Clinical trial NCT01831856
Conditions: Atrial Fibrillation
Keywords: Cardiovascular diseases Chronic Heart Failure
Sponsor: Pierre Fabre Medicament
Start date: 2013-04-01; Completion date: 2017-06-21
Enrollment: 135 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the efficacy of F373280 on the maintenance of normal cardiac rhythm after direct electric cardioversion in patients with persistent atrial fibrillation and cardiac failure.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: 1g of F373280 intervention 2: Placebo
Intervention descriptions: intervention 1: Oral administration, one capsule each evening with dinner. intervention 2: Oral administration, one capsule each evening with dinner.

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY REPORT 
EFFICACY AND SAFETY STUDY OF F373280 FOR MAINTENANCE OF 
SINUS RHYTHM AFTER ELECTRICAL CARDIOVERSION IN PATIENTS 
WITH PERSISTENT ATRIAL FIBRILLATION AND CHRONIC HEART 
FAILURE 
16. APPENDICES
16.1. STUDY INFORMATION 
16.1.1. Protocol and protocol amendments
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Study F323280 CA 2 01 
16.1. STUDY INFORMATION 
 
16.1.1. Protocol and protocol amendments 
 
 
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16.1.1.1. Protocol and appendices (version 1: 09 November 2012) 
16.1.1.2. Protocol and appendices (version 2: 15 January 2013) 
16.1.1.3. Protocol amendment n° PA01 - local (Italy) and substantial - dated on 01 
March 2013 linked to Protocol and appendices (version3: 01 March 2013) 
16.1.1.4. Protocol amendment n°PA02 - General and non-substantial - dated on 28 
March 2013 linked to Protocol and appendices (version 4: 28 March 2013) 
16.1.1.5. Protocol amendment n°PA03 - General and substantial - dated on 23 October 
2013 linked to Protocol and appendices (version 5: 23 October 2013)  
16.1.1.6. Protocol and appendices (version 6: 02 December 2013)  
16.1.1.7. Protocol amendment n°PA04 - General and non-substantial - dated on 03 
June 2014 linked to Protocol and appendices (version 7: 03 June 2014) 
16.1.1.8 
Protocol amendment n°PA05 - General and substantial - dated on 22 October 
2014 linked to Protocol and appendices (version 8: 22 October 2014) 
16.1.1.9 
Protocol amendment n°PA06 - General and non-substantial - dated on 06 
June 2016  
16.1.1.10 Protocol amendment n°PA07 - General and substantial - dated on 28 
September 2016 linked to Protocol and appendices (version 9: 28 September 
2016) 
16.1.1.11 Protocol amendment n° PA07 - Local (Italy) and non-substantial - dated on 
06 December 2016 linked to Protocol and appendices (version 9: 06 
December 2016) 
 
 
 
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16.1.1.1. 
Protocol and appendices  
(version 1: 09 November 2012) 
 
 
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F 373280 CA 2 01 
 
 
 
 
 
 
 
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Pierre Fabre Médicament 
Represented by: Institut de Recherche Pierre Fabre 
45, Place Abel Gance 
F-92100 Boulogne 
 
CLINICAL STUDY PROTOCOL 
 
Efficacy and safety study of F373280 for maintenance of sinus rhythm after 
electrical cardioversion in patients with persistent Atrial Fibrillation and 
Chronic Heart Failure. 
International, multicentric, randomised, double-blind, placebo controlled study 
F373280 / Soft Capsules / 1g  
 
Pierre Fabre Study Code: 
EudraCT Number: 
 
Sponsor's Representative: 
 
 
 
 
 
 
 
 
 
Study Coordinating Investigator 
F 373280 CA 2 01  
2012 – 003487 - 48 
 
Marlène GUIRAUD, Pharm D  
INSTITUT DE RECHERCHE PIERRE FABRE - 
Centre de R&D Pierre Fabre - BP 13562  
3 avenue Hubert Curien  
31035 TOULOUSE Cédex 1 
Phone: +33 5 34 50 63 48  
Fax:+33 5 34 50 65 92  
E-mail:marlene.guiraud@pierre-fabre.com  
 
Pr Savina NODARI 
Section of Cardiology  
Department of Experimental and Applied Sciences 
University of Brescia 
BRESCIA, ITALY 
Phone: +39 030 3996 587 - Fax: +39 030 3700 359 
E-mail: savinanodari@gmail.com  
 
Version 1– 09 NOV 2012 
 
The information contained in this document is confidential and is the property of the Sponsor, Pierre Fabre 
Medicament. This information is given for the needs of the study and must not be disclosed without prior written 
consent of the Sponsor Pierre Fabre Medicament. Persons to whom this information is given for the needs of the 
study must be informed that it is confidential and must not be disclosed. 
 
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SPONSOR PERSONNEL 
PIERRE FABRE MEDICAMENT 
represented by 
Institut de Recherche Pierre Fabre 
 
Clinical Study Manager (Monitor) 
Marlène GUIRAUD, Pharm D 
Phone: +33 5 34 50 63 48 
Fax: + 33 5 34 50 65 92 
E-mail: marlene.guiraud@pierre-
fabre.com 
Institut de Recherche Pierre Fabre 
Centre de R&D Pierre Fabre 
BP 13 562 
3, Avenue Hubert Curien 
31035 TOULOUSE Cedex 1 
 
Head of Therapeutic Area 
Alain DELARUE, MD 
Phone: + 33 5 34 50 61 88 
Fax: +33 5 34 50 65 92 
E-mail: alain.delarue@pierre-
fabre.com 
Institut de Recherche Pierre Fabre 
Centre de R&D Pierre Fabre 
BP 13 562 
3, Avenue Hubert Curien 
31035 TOULOUSE Cedex 1 
 
Clinical Development Physician 
Richard ROCHE, MD 
Phone: +33 5 34 50 61 94 
Fax: +33 5 34 50 65 92 
E-mail: richard.roche@pierre-
fabre.com 
Institut de Recherche Pierre Fabre 
Centre de R&D Pierre Fabre 
BP 13 562 
3, Avenue Hubert Curien 
31035 TOULOUSE Cedex 1 
 
 
 
 
 
 
 
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CONTRACT RESEARCH ORGANISATIONS 
 
 
 
 
For Feasibility, Monitoring and Regulatory issues: 
Pharmaceutical Service Network (PSN) 
Rufino Gonzalez 
28 037 Madrid - SPAIN 
Phone: +34 91 375 6930 - Fax: +34 91 375 6931 
E-mail: www.psnglobal.org 
 
 
For Centralised Randomisation and Electronic Case Report Form 
S-Clinica 
6, Chaussée de Boondael 
B-1050 Brussels - BELGIUM 
Phone: +32 2 645 0567 - Fax: +32 2 645 0569 
E-mail: irena.seredina@s-clinica.com 
 
 
 
For Centralised Reading of Holder ECG and TTEM and equipment supply: 
Biomedical System 
1945 Chaussée de Wavre 
B-1160 Brussels - BELGIUM 
Phone: +32 2 661 20 70 - Fax: +32 2 661 20 71 
E-mail: sjacobs@biomedsys.com 
 
 
 
For intra erythrocyte DHA dosage 
Agrocampus Ouest 
Laboratoire de Biochimie 
65 rue de Saint Brieuc – CS 84215 
35042 RENNES Cedex - FRANCE 
Phone: +33 2 23 48 55 49 - Fax: +33 2 23 48 55 50 
E-mail: daniel.catheline@agrocampus-ouest.fr 
 
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Protocol F 373280 CA 2 01 
COUNTRY COORDINATING  INVESTIGATOR  
SIGNATURE FORM 
Protocol Version 1 – 09 NOV 2012 
 
 
Country: …………………….. 
 
Country Coordinating Investigator:  
"Name"  
Date:   
 
 
 
 
 
 
Signature:  
 
 
 
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Protocol F 373280 CA 2 01 
INVESTIGATOR SIGNATURE FORM 
Protocol Version1 – 09 NOV 2012 
 
 
 
By my signature below, I, Dr / Pr "                                         ", hereby confirm that I agree: 
♦ to conduct the trial described in the protocol F 373280 CA 2 01, dated 09 November 2012 in 
compliance with GCP, with applicable regulatory requirements and with the protocol 
agreed upon by the Sponsor Pierre Fabre Médicament and given approval / favourable* 
opinion by the Ethics Committee; 
♦ to document the delegation of significant study-related tasks and to notify the Sponsor of 
changes in site personnel involved in the study; 
♦ to comply with the procedure for data recording and reporting; 
♦ to allow monitoring, auditing and inspection; 
♦ to retain the trial-related essential documents until the Sponsor informs that these documents 
are no longer needed. 
Furthermore, I hereby confirm that I will have and will use the available adequate resources, 
personnel and facilities for conduct this trial. 
 
I have been informed that certain regulatory authorities require the Sponsor Pierre Fabre 
Médicament to obtain and supply details about the investigator’s ownership interest in the 
Sponsor or the study drug, and more generally about his/her financial relationships with the 
Sponsor. The Sponsor will use and disclose the information solely for the purpose of complying 
with regulatory requirements. 
Hence I agree: 
♦ to supply the Sponsor with any information regarding ownership interest and financial 
relationships with the Sponsor (including those of my spouse and dependent children); 
♦ to promptly update this information if any relevant changes occur during the course of the 
study and for 1 year following completion of the study; 
♦ that the Sponsor may disclose this information about such ownership interests and financial 
relationships to regulatory authorities. 
* To be adapted  
 
Date:  
Signature:  
 
 
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TABLE OF CONTENTS OF CLINICAL STUDY PROTOCOL 
 
1. 
INTRODUCTION AND STUDY RATIONALE ................................................................ 21 
1.1. 
TARGET PATHOLOGY AND THERAPY ........................................................................ 21 
1.2. 
INFORMATION ON THE TEST PRODUCT .................................................................... 23 
1.2.1. 
Chemical and pharmaceutical characteristics .................................................................... 24 
1.2.1.1. 
Nomenclature and structure ............................................................................................ 24 
1.2.1.2. 
Physical and chemical general properties ...................................................................... 24 
1.2.2. 
Non-clinical Data .............................................................................................................. 25 
1.2.2.1. 
Pharmacological profile ................................................................................................. 25 
1.2.2.2. 
Safety pharmacology ...................................................................................................... 26 
1.2.2.3. 
Toxicology profile .......................................................................................................... 26 
1.2.2.4. 
Pharmacokinetic data ..................................................................................................... 26 
1.2.3. 
Clinical data ....................................................................................................................... 26 
1.3. 
STUDY RATIONALE ......................................................................................................... 29 
1.4. 
OVERALL RISK AND BENEFIT ASSESSMENT ............................................................ 29 
2. 
STUDY OBJECTIVES ......................................................................................................... 32 
2.1. 
PRIMARY OBJECTIVE ..................................................................................................... 32 
2.2. 
SECONDARY OBJECTIVES ............................................................................................. 32 
3. 
ETHICAL CONSIDERATIONS RELATING TO THE STUDY .................................... 32 
4. 
STUDY DESIGN ................................................................................................................... 34 
4.1. 
OVERALL DESCRIPTION ................................................................................................ 34 
4.2. 
DISCUSSION OF THE STUDY DESIGN .......................................................................... 35 
4.2.1. 
Choice of the Study Population ......................................................................................... 35 
4.2.2. 
Choice of the Study Design ............................................................................................... 36 
4.2.3. 
Choice of the Dose ............................................................................................................ 37 
4.2.4. 
Choice of the Sample Size ................................................................................................. 38 
5. 
STUDY POPULATION ........................................................................................................ 38 
5.1. 
INCLUSION CRITERIA ..................................................................................................... 38 
5.2. 
NON INCLUSION CRITERIA ........................................................................................... 38 
5.3. 
NUMBER OF  PATIENTS .................................................................................................. 39 
5.4. 
RECRUITMENT MODALITIES ........................................................................................ 40 
5.5. 
PATIENTS IDENTIFICATION .......................................................................................... 40 
5.6. 
WITHDRAWAL CRITERIA ............................................................................................... 40 
5.7. 
REPLACEMENT OF PATIENTS ....................................................................................... 41 
5.8. 
POST-STUDY EXCLUSION PERIOD .............................................................................. 41 
5.9. 
STUDY CARD ..................................................................................................................... 41 
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6. 
STUDY TREATMENT ......................................................................................................... 42 
6.1. 
SOURCE, PRESENTATION AND COMPOSITION OF  INVESTIGATIONAL 
PRODUCT ........................................................................................................................... 42 
6.2. 
PACKAGING AND LABELLING ..................................................................................... 42 
6.2.1. 
Packaging .......................................................................................................................... 42 
6.2.2. 
Labelling ............................................................................................................................ 43 
6.3. 
DISTRIBUTION TO CENTRE AND STORAGE .............................................................. 44 
6.4. 
ALLOCATION OF TREATMENTS AND DISPENSATION TO PATIENT ................... 44 
6.5. 
DRUG ADMINISTRATION ............................................................................................... 46 
6.5.1. 
Duration of Treatment ....................................................................................................... 46 
6.5.2. 
Dose Schedule ................................................................................................................... 46 
6.5.3. 
Route and Conditions of Administration ........................................................................... 46 
6.6. 
ACCOUNTABILITY ON SITE AND RETURN/DESTRUCTION OF  
INVESTIGATIONAL PRODUCT ...................................................................................... 46 
6.7. 
RECALL OF INVESTIGATIONAL PRODUCTS ............................................................. 47 
7. 
CONCOMITANT TREATMENTS ..................................................................................... 47 
7.1. 
ANTI-VITAMIN K TREATMENT ..................................................................................... 48 
7.2. 
PROHIBITED TREATMENTS ........................................................................................... 48 
7.3. 
AUTHORISED TREATMENTS ......................................................................................... 48 
8. 
EVALUATION CRITERIA ................................................................................................. 49 
8.1. 
PRIMARY EFFICACY CRITERION: ................................................................................ 49 
8.1.1. 
Time to the first Atrial Fibrillation Recurrence ................................................................. 49 
8.1.1.1. 
Definition ........................................................................................................................ 49 
8.1.1.2. 
Schedule ......................................................................................................................... 49 
8.1.1.3. 
Evaluation Methods ........................................................................................................ 49 
8.1.2. 
Secondary Efficacy Criteria .............................................................................................. 50 
8.1.2.1. 
Numbers of Atrial Fibrillation episodes in the first week following visit 3   (ECV 
visit) ................................................................................................................................ 50 
8.1.2.2. 
Duration of Atrial Fibrillation episodes in the first week following visit 3   (ECV 
visit) ................................................................................................................................ 51 
8.1.2.3. 
Clinical parameters evaluation ....................................................................................... 51 
8.1.2.4. 
Cardioversion assessment ............................................................................................... 52 
8.1.2.5. 
Evolution of echocardiographic parameters ................................................................... 53 
8.2. 
BIOMARKER ASSESSMENT: RED BLOOD CELL   CONCENTRATIONS OF 
DHA ..................................................................................................................................... 53 
8.2.1. 
Definition ........................................................................................................................... 53 
8.2.2. 
Blood samples ................................................................................................................... 54 
8.2.2.1. 
Collection schedule ........................................................................................................ 54 
8.2.2.2. 
Technical handling ......................................................................................................... 54 
8.2.3. 
DHA concentration measurement ..................................................................................... 54 
8.3. 
SAFETY ASSESSMENT .................................................................................................... 55 
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8.3.1. 
Adverse Events .................................................................................................................. 55 
8.3.2. 
Laboratory Investigations .................................................................................................. 55 
8.3.2.1. 
Schedule ......................................................................................................................... 55 
8.3.2.2. 
Technical Procedures and Parameters ............................................................................ 55 
8.3.3. 
Global Physical Examination ............................................................................................ 56 
8.3.4. 
Vital Signs ......................................................................................................................... 56 
8.3.4.1. 
Schedule ......................................................................................................................... 56 
8.3.4.2. 
Technical Procedure and Parameters.............................................................................. 57 
8.3.5. 
Electrocardiogram (ECG) .................................................................................................. 57 
8.3.5.1. 
Schedule ......................................................................................................................... 57 
8.3.5.2. 
Technical Procedure and Parameters.............................................................................. 57 
8.3.6. 
Coagulation parameters ..................................................................................................... 57 
8.3.7. 
Concomitant Treatments ................................................................................................... 58 
8.4. 
COMPLIANCE .................................................................................................................... 58 
9. 
STUDY PROCEDURES ....................................................................................................... 59 
10. ADVERSE EVENTS: DEFINITION AND REPORTING ............................................... 65 
10.1. ADVERSE EVENTS ........................................................................................................... 65 
10.1.1. Definition of Adverse Events ............................................................................................ 65 
10.1.2. Grading of Adverse Events ............................................................................................... 65 
10.1.3. Reporting of Adverse Events ............................................................................................ 66 
10.2. SERIOUS ADVERSE EVENTS (SAE) .............................................................................. 66 
10.2.1. Definition ........................................................................................................................... 66 
10.2.2. Reporting of SAE .............................................................................................................. 67 
10.2.3. Follow-up of SAE ............................................................................................................. 67 
10.2.4. SAE Occurring After the Study ......................................................................................... 67 
10.3. REPORTING OF OVERDOSAGE TO THE SPONSOR ................................................... 68 
10.4. REPORTING OF PREGNANCY TO THE SPONSOR ...................................................... 68 
10.5. SPONSOR'S RESPONSIBILITIES FOR SAFETY REPORTING  PURPOSES ............... 69 
11. DATA COLLECTION AND STUDY MONITORING ..................................................... 69 
11.1. DATA COLLECTION ......................................................................................................... 69 
11.1.1. Case Report Form .............................................................................................................. 69 
11.1.2. Source Documents ............................................................................................................. 70 
11.2. STUDY MONITORING ...................................................................................................... 70 
11.2.1. Monitoring visits ............................................................................................................... 70 
11.2.1.1. Site Preselection Visit .................................................................................................... 70 
11.2.1.2. Initiation Visit ................................................................................................................. 71 
11.2.1.3. Follow-up Visits ............................................................................................................. 71 
11.2.1.4. Closing Visit ................................................................................................................... 71 
11.2.2. Direct Access to Source Documents ................................................................................. 72 
11.3. INDEPENDENT DATA MONITORING COMMITTEE ................................................... 72 
12. DATA MANAGEMENT ...................................................................................................... 72 
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12.1. DATA ENTRY ..................................................................................................................... 73 
12.2. DATA CLEANING ............................................................................................................. 73 
12.3. DATA CODING .................................................................................................................. 73 
12.4. DATA STORAGE ............................................................................................................... 73 
12.5. DATABASE LOCK ............................................................................................................. 74 
13. STATISTICAL ANALYSIS ................................................................................................. 74 
13.1. GENERAL CONSIDERATIONS ........................................................................................ 74 
13.2. SAMPLE SIZE ..................................................................................................................... 74 
13.3. PROTOCOL DEVIATIONS ................................................................................................ 75 
13.4. DATA SETS ANALYSED .................................................................................................. 75 
13.5. HANDLING OF DROPOUTS AND MISSING DATA ..................................................... 76 
13.5.1. Dropouts ............................................................................................................................ 76 
13.5.2. Repositioning of Visits ...................................................................................................... 76 
13.5.3. Missing Data ...................................................................................................................... 76 
13.6. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ............................... 76 
13.7. EFFICACY ANALYSIS ...................................................................................................... 77 
13.7.1. Primary Criterion ............................................................................................................... 77 
13.7.1.1. Primary Analysis ............................................................................................................ 77 
13.7.1.2. Supportive Analysis ....................................................................................................... 77 
13.7.2. Secondary Criteria ............................................................................................................. 77 
13.7.2.1. Numbers of Atrial Fibrillation Episodes ........................................................................ 77 
13.7.2.2. Duration of Atrial Fibrillation Episodes ......................................................................... 77 
13.7.2.3. Time to first AF recurrence less than 10 minutes or symtomatic .................................. 77 
13.7.2.4. Clinical parameters evaluation ....................................................................................... 78 
13.7.2.5. Biomarker analysis: red blood cell concentrations of DHA ........................................... 78 
13.8. SAFETY ANALYSIS .......................................................................................................... 78 
13.8.1. Adverse Events .................................................................................................................. 78 
13.8.2. Clinical Laboratory Evaluation ......................................................................................... 80 
13.8.3. Global Physical Examination ............................................................................................ 81 
13.8.4. Vital Signs, Physical Findings and Other Observations Related to Safety ....................... 82 
13.8.4.1. Vital Sign Measurements Over Time ............................................................................. 82 
13.8.4.2. Body weight ................................................................................................................... 82 
13.8.4.3. Individual Patient Changes ............................................................................................. 82 
13.8.5. ECG ................................................................................................................................... 82 
13.8.6. Coagulation parameters ..................................................................................................... 83 
13.9. CONCOMITANT TREATMENTS ..................................................................................... 83 
13.10. COMPLIANCE .................................................................................................................... 83 
13.11. INTERIM ANALYSIS AND DATA MONITORING ........................................................ 83 
14. GENERAL ETHICAL CONSIDERATIONS .................................................................... 84 
14.1. ETHICAL CONDITIONS ................................................................................................... 84 
14.2. ETHICS COMMITTEE AND LEGAL REQUIREMENTS ................................................ 84 
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14.3. PATIENT'S INFORMATION LEAFLET AND INFORMED CONSENT  FORM ........... 84 
14.4. PERSONAL DATA PROTECTION ................................................................................... 85 
14.5. INSURANCE POLICY ........................................................................................................ 85 
15. ADMINISTRATIVE PROCEDURES ................................................................................ 86 
15.1. PROTOCOL AMENDMENT .............................................................................................. 86 
15.2. SOURCE DOCUMENTS, INVESTIGATOR'S FILE STORAGE ..................................... 86 
15.3. END OF THE STUDY ......................................................................................................... 87 
15.3.1. Definition of the End of Study .......................................................................................... 87 
15.3.2. Early Study Termination ................................................................................................... 87 
15.3.2.1. Early Study Termination Decided by the Sponsor ......................................................... 87 
15.3.2.2. Early Study Termination Decided by the Competent Authorities.................................. 87 
15.4. AUDIT .................................................................................................................................. 88 
15.5. INSPECTION ....................................................................................................................... 88 
15.6. CONFIDENTIALITY .......................................................................................................... 88 
15.7. CLINICAL STUDY REPORT ............................................................................................. 88 
15.8. STUDY RESULTS COMMUNICATION .......................................................................... 89 
15.9. STUDY RESULTS PUBLICATION ................................................................................... 89 
16. REFERENCES ...................................................................................................................... 91 
17. APPENDICES ....................................................................................................................... 94 
17.1. DECLARATION OF HELSINKI ........................................................................................ 95 
17.2. SAE REPORT FORM .......................................................................................................... 99 
17.3. PREDEFINED LIMITS OF LABORATORY AND VITAL SIGN POTENTIALLY 
CLINICALLY SIGNIFICANT CHANGES AND VALUES ............................................ 102 
 
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SYNOPSIS 
 
Name of Sponsor: 
Pierre Fabre Médicament represented by the Institut de Recherche Pierre Fabre (IRPF) 
Name of Finished Product: 
Not applicable 
Name of Active Substance:  
F373280 (Panthenyl-Ester of DHA) 
Title of the Study: 
Efficacy and safety study of F373280 for maintenance of sinus rhythm after electrical 
cardioversion in patients with persistent Atrial Fibrillation and Chronic Heart Failure. 
 
Abbreviated Title: 
Not applicable 
Study Coordinating Investigator: 
Pr Savina NODARI 
 
Study Centres: 
International, multicentric 
Publication / Rationale: 
F373280 is a new therapy based on DHA delivery (pro-drug) developed for the maintenance 
of sinus rhythm after electrical cardioversion in persistent atrial fibrillation (AF) patients with 
chronic heart failure. 
The results of a pharmacological study performed in animals evidenced that DHA reduces the 
duration of Atrial Fibrillation (AF) induced by burst pacing.[1] 
Moreover, the effectiveness of PUFA (PolyUnsaturated Fatty Acid) has been proven in the 
following conditions: 
− 
prevention of Atrial Fibrillation recurrence in patients with persistent Atrial 
Fibrillation, in co-administration with amiodarone (add on therapy) [2]  
− 
Improvement of ventricular functional parameters, morbi-mortality and duration 
of hospitalisation in patients with heart failure [3, 4, 5] 
Taking into account these studies, it seems that DHA might be of therapeutic interest in the 
treatment of patients with both persistent atrial fibrillation and chronic heart failure. 
This phase IIa study is designed to assess the efficacy and the safety of the investigational 
product (F373280) for maintenance of sinus rhythm after electrical cardioversion (ECV) in 
patients with persistent atrial fibrillation and chronic heart failure. 
Planned Study Period: 
January 2013 –  April 2014 
Clinical Phase: IIa 
 
Objectives: 
Primary: 
- Efficacy of F373280 on the maintenance of sinus rhythm after direct electrical 
cardioversion in patients with persistent atrial fibrillation and chronic heart failure 
Secondary: 
- Efficacy of F373280 on the efficiency of direct electrical  cardioversion 
- Effect of F373280 on echocardiographic parameters 
- Safety and tolerability of F373280 
Methodology: 
- International, multicentre, randomised, double-blind, placebo-controlled 
- Selection period 
- Start of treatment 4 weeks before ECV 
• 
Condition to ECV:  
− 
INR 2-3 (anti-vitamin K should be given at least 3 weeks before ECV) 
− 
No spontaneous cardioversion before ECV 
- Follow-up 20 weeks after visit 3  (ECV visit) 
• 
Condition: successful ECV or spontaneous CV 
- Cardiac monitoring: 
• 
7-days continuous ECG ambulatory recording (Holter ECG)  between visit 3 (ECV 
visit) and visit 4  (week 5) in patients with sinusal rhythm 
• 
TTEM: daily transmission from week 6 to week 8; then every two days from week 
9 to week 24, and in case of AF symptoms 
- Treatment duration: 24 weeks 
Study Schedule 
9 visits will be scheduled: 
- V1/ W-4 to W-1: selection visit (7 to 28 days before the inclusion visit)  
- V2/ D1: Inclusion visit (start of treatment) 
- V3/ W4 (D28 -2/+7 days): cardioversion visit (Outpatient or hospitalization according to 
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clinical practice of the centre) (installation of the Holter device) 
- V4/ W5 (D35± 2 days): follow-up visit (removing of the Holter device and installation of 
the TTEM) 
- V5/ W8 (D56± 7 days): follow-up visit 
- V6/ W12 (D84 ± 7 days): follow-up visit 
- V7/ W16 (D112 ± 7 days): follow-up visit 
- V8/ W20 (D140 ± 7 days): follow-up visit 
- V9/ W24 (D168 ± 7 days): final study visit 
 
Number of  Patients: 
76 x 2 patients  
Diagnosis and Criteria for Inclusion: 
Inclusion Criteria: 
Demographic Characteristics and Other Baseline Characteristics: 
1. 
Men or women aged more than 18 years (inclusive), 
2. 
Patients with persistent AF between 7 days and 6 months duration for whom electrical 
cardioversion is warranted. 
3. 
History of first documented persistent AF less than 1 year 
4. 
History of ischemic or non ischemic heart failure  
5. 
NYHA class I or II chronic heart failure at selection and at inclusion 
6. 
Reduced left ventricular ejection fraction between 30% and 45% inclusive (using the 
two-dimensional echocardiography biplane Simpson’s rule) ) at selection and at 
inclusion 
7. 
On appropriate, stable medical treatments for heart failure, including a diuretic and/or 
angiotensin-converting enzyme, and/or angiotensin-receptor blocker and/or 
mineralocorticoid receptor (MR) antagonists, and/or betablockers 
8. 
Left atrial area ≤ 40 cm² ) at selection and at inclusion 
9. 
Patients treated or having to be treated by anti-vitamin K 
10. For female patient of child-bearing potential:  
- 
use of an effective method of contraception (hormonal contraception or intra-
uterine device) assessed by the investigator, for at least 2 months before the 
selection in the study, and agreement to go on using it during the whole duration of 
the study and up to 1 month after the last dose of the study treatment 
- 
documented as surgically sterilized 
11. For female patient of child-bearing potential: negative urine pregnancy test at inclusion 
Ethical /legal considerations: 
12. Having signed his/her written informed consent, 
13. Affiliated to a social security system, or is beneficiary (if applicable in the national 
regulation) 
 
Non-Inclusion Criteria: 
Criteria related to pathologies: 
1. 
History of first documented episode of persistent AF more than 1 year 
2. 
More than two successful cardioversions (electrical or pharmacological) in the last 6 
months 
3. 
Secondary Atrial Fibrillation due to alcohol or severe valvular heart disease (grade III to 
IV) 
4. 
NYHA class III or IV heart failure at selection or at inclusion 
5. 
Thyroid disease uncontrolled by treatment: TSH ± T4L ± T3L to be checked in case of 
treatment for thyroid disease 
6. 
Myocardial infarction or unstable angina or presence of unstable ischemic 
coronaropathy assessed by coronarography or cardiac stress test (Echo stress, exercice 
stress test, nuclear or MR perfusion evaluation methods) within 6 months before 
selection 
7. 
Severe chronic kidney disease (creatinine 25 mg/L or estimated glomerular filtration rate 
< 30 mL/min) at selection 
8. 
Bradycardia (HR ≤ 50 bpm) 
9. 
Hyperkalemia or hypokalemia (K>5.5 mEq/L or K < 3.5 mEq/L) at selection  
10. Cardiac surgery within 3 months before selection or planned during the study duration 
 
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Criteria related to treatments: 
11. Previously ineffective pharmacological or electrical cardioversion 
12. Concomitant treatment with any anti-arrhythmic drug (within 7 days prior to selection), 
except stable dose of digoxin, betablockers, calcium-blockers 
13. Previous treatment with oral amiodarone within 12 months prior to inclusion 
14. Previous treatment with intravenous amiodarone within 6 months prior to inclusion 
15. Patient requiring a cardiac resynchronization therapy (CRT) or having undergone CRT 
implantation within the last 6 months  
16. Treatment with any Polyunsaturated Fatty Acid (PUFA) within the last 3 months 
17. Dietary supplement with ω3 or ω6 according to investigator’s judgement 
18. Having undergone any form of ablation therapy for AF 
19. Patient treated with other anticoagulant treatment than antivitamin K: thrombin inhibitor 
such as Dabