
events is not anticipated to be a concern as this information is routinely collected in the patient’s 
hospital record.  Therefore these event rates at the completion of the study would not be biased 
downward. Further, any possible observer bias by selecting patients retrospectively will be minimised 
by only including patients with the key data variables as stipulated in section 7.2.1 and the assessment 
of whether an event is characterized as an HOI is adjudicated by an independent Safety Review 
Committee (SRC).    
Informed consent 
 
Patients who fulfil the criteria above will be contacted either at clinic during their next routine follow 
up cardiology appointment, or by phone and / or mail. The approved informed consent form will then 
be discussed in detail with the patient and if they agree to take part, the patient will personally sign 
and date the consent form. 
If local regulations permit, sites may also ask their IEC for an informed consent waiver. 
Identification of retrospective patients 
As soon as local regulatory and Ethics Committee approval are obtained (where applicable) sites will 
be able to enrol retrospective patients concurrently with prospective patients. 
Strategies for identifying retrospective patients will vary between sites as a result of varying staff 
availability and record keeping. Sites with searchable electronic patient records for example will find 
it easier to identify patients than sites without. 
Several methods will be employed to identify retrospective patients who have been treated with 
Brinavess since April 2013. 
1. Patients will be approached at their routine clinic visit. If a study team member notices during 
this visit that Brinavess treatment has been previously given, the study will be discussed with 
the patient at this time and asked if they are willing to give their consent to take part. 
2. Following a search of the hospital records,  
a. Identified patients will receive a telephone call, the study discussed with them and at 
their next routine visit asked if they are willing to give their consent to take part. OR 
b. Identified patients will receive a telephone call, the study discussed with them, 
information mailed to the patient and then the patient will be asked to sign and mail 
back the completed consent form. OR 

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c. Identified patients will receive a letter with information regarding the study and if 
willing to take part, sign the consent form at their next routine visit. OR 
d. Identified patients will receive a letter with information regarding the study and if 
willing to take part, sign and mail back the completed consent form. 
Example letters that the site may wish to use can be found in Appendix II. These letters will be sent 
by the study coordinator or Investigator to the patient. To maintain patient confidentiality copies of 
the letters sent will not be seen by, or provided to, the Sponsor. 
7.2.1 Required key data elements for retrospective data collection 
 
The data elements listed in section 7.1.1 will be collected for all patients enrolled retrospectively, with 
the exception of the following which may not be available retrospectively in the patients’ hospital 
records; 
Patient demographics 
• Height 
 
Presenting medical conditions 
• NYHA heart failure class  
 
Where NYHA class is not routinely recorded in the patients’ hospital records, as the NYHA 
classification system is based on patients’ symptoms, where possible the investigator should classify 
this retrospectively as any severe symptoms will be documented. Patient eligibility is expected to 
follow hospital’s standard procedures and SmPC guidelines. 
 
Other medical and lifestyle history 
• Smoking 
 
Dosing/administration of vernakalant IV 
• Stop time for each infusion 
• Time to conversion 
 
The total infusion time is expected to follow both SmPC and hospital guidelines. 
 
Methods of site monitoring of patients during and following each vernakalant IV 
infusion per SmPC guidance 
• Duration and frequency of blood pressure measurements during each infusion, during 
15 minute post-infusion and up to two hours post-infusion, and type of healthcare 
provider performing such monitoring 

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• Type and duration of cardiac rhythm monitoring during and up to two hours post- 
infusion, and type of healthcare provider performing such monitoring 
 
 
8 
SAFETY MEASUREMENTS 
 
As discussed in Section 5.0, the study is a prospective, observational PASS of patients 
administered vernakalant IV under normal conditions of use.  There are no mandated 
interventions or procedures, nor will the PASS provide or recommend any specific medication 
use or other treatment.  All direction for medication usage and treatment is at the discretion of 
the physician in accordance with their usual practice. 
 
8.1 
Definitions of AEs 
 
An AE is defined as any untoward medical occurrence in a patient administered a 
pharmaceutical product at any dose that does not necessarily have a causal relationship with 
vernakalant IV treatment.  An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of the medicinal product, whether or not considered related to the 
pharmaceutical product.  This definition includes intercurrent illnesses or injuries and 
exacerbation of preexisting conditions. 
 
 
If the onset of an event occurred before the patient entered the study (e.g., any preplanned 
hospitalisation or non-emergency routine visits for a pre-existing condition), the condition or 
pre-existing condition would not be considered an AE unless it worsened following medicinal 
product use or hospitalisation was prolonged due to a worsening of the pre-existing condition. 
 
 
A preexisting condition is a clinical condition (including a condition being treated) which is 
diagnosed prior to use of a Cardiome product or protocol-specified intervention, and which is 
documented as part of the subject’s medical history (e.g., pre-planned hospitalization or a routine 
visit for the pre-existing condition). Any worsening of a preexisting condition temporally 
associated with the use of a Cardiome product is by definition an adverse experience. 
 
 
 
8.2 
Definition of SAEs 
 
An SAE is defined as an adverse experience which is fatal or life threatening, results in 
persistent or significant disability, requires inpatient hospitalisation, prolongation of existing 
inpatient hospitalisation, or is a congenital anomaly, cancer, the result of an overdose or is 
another important medical event. Other important medical events that may not result in death, 
may not be life-threatening, or may not require hospitalisation may be considered a SAE when 
based upon appropriate medical judgment, they may jeopardise the patient or subject and may 
require medical or surgical interventions to prevent one of the other outcomes listed previously. 
 

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Note:  AEs which do not meet the above criteria are defined as non-serious adverse 
experiences (NSAE). For regulatory reporting requirements in the European Union, SAEs and 
NSAEs that are at least possibly drug related are defined as serious adverse reactions (SADR) 
and non-serious adverse reactions, respectively. 
 
8.3 
Definition of Experiences of Clinical Interest 
 
Medically significant HOIs are classified as experiences of clinical interest.  Definitions of HOIs 
have been provided previously in Section 7.1.1. 
 
 
For reporting purposes, Experiences of Clinical Interest (ECIs) must be identified and reported 
within the same timeframes as SAEs. 
 
8.4 
Reporting by Investigators 
 
Reporting of all SAEs and HOIs that occur during the study follow-up period (earlier of 24 hours 
post vernakalant IV administration or hospital discharge) are mandated as part of this protocol 
and should be reported to the study CRO by the study investigator within 24 hours of 
identification. All serious AEs and HOIs that occur during the study follow-up period will be 
recorded by the investigator in the serious AE eCRF and will result in an automated notification 
to the study's CRO. 
All subjects/patients with SAEs must be followed up for outcome of the event.  Any follow-up 
information on the SAE should be provided by the investigator to the CRO within the same 
reporting period (within 24 hours of identification). 
 
 
An investigator who is a qualified physician, will evaluate AEs for relationship to vernakalant IV 
according to the following categorisation: 
 
• Definitely related 
• Probably related 
• Possibly related 
• Probably not related 
• Definitely not related 
 
 
If a non-Cardiome Product is considered by the investigator to be co-suspect, the 
investigator is responsible for reporting the SAE to the manufacturer of the non-Cardiome 
Product. 
 
If an investigator reports a non-serious AE, it will be collected in the non-serious AE eCRF. 
 
8.5 
Confirmation of SAEs and HOIs 
 
All SAEs and HOIs that are reported in the eCRF by the study physician will be confirmed for 

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source verification through review of patient records at the treating medical centre and/or direct 
follow-up with the treating physician.  If fatal events occur, a death certificate with cause of 
death will be requested.  Baseline ECG tracings and ECGs corresponding to arrhythmic HOIs 
and SAEs may be requested. 
 
Medical Dictionary for Regulatory Activities (MedDRA) will be the dictionary for all medical 
coding of SAEs and HOIs reported. 
 
8.6 
Safety Reporting to Competent Authorities 
 
Once the investigator reports an SAE using the eCRF, the CRO will immediately transmit the 
SAE report to one of the individual(s) listed on the contact information page of the site study 
binder. 
 
All SAEs and HOIs, regardless of attribution to vernakalant IV that occur during the study 
follow-up period (from start of first infusion through the 24-hour period following last infusion 
of vernakalant IV or discharge/end of medical encounter, whichever is earlier) will be reported to 
the relevant competent authority in compliance within local reporting requirements. 
 
If an investigator becomes aware of an SAE that is at least possibly related to Vernakalant IV 
(BRINAVESS) that occurs after the study follow-up period has concluded, the investigator 
should report the event to the Sponsor in accordance with local requirements for spontaneous 
adverse event reporting. 
 
 
In addition, non-interventional post-authorisation safety studies are covered by the provisions of 
the Directive 2001/83/EC, Regulation (EC) No. 726/2004 and the Guideline on good 
pharmacovigilance practices (GVP), Module VIII [Ref. 5.4: 436].  According to “Volume 9A of 
The Rules Governing Medicinal in the European Union Guidelines on Pharmacovigilance for 
Medicinal Products for Human Use” Section 7.4.2, [Ref. 5.4: 435] the Sponsor will be 
responsible to report all serious adverse reactions (SADR) arising from the study within the EU 
no later than 15 days following the receipt of the information to the Competent Authority of the 
Member State on whose territory the incident occurred.  Further, in accordance with section 
7.4.2, all SADRs will be included in PSURs. [Ref. 5.4: 435] 
 
 
 
 
 
 
 
 
 
 
 
 

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All SAEs  and HOIs occurring during 
first 24 hours after last  infusion of 
vernakalant IV or discharge/end of 
medical encounter. 
 
Within 24 hours of 
SAE/HOI 
 
Investigator reports the SAE/ HOI 
by entering the data in t he study’s 
EDC system (eCRF). 
 
Immediate 
transmission via fax 
 
Sponsor & CRO receive the 
SAE/HOI report and follow up 
with investigator if necessary. 
 
Within 1 5 days from 
receipt of SAE/HOI 
 
Sponsor submits the SAE/HOI to 
Competent Authorities in  
compliance wit h local regulatory 
requirements. 
 
 
 
 
Reports of non-serious adverse reactions received by the CRO will be included in the end of 
study summary report to the CHMP. 
 
The study investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs involving his/her patients to the Ethics Committee (EC that approved the 
study).  When direct reporting by an investigator is not clearly defined by national or 
site-specific regulations, the study physician will be responsible for promptly notifying the 
concerned EC of any safety reports provided by the Sponsor and of filing copies of all related 
correspondence in the Site File. 
 
8.7 
SPONSOR Responsibility for Reporting Adverse Experiences 
 
All AEs will be reported to the Competent Authorities, ECs, regulatory agencies, IECs, and 
investigators in accordance with all applicable global laws and regulations. 

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9 
EFFECTIVENESS 
 
9.1 
Definition of Effectiveness Endpoint 
 
Effectiveness of vernakalant IV will be assessed as a secondary endpoint, defined as the 
proportion of patients who are converted to sinus rhythm for at least one minute within 90 
minutes of start of first vernakalant IV administration.  [Ref. 5.4: 104] 
 
 
 
 
10   STATISTICAL METHODS AND ANALYSES 
 
10.1  Analysis Population 
 
The population for analysis includes all enrolled patients who are documented as having received 
vernakalant IV. 
 
10.2  Primary analyses 
 
Analyses corresponding to the specific research objectives of the study are planned as follows. 
 
Primary Objective 1: Estimate the incidence of the following medically significant HOIs 
reported during treatment and during the first 24 hours after last infusion of vernakalant IV or 
until discharge/end of medical encounter, whichever occurs earlier. 
 
• Significant hypotension defined as: symptomatic hypotension with systolic BP 
<90 mmHg, requiring treatment with vasopressors 
• Significant Ventricular arrhythmia defined as: 
- 
Sustained ventricular tachycardia (VT) with a ventricular heart rate > 120 
beats per minute with duration > 30 seconds or VT that required intervention 
with either electrical shock or anti-arrhythmic drugs, or 
- 
Torsade de Pointes with a duration of >10 seconds, or 
- 
Ventricular fibrillation of any duration 
• Significant atrial flutter defined as: atrial flutter with 1:1 atrioventricular 
conduction of >10 seconds duration and a ventricular rate >200 bpm 
• Significant bradycardia defined as: bradycardia requiring electrical pacing 
(temporary or permanent) or any other serious adverse event reports involving 
bradycardia 
 
Both adjusted (based on method of patient enrolment; prospective vs retrospective) and unadjusted 
cumulative incidence of HOIs (and their associated 95% confidence intervals) will be reported.  In 
addition, results will also be reported separately by method of enrolment. For the significant 
bradycardia HOI, the adjusted (based on method of patient enrolment; prospective vs  

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retrospective) and unadjusted incidence and 95% confidence interval will be reported.  In addition, 
results will also be reported separately by method of enrolment. Results will be calculated for the 
combined endpoint of (1) bradycardia requiring electrical pacing (temporary or permanent) or (2) 
any other serious adverse events reports involving bradycardia, and for each endpoint separately. 
Numbers and rates of HOIs will also be presented according to time intervals since start of 
vernakalant IV administration, i.e., 0 to less than 2 hours, 2 to less than 4 hours, and 4 hours to a 
maximum of 24 hours. Characteristics of patients with HOIs, which may include prior medical 
history, presenting conditions, medication use, dosing/administration of vernakalant IV, and 
concomitant therapies,  and assessment of relatedness as provided by the investigator will be 
summarised in a listing of individual HOI events in study reports.  Case narratives will also be 
provided for each HOI. 
 
The primary analysis for HOI incidence is the 0-2 hour post infusion timepoint.  Given the lower 
expected sample size, vernakalant's mode of action and the non-interventional nature of the study 
design, the 2-4 and 4-24 hour post infusion timepoints are considered secondary and tertiary 
analyses, respectively. 
 
It is anticipated that rates of HOIs may be somewhat higher in this real-world study setting 
compared to rates observed in the vernakalant clinical trial program due to the selective patient 
entry criteria of these randomized clinical trials. Likewise, comparisons to the published 
literature are not planned and would prove difficult due to differences in case definitions for each 
specific HOI  and variability of reported follow-up periods from administration of a given study 
drug or intervention to time of the event.  However, the frequency of HOIs will be carefully 
monitored by the Sponsor, the CRO, and the independent Safety Review Committee throughout 
the duration of the registry study. 
 
Primary Objective 2: In order to investigate the potential risk of overdose and medication error, 
describe vernakalant IV administration/dosing by summarising patient body weight, total dose 
with each IV infusion, and length of time for each IV infusion. 
 
Distributions of patient body weight, total dose administered with each IV infusion stratified 
by body weight, and length of time for each infusion will be summarised in tables overall and 
stratified by method of patient enrollment. 
Continuous variables will be reported using appropriate measures of dispersion and central 
tendency (means, medians, ranges and standard deviations) while categorical variables will be 
summarised as number and percentage of the total study population.  All results will be 
reported overall and stratified by method of patient enrollment. 
Additionally characteristics of patients administered vernakalant IV according to the product 
label and any patients administered vernakalant IV outside of the dosing guidelines will be 

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described. Patient age, body weight, presenting conditions and medical history, and details 
of dosing and administration will be presented separately for each group.  All results will be 
reported overall and stratified by method of patient enrollment. 
 
10.3  Secondary Analyses 
 
Safety 
 
Secondary Objective 1: Summarise the count and rate of all serious adverse experiences (SAEs) 
for HOIs that may not meet the definitions of medically significant HOIs as defined above, as 
well as all other SAEs reported during treatment and during the first 24 hours after the last 
infusion of vernakalant IV or until discharge/end of medical encounter, whichever occurs 
earlier. 
 
Tables with counts of SAEs will be provided and summarised by Medical Dictionary for 
Regulatory Activities (MedDRA), system organ class (SOC), high level term (HLT), and preferred 
term (PT), and also stratified by outcome (recovered, recovered with sequelae, not recovered), fatal 
or non-fatal, and relationship to the study drug (definitely related, probably related, possibly 
related, probably not related, definitely not related). These summaries will be reported overall and 
stratified by method of patient enrollment. 
Characteristics of patients with SAEs, which may include prior medical history, presenting 
conditions, medication use, dosing/administration of vernakalant IV, and concomitant therapies, 
will be summarised in a listing of individual SAEs in study reports.  Case narratives will also be 
provided for each SAE. 
 
Non-serious AEs 
 
Tables with counts of non-serious AEs will be provided and summarised by MedDRA SOC, 
HLT, and PT and stratified by relationship to the study drug once for the final study report. 
These summaries will be reported overall and stratified by method of patient enrollment. 
 
Secondary Objective 2: Characterise patients administered vernakalant IV in terms of patient 
demographics, medical history, and presenting conditions. Specific conditions to be summarised 
include: 
 
• Heart failure, NYHA class 
• Prolonged QT, severe bradycardia, sinus node dysfunction, second or third degree 
heart block, clinically meaningful valvular stenosis, hypertrophic obstructive 
cardiomyopathy, restrictive cardiomyopathy, constrictive pericarditis 
• History of hyperthyroidism 
• Severe aortic stenosis, low systolic BP 

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• Recent acute coronary syndrome (including MI) 
• Pacemaker implantation 
• Hepatic impairment 
 
Descriptive data summarising characteristics of enrolled patients will be reported for patient 
demographics including country, age, gender, race, medical history, and presenting 
conditions. Continuous variables will be reported using appropriate measures of dispersion 
and central tendency (means, medians, ranges and standard deviations) while categorical 
variables will be summarised as numbers and percentages of the total study population.  
These summaries will be reported overall and stratified by method of patient enrollment. 
 
Secondary Objective 3: Document the administration of concomitant treatment modalities to 
restore or maintain sinus rhythm during the index hospitalisation (e.g., oral or IV anti- 
arrhythmics, electrical cardioversion, ablation, Maze procedure) 
 
A table summarising the frequency of administration of each concomitant treatment 
modality during the index medical encounter, stratified by the timing of administration 
relative to vernakalant IV administration (prior, concurrent, subsequent), will be provided. 
This summarisation will include class I or III anti-arrhythmics as well as other concomitant 
medications received during the hospitalisation.  These summaries will be reported overall 
and stratified by method of patient enrollment. 
 
Effectiveness 
 
Secondary Objective 4: Rate of successful conversion to sinus rhythm for at least one minute 
within 90 minutes from the start of first vernakalant IV administration will be expressed as the 
proportion of patients with successful conversion, together with the associated 95% confidence 
interval. Time (in hours) from start of vernakalant infusion to patient discharge/end of medical 
encounter will be summarized using appropriate measures of dispersion and central tendency 
(means, medians, ranges and standard deviations). These summaries will be reported overall 
and stratified by method of patient enrollment. 
 
10.4  Subgroups 
 
There are no pre-specified subgroups for analysis.  Patient characteristics (and dosing 
information) will be presented for individual countries, however, rates of HOIs will not be 
reported by country as individual events are expected to be rare, and stratification of event rates 
will yield statistically unstable results. 
 
Secondary analysis may be conducted for subgroups of patients with certain medical 
characteristics if the sample size is sufficient to allow for reasonably precise point estimates of 

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HOI incidence (in general, 500 patients or more).  Regardless, a description of each patient with 
medically significant HOIs will be given in narrative form. 
 
10.5 Statistical Analysis Plan 
 
A detailed Statistical Analysis Plan (SAP) inclusive of further details and specification of 
analytic methods to be used and shell tables, figures, and listings for interim and final reports 
will be developed by the CRO and approved by the Sponsor prior to the start of any patient 
enrolment in the study. 
 
10.6  Analysis Software and Coding 
 
All AE verbatim terms will be recorded and coded using MedDRA terms and are presented by 
system organ class (SOC), high level term (HLT), and preferred term (PT). 
 
All computations and generation of tables, listings and data for figures will be performed using 
SAS® version 9.2 (SAS Institute, Cary, NC, USA). 
 
10.7  Sample Size 
 
The study will enroll 2,000 patients across participating EU countries.  The target sample size 
was selected in order to have adequate statistical precision as expressed by a 2-sided, 95% 
confidence limit around the expected incidence rate for each HOI for sample sizes of 500, 1,000 
1,500; and 2,000 patients.  The incidence of each HOI during the first 24 hours post-vernakalant 
IV administration as defined in Section 5.0 and 10.2 above among patients randomised to receive 
vernakalant IV in the pooled phase II/III clinical trial database (n=889, including the AVRO 
Study) ranged from 0% to 0.22% for each HOI. 
 
 
Table 1 shows the margins of error, defined as the distance from the expected proportion to the 
upper limit of the confidence interval as shown in the table, and confidence limits of the two- 
sided 95% confidence intervals with sample size of 500, 1,000, 1,500, and 2,000, respectively. 
For example, if the expected proportion of significant hypotension is 0.003 and the sample size is 
1,500, the margin of error is 0.004, and the lower and upper bounds of the two-sided 95% 
confidence interval will be 0.001 and 0.007, respectively.  The calculation of the confidence 
intervals was performed using the Clopper-Pearson exact method  [Ref. 5.4: 406] and PASS 
software (2008, Kaysville, Utah). 

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Table 1.  Margins of error and confidence limits of the two-sided 95% confidence intervals 
for one sample proportion with various sample sizes. 
 
Since the confidence interval is not symmetric around the expected proportion of patients with events, the margin of 
error is the distance from the expected proportion to the upper limit of the confidence interval as shown in this table. 
Sample 
Size 
N=500 
N=1,000 
N=1,500 
N=2,000 
Expected 
Prop. 
Margin of 
Error 
Lower and 
Upper Limit 
Margin of 
Error 
Lower and 
Upper Limit 
Margin of 
Error 
Lower and 
Upper Limit 
Margin of 
Error 
Lower and 
Upper Limit 
0.001 
0.008 
0.000, 0.009 
0.005 
0.000, 0.006 
0.003 
0.000, 0.004 
0.003 
0.000, 0.004 
0.002 
0.009 
0.000, 0.011 
0.005 
0.000, 0.007 
0.004 
0.000, 0.006 
0.003 
0.001, 0.005 
0.003 
0.010 
0.000, 0.013 
0.006 
0.001, 0.009 
0.004 
0.001, 0.007 
0.004 
0.001, 0.007 
0.004 
0.010 
0.000, 0.014 
0.006 
0.001, 0.010 
0.005 
0.001, 0.009 
0.004 
0.002, 0.008 
0.005 
0.011 
0.001, 0.016 
0.007 
0.002, 0.012 
0.005 
0.002, 0.010 
0.004 
0.002, 0.009 
0.006 
0.011 
0.001, 0.017 
0.007 
0.002, 0.013 
0.005 
0.003, 0.011 
0.004 
0.003, 0.010 
0.007 
0.012 
0.002, 0.019 
0.007 
0.003, 0.014 
0.006 
0.003, 0.013 
0.005 
0.004, 0.012 
0.008 
0.012 
0.002, 0.020 
0.008 
0.003, 0.016 
0.006 
0.004, 0.014 
0.005 
0.005, 0.013 
0.010 
0.013 
0.003, 0.023 
0.008 
0.005, 0.018 
0.006 
0.006, 0.016 
0.005 
0.006, 0.015 
0.012 
0.014 
0.004, 0.026 
0.009 
0.006, 0.021 
0.007 
0.007, 0.019 
0.006 
0.008, 0.018 
0.015 
0.015 
0.006, 0.030 
0.010 
0.008, 0.025 
0.008 
0.009, 0.023 
0.006 
0.010, 0.021 

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Figure 1.Plot of sample size and margin of error at various levels of expected proportion of 
patients with events. 
 
 
 
Footnote: Margin of error (half-width of confidence interval) is defined as the distance between the expected 
proportion (point estimate) and upper bound of the two-sided 95% confidence limit as the confidence interval is not 
symmetric. 
 
 
 
10.8  Missing data 
 
Reasonable attempts should be made by the treating physician and/or site personnel to limit the 
amount of missing data.  No imputation will be made for missing data. The proportion of 
missing data is expected to be low for this study, especially with regard to the details of 
administration of vernakalant IV and concomitant therapies, collected blood chemistry values, 
and occurrence of HOIs during the brief, in-hospital follow-up period.  Reasonable attempts will 
be made to limit the amount of missing medical history data to ensure that important information 
is captured 
 
10.9  Interim and Final Analyses and Reporting 
 
Interim analyses will include descriptive summaries of patient characteristics and vernakalant IV 
administration and dosing, as well as frequencies and cumulative incidence of HOIs and SAEs 
following administration.  Two-sided 95% confidence intervals around rates of HOIs will be 
computed. 

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A final study report summarising patient characteristics and details of vernakalant IV 
administration and dosing, administration of concomitant treatment modalities, frequencies and 
cumulative incidence of HOIs and SAEs over the full study period, as well as effectiveness and 
frequencies of non-serious AEs will be prepared. 
 
Full explanation of study methods, results, and discussion and interpretation will be included 
with interim and final study reports. 
 
 
 
 
11   MANAGEMENT OF THE STUDY 
 
The Sponsor has contracted with Outcome Sciences LLC (formerly operating as Outcome 
Sciences Inc.) together with its affiliate Quintiles Switzerland Sarl, a CRO specialising in registries 
and observational post market studies. The CRO will design and manage the study with input, 
review and approval by the Sponsor  Each participating site will receive appropriate training, 
which describes all processes that the physician or representative must understand.  The training 
will outline all processes required for enrolling patients, providing follow-up data on enrolled 
patients, maintaining study documents or files, reporting of medically significant HOIs and SAEs, 
and closing the study.  All site staff who participate in enrolling patients and collecting or entering 
data for the study will be required to undergo appropriate training. 
 
11.1 Data Entry 
 
Data for the study will be collected using a secure web-based electronic data capture (EDC) 
system (Outcome System®).  Data captured during or shortly following the administration of 
vernakalant IV are entered into the eCRF by the physician or delegated site staff in a timely 
manner. 
 
11.2 Source Documents 
 
The physician should maintain source documents for each patient enrolled in the study.  Source 
documents include patient charts, doctors’ notes, study-specific supplementation data collection 
forms, ECG tracings (including conversion to sinus rhythm ECGs within 90 minutes of 
vernakalant IV treatment), lab results slips, supportive documentation of all HOIs and SAEs, and 
worksheets designed to collect the data to be entered in the CRF and will be kept as part of the 
patients’ medical records. Baseline ECG tracings recorded as part of standard of care during the 
index hospitalization and prior to vernakalant administration and ECGs corresponding to 
arrhythmic HOIs and SAEs during the follow-up period may also be requested. 
 
Data recorded into the e-CRF should also be downloaded and stored on local computers at the 
site.  Should this not be possible sites will print a date-stamped version of the completed CRF for 
each patient to be signed by the study physician and stored in files at the site. 

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11.3  File Retention and Archiving 
 
The physician and trained staff at the study sites will maintain a record of each enrolled patient. 
Physicians will be instructed on source documentation that must be available to substantiate 
patient identification, eligibility and participation, proper informed consent procedures, dates of 
data collection, adequate reporting and follow-up of medically significant HOIs and SAEs, 
concomitant medication, and drug administration.  Specific items required as source documents 
will be reviewed with the physician before the study. 
 
Physicians must retain all study records required by the Sponsor and by the applicable 
regulations a secure and safe facility.  The physician must notify the Sponsor or its representative 
before disposal of any study records, including the medical records of study participants, and 
must notify the sponsor of any change in the location, disposition, or custody of the study files. 
In the event that archiving of study records is not possible at the site, the physician will be 
instructed to notify the Sponsor or its representative. 
 
11.4  Quality Assurance 
 
The study database will be housed at the CRO in a physically and logically secure computer 
system maintained by the CRO in accordance with company written security policies.  The 
system meets approved established standards for the security of health information and is 
validated.  The system also meets the standards of the International Committee on Harmonisation 
(ICH) guideline E6R1 regarding electronic study data handling and is available for audit upon 
request.  Each step of the data capture procedures and the handling of data, as well as the 
eventual study report may be subject to independent quality assurance audits.  The CRO, the 
Sponsor, and the Competent Authorities may conduct site audits at any time during or after the 
study to ensure the validity and integrity of the data. 
 
11.5  Data Management 
 
A data management plan will be created and will describe all functions, processes, and 
specifications for data collection, cleaning and validation. The eCRFs will include 
programmable edits to obtain immediate feedback if data are missing, out of range, illogical or 
potentially erroneous.  Concurrent manual data review will be performed based on parameters 
dictated by the plan. Ad hoc queries will be generated within the EDC system and followed up 
for resolution. 
 
11.6  Monitoring 
 
Monitoring will be performed by a CRO clinical research associate (CRA).  During the site 
initiation visit, the CRA will provide training on the conduct of the study to the participating 
physician and all site staff involved in the study.  All monitoring procedures and the frequency of 
monitoring visits will be described in a monitoring plan.  The CRA will closeout each site after 

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CONFIDENTIAL AND PROPRIETARY 
 
the last patient’s final follow-up assessment is completed and all e-CRF data has been entered 
and all outstanding monitoring issues have been resolved or addressed.  In the case where a site 
is closed before completion of the study, the CRA will close out the site but will maintain contact 
with the physician regarding the study status and in case follow-up information is required. 
 
11.7  External Safety Review Committee (SRC) 
 
The Sponsor will assemble a team of external advisors for an SRC and will employ a charter for 
the SRC developed jointly by the Sponsor and the CRO.  The SRC will consist of three members 
(single Chairperson and two members) based in Europe with expert knowledge in AF and 
therapeutic modalities for cardioversion.  Two experts will have clinical experience in treatment 
of AF while the third member will be an applied epidemiologist or statistician with experience in 
the design and execution of observational safety study studies. 
 
The Sponsor will contact each advisor to review the requirements and expectations of 
participation in the SRC. Regularly-scheduled meetings of the SRC (teleconference, webex, or 
face-to-face) will be convened prior to the start of study enrolment and at least annually 
thereafter, to review interim and final reports of safety data and monitor overall study progress. 
Specifically, the SRC will be responsible for (1) review of individual patient listings of serious 
adverse event (SAE) reports and aggregated data in the form of predefined tables and study 
result reports; (2) periodic assessment of subject accrual rate and study status; (3) evaluation on 
an ad hoc basis of any urgent safety issue identified by the Sponsor, CRO or the SRC; 
(4) document and communicate in writing all SRC activities to Sponsor, and (5) adjudication of 
Health Outcomes of Interest (HOIs)/Serious Adverse Events (SAEs).   
Source documentation routinely collected for the study which may include ECG tracings 
corresponding to arrhythmic events if performed as part of standard of care will also be provided to 
the SRC for review of individual HOIs and SAEs. 
11.8  Changes to Protocol 
 
Changes to the protocol will be documented in written protocol amendments.  Major (substantial, 
significant) amendments will usually require submission to the competent authorities and to the 
relevant ECs for approval or favourable opinion.  In such cases, the amendment will be 
implemented only after approval or favourable opinion has been obtained.  Minor 
(non-substantial) protocol amendments, including administrative changes, will be filed by the 
Sponsor and/or the CRO and at each participating site.  They will be submitted to the relevant 
EC or to competent authorities where required by pertinent regulations. 
As noted below in Section 12.1 regarding Informed Consent, any amendment that could have an 
impact on the patient’s agreement to participate in the study (e.g., changing the nature of the data 
collected) requires re-consent of the patient prior to implementation, except if a waiver of 
consent has been approved by the relevant EC or competent authorities. 
 
 

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CONFIDENTIAL AND PROPRIETARY 
 
11.9  Publication Policy 
 
The Sponsor will post a study design synopsis on www.clinicaltrials.gov within 60 days after the 
study protocol is approved by the CHMP, and will post final study results within 12 months after 
the last patient is enrolled in the study.  In addition, publication may also include any or all of the 
following: posting of a synopsis online abstract and/or presentation at a scientific conference, or 
publication of a full manuscript. 
 
In the event that the key design elements from the protocol, including methods, and main results 
of the study are made public through publication in peer-reviewed journals, it is anticipated that 
one central draft manuscript will be prepared with input from key investigators and leadership 
from the CRO and the Sponsor. 
 
Authorship credit should be based on 1) substantial contributions to conception and design, or 
acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising it 
critically for important intellectual content; and 3) final approval of the version to be published. 
Authors should meet conditions 1, 2, and 3.  Significant contributions to study execution may 
also be taken into account to determine authorship, provided that contributions have also been 
made to all three of the preceding authorship criteria. Although publication planning may begin 
before conducting the study, final decisions on authorship and the order of authors’ names will 
be made based on participation and actual contributions to the study and writing, as discussed 
above. The first author is responsible to defend the integrity of the data, method(s) of data 
analysis, and the scientific content of the manuscript. 
 
The Sponsor must have the opportunity to review and comment on all proposed abstracts, 
manuscripts, or presentations regarding this study 60 days prior to submission for 
publication/presentation.  During this 60 day period, Sponsor may respond with any requested 
revisions.  Any information identified by the Sponsor as confidential must be deleted prior to 
submission.  If reasonably requested, Sponsor will take reasonable steps to expedite the review 
process to meet publication deadlines. Submission may be made upon notification by Sponsor 
that such review has been completed and after information identified by Sponsor as confidential 
is deleted.  Sponsor also has the right to publish the results of this study. Publications and 
authorship will be guided by the Uniform Requirements for Manuscripts Submitted to 
Biomedical Journals: Writing and Editing for Biomedical Publication of the International 
Committee of Medical Journals Editors, updated April 2010. 
 
 
 
 
 
 
 
 
 
 

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12   ETHICAL AND REGULATORY CONSIDERATIONS 
 
This is an observational study which sets forth to observe the safety outcomes of patients having 
been administered vernakalant IV.  To ensure the quality and integrity of 
pharmacoepidemiologic research, the study will be conducted in compliance with all applicable 
national and local regulations and guidelines, accepted standards of Good Clinical Practice, the 
Guidelines for Good Pharmacoepidemiology Practices (GPP), [Ref. 5.4: 437] the ethical 
principles that have their origin in the Declaration of Helsinki  [Ref. 5.4: 440],EudraLex Volume 
9A, Part 1, Chapter I.7.  [Ref. 5.4: 435] and the Guideline on good pharmacovigilance practices 
(GVP), Module VIII [Ref. 5.4: 436]. 
 
12.1  Patient Information and Informed Consent/Assent 
 
It is expected that a prerequisite for a patient’s participation in the study is informed consent 
from the patient or a legal representative; however the possibility of conducting this study with a 
waiver of consent will be explored in each country. 
 
The physician will obtain written informed consent as needed from each patient or a legal 
representative if incapacitated prior to enrolment and data collection.  The physician, or 
delegated personnel, is required to provide patient or legal representative with the informed 
consent in their local language.  The informed consent document contains adequate information 
on risks of study participation, in this case, limited to communication of personal identifiers and 
health information.  This informed consent document will be approved by the appropriate EC as 
will any revisions to the document.  Each patient or legal representative will be provided a copy 
of the informed consent document and the original will be maintained at the site.  Confirmation 
of signed informed consent documents obtained as required will be one of the primary activities 
performed by the CRA during onsite monitoring as defined in the monitoring plan. 
 
12.2  Patient Identification and Privacy 
 
By signing the protocol, the clinical site and/or physician commit to complying with all related 
applicable local laws and regulations as well as any applicable EU regulations, such as the EU 
Data Protection Act. 
 
 
Each patient will be unambiguously identified by a code, which allows the identification of all the 
data reported for each patient.  The code will be an 8-digit number resulting from the 
combination of the site number and the patient number. The first four digits represent the site and 
the last four digits represent the patient.  Should a patient be withdrawn from the study, his or her 
unique identification number will not be reallocated. 
 
 
 
 

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CONFIDENTIAL AND PROPRIETARY 
 
12.3  Independent Ethics Committees 
 
Patient enrolment will not start at any site before the Sponsor has obtained written confirmation 
of a favourable opinion/approval from the concerned EC.  At certain sites it may be deemed 
unnecessary for an EC to review an observational study. If this is the case, confirmatory 
documentation will be maintained on file with both the Sponsor and the clinical site. 
 
Before implementation of any substantial changes to the protocol, protocol amendments will also 
be submitted to the relevant EC in a manner consistent with local regulations.  Pertinent safety 
information will be submitted to the relevant ECs during the course of the study in accordance 
with local regulations and requirements. 

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CONFIDENTIAL AND PROPRIETARY 
 
 
References 
 
 
[Ref. 5.4: 62] 
Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, et al. 
Prevalence of diagnosed atrial fibrillation in adults: national implications 
for rhythm management and stroke prevention: the AnTicoagulation and 
Risk    Factors    In    Atrial    Fibrillation    (ATRIA)    Study.    JAMA 
2001;285(18):2370-5. 
 
[Ref. 5.4: 72]            Heeringa J, van der Kuip DAM, Hofman A, Kors JA, van Herpen G, 
Stricker BHC, et al. Prevalence, incidence and lifetime risk of atrial 
fibrillation: the Rotterdam study. Eur Heart J 2006;27:949-53. 
 
[Ref. 5.4: 104]          Roy D, Pratt CM, Torp-Pedersen C, Wyse DG, Toft E, Juul-Moller S, et 
al. Vernakalant hydrochloride for rapid conversion of atrial fibrillation: a 
phase 3, randomized, placebo-controlled trial. Circulation 2008;117:1518- 
25. 
 
[Ref. 5.4: 150]          Wyse D, Waldo A, DiMarco J, Domanski M, Rosenberg Y, Schron E. A 
comparison  of  rate  control  and  rhythm  control  in  patients with  atrial 
fibrillation. N Engl J Med 2002;347(23):1825-33. 
 
[Ref. 5.4: 210] 
Kowey PR, Dorian P, Mitchell LB, Pratt CM, Roy D, Schwartz PJ, et al. 
Vernakalant hydrochloride for the rapid conversion of atrial fibrillation 
after  cardiac  surgery:  a  randomized,  double-blind,  placebo-controlled 
trial. Circ Arrhythm Electrophysiol 2009;2:652-9. 
 
[Ref. 5.4: 345]            Fuster V, Rydén LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, 
et al. ACC/AHA/ESC 2006 guidelines 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 European Society of Cardiology Committee for 
Practice Guidelines (Writing Committee to Revise the 2001 Guidelines 
for  the  Management  of  Patients  with  Atrial  Fibrillation).  J  Am  Coll 
Cardiol 2006;48(4):e149-e246. 
 
[Ref. 5.4: 371] 
Conway E, Musco S, Kowey PR. New horizons in antiarrhythmic therapy: 
will    novel    agents    overcome    current    deficits.    Am    J    Cardiol 
2008;102(Suppl 6A):12H-9H. 
 
[Ref. 5.4: 406] 
Newcombe RG. Two-sided confidence intervals for the single proportion: 
comparison of seven methods. Stat Med 1998;17:857-72. 
 
[Ref. 5.4: 430] 
Le Heuzey J-Y, Paziaud O, Piot O, Said MA, Copie X, Lavergne T, et al. 
Cost of care distribution in atrial fibrillation patients: the COCAF study. 
Am Heart J 2004;147(1):121-6. 

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CONFIDENTIAL AND PROPRIETARY 
 
 
[Ref. 5.4: 431] 
Lip GYH, Tse H-F. Management of atrial fibrillation. Lancet 
2007;370:604-18. 
 
[Ref. 5.4: 432]          Lloyd-Jones DM, Wang TJ, Leip EP, Larson MG, Levy D, Vasan RS, et 
al. Lifetime risk for development of atrial fibrillation: the Framingham 
Heart Study. Circulation 2004;110:1042-6. 
 
[Ref. 5.4: 433]          Reynolds MR, Essebag V, Zimetbaum P, Cohen DJ. Healthcare resource 
utilization   and   costs   associated   with   recurrent   episodes   of   atrial 
fibrillation: the   FRACTAL   registry.   J   Cardiovasc   Electrophysiol 
2007;18(6):628-33. 
 
[Ref. 5.4: 434]          Thrall G, Lane D, Carroll D, Lip GYH. Quality of life in patients with 
atrial  fibrillation:  a  systemic  review.  Am  J  Med  2006;119(5):448.e1- 
448.e19. 
 
[Ref. 5.4: 435]            Volume 9A of the Rules Governing Medicinal Products in the European 
Union:  guidelines  on  pharmacovigilance  for  medicinal  products  for 
human use, Sep-2008. 
 
 [Ref. 5.4: 436] 
Guideline on good pharmacovigilance practices (GVP)-Module VIII, July 
2012, revision 1 April 2013. 
 
[Ref. 5.4: 437]       International Society for Pharmacoepidemiology.  Guidelines for good 
pharmacoepidemiology practices (GPP). 
 
[Ref. 5.4: 440]          World Medical Association Declaration of Helsinki: Ethical principles for 
medical research involving human subjects, 22-Oct-2008. 
 
[Ref. 5.4: 441] 
Cheng JWM. Vernakalant in the management of atrial fibrillation. Ann 
Pharmacother 2008;42(4):533-42. 
 
[Ref. 5.4: 442] 
Vidaillet HJ, Kavanagh KM, Kitt T, McNutt B, Yan B, Dickinson G, et al. 
Vernakalant hydrochloride injection for recent-onset atrial fibrillation: 
summary from two randomized, controlled trials and one open-label study 
[Abstract]. J Am Coll Cardiol 2008;51(10 Suppl A):A9. 
 
[Ref. 5.4: 443]          1994  revisions  to  classification  of  functional  capacity  and  objective 
assessment of patients with diseases of the heart, 1994. 
 
[Ref. 5.4: 445]          Roy D, Talajic M, Dubuc M, Thibault B, Guerra PG, Macle L, et al. Atrial 
fibrillation and congestive heart failure. Curr Opin Cardiol 2008;24:29- 
34. 

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CONFIDENTIAL AND PROPRIETARY 
 
A Prospective Observational Registry Study to Characterise Normal Conditions of Use, Dosing and 
Safety Following Administration of Vernakalant IV Sterile Concentrate 
 
Post-Authorisation Safety Study (PASS) Study  
Annex to Protocol for German Sites – 29 October 2015 
Purpose of the Annex 
To clarify selection of patients at German sites. 
 
 
Inclusion Criteria 
 
The inclusion criteria for enrolment are: 
 
1. Patients treated independently from this study with vernakalant IV in accordance with the 
SmPC, for rapid conversion of recent onset atrial fibrillation to sinus rhythm in adults:  
• For non-surgery patients: atrial fibrillation ≤ 7 days duration 
• For post-cardiac surgery patients: atrial fibrillation ≤ 3 days duration 
 
2. 
Subjects and/or legal guardians willing to provide informed consent and/or informed 
assent according to local regulations 
 
Exclusion Criteria 
 
The exclusion criteria for enrolment are: 
 
1. Patients with the following contraindications: 
• Hypersensitivity to the active substance or to any of the excipients.  
• Patients with severe aortic stenosis, patients with systolic blood pressure < 100 mm 
Hg, and patients with heart failure class NYHA III and NYHA IV. 
• Patients with prolonged QT at baseline (uncorrected > 440 msec), or severe 
bradycardia, sinus node dysfunction or second degree and third degree heart block in 
the absence of a pacemaker. 
• Use of intravenous rhythm control antiarrhythmics (class I and class III) within 4 hours 
prior to, as well as in the first 4 hours after, BRINAVESSTM administration. 
• Acute coronary syndrome (including myocardial infarction) within the last 30 days. 
 
2. 
Enrolment in an investigational drug or device clinical trial in the 30 days prior to study 
enrolment. Participation in another non-interventional drug or device study or registry is 
permitted. 
 
 
 

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CONFIDENTIAL AND PROPRIETARY 
 
A Prospective Observational Registry Study to Characterise Normal Conditions of Use, Dosing and 
Safety Following Administration of Vernakalant IV Sterile Concentrate 
 
Post-Authorisation Safety Study (PASS) Study  
Annex to Protocol for German Sites 
INVESTIGATOR SIGNATURE PAGE 
 
I have read and understand this Annex to the protocol dated 29 October 2015 and agree to conduct 
this clinical study in accordance with the provisions stated. 
 
 
 
 
 
 
Investigator Signature 
DATE 
 
 
 
 
Investigator Name 
 
 

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CONFIDENTIAL AND PROPRIETARY 
 
 
A Prospective Observational Registry Study to Characterise Normal Conditions of Use, Dosing and 
Safety Following Administration of Vernakalant IV Sterile Concentrate 
 
Post-Authorisation Safety Study (PASS) Study  
Annex to Protocol for German Sites – 29 October 2015 
SPONSOR SIGNATURE PAGE 
 
Reviewed and Approved by: 
 
 
 
 
 
Lucy Brindle  
Date 
Clinical Project Manager 
 
 
 
 
 
 
 
 
Dr Steen Juul-Moller 
Date 
Medical Director 
 
 

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CONFIDENTIAL AND PROPRIETARY 
 
A Prospective Observational Registry Study to Characterise Normal Conditions of Use, Dosing and 
Safety Following Administration of Vernakalant IV Sterile Concentrate 
 
Post-Authorisation Safety Study (PASS) Study  
Appendix I  
Calculation of Enrolment Rates Post Amendment 2 Approval 
The table below shows an estimate of enrolment per country to enroll 810 patients and reach the 2000 
patient recruitment target by Q4 2017. 
Country 
2015 average 
enrolment rate 
(pts/site/month) 
Number 
active 
sites 
Number pts to be enrolled 
Enrolment rate 
post protocol 
amendment 
(pts/site/month) 
Total 
number 
pts to 
be 
enrolled 
Prospectively  Retrospectively 
Austria 
1.1 
8 
110 
0 
1.1 
110 
Denmark 
1.1 
1 
15 
0 
1.1 
15 
Germany 
0.4 
8 
55 
0 
0.4 
55 
Spain 
0.6 
7 
60 
20 
0.8 
80 
Sweden 
0.8 
3 
35 
70 
2.0 
105 
Finland 
(enrolment 
to start Jan 
2017) 
- 
5 
100 
345 
10 
445 
Total 
0.64 
33 
375 
435 
3.4 
810 
 
 

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CONFIDENTIAL AND PROPRIETARY 
 
 
Market Uptake of Brinavess 
Vials sold per year since study started in 2011. 
  
No. vials 
sold 2011 
No. vials 
sold 2012 
No. vials 
sold 2013 
No. vials 
sold 2014 
No. vials 
sold 2015 
Austria 
 705 
 844 
537 
 919 
 1105 
Denmark 
 120 
 117 
 118 
 130 
 70 
Spain 
 60 
 326 
 139 
 360 
 529 
Sweden 
 311 
 568 
 435 
 752 
 896 
Germany 
 1773 
 1000 
 442 
 647 
 548 
Finland 
 655 
 813 
 336 
 761 
 1320 
 

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A Prospective Observational Registry Study to Characterise Normal Conditions of Use, Dosing and 
Safety Following Administration of Vernakalant IV Sterile Concentrate 
 
Post-Authorisation Safety Study (PASS) Study  
Appendix II 
Template letters that may be used to contact potential patients retrospectively 
Site details 
Patient address 
DATE 
Invitation to participate in an observational research study (called Spectrum) 
 
Dear _______________, 
 
We would like to invite you to participate in an observational research study. You are being invited because 
your atrial fibrillation was treated with Brinavess (Vernakalant) at our clinic. As your next scheduled visit at 
our clinic is on DD MMM YYYY, we would like to approach you by means of this letter. 
 
The purpose of the Spectrum study is to learn more about Brinavess (Vernakalant) and about how doctors 
use it to treat atrial fibrillation in the hospital. If you decide to take part, information from your medical chart 
will be collected. There will be no medications or other treatments as part of this study and there will be no 
extra visits or additional medical procedures. 
For more information, I have enclosed two (2) copies of a patient information sheet and informed consent 
form for your review. 
  
If you are interested in taking part, we will review and discuss the study and the consent form with you at 
your next clinic visit. We will also address any questions you may have about the study at this time. 
 
You do not have to take part in the study. You can say no without giving any reason. This will not affect 
your future care or your relationship with your doctor. 
 
If you have any questions or concerns about the study before your next clinic visit, please feel free to contact 
us at any time on <Phone no.>.  
 
Sincerely, 
<Name> <Title> 
 

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Site details 
 
Patient address 
 
DATE 
 
Invitation to participate in an observational research study (called Spectrum) 
 
 
Dear _______________, 
 
We would like to invite you to participate in an observational research study. You are being invited because 
your atrial fibrillation has been treated with Brinavess (Vernakalant) at our clinic. As your next scheduled visit 
is not due yet, we would like to approach you by means of this letter. 
 
The purpose of the Spectrum study is to to learn more about Brinavess (Vernakalant) and about how doctors 
use it to treat atrial fibrillation in the hospital. If you decide to take part, information from your medical chart 
will be collected. There will be no medications or other treatments as part of this study and there will be no 
extra visits or additional medical procedures. 
For more information, I have enclosed two (2) copies of the patient information sheet and informed consent 
form for your review. 
  
I will call you shortly to review and discuss the study and the consent form with you. We will also address all 
your questions during the call.  
 
You do not have to take part in the study. You can say no without giving any reason. This will not affect 
your future care or your relationship with your doctor. 
 
If you would like to take part, we will discuss during our call how to complete the consent forms.  
 
If you have any questions or concerns about the study, please feel free to contact us at any time on <phone>.  
 
Sincerely, 
 
<Name> 
<Title>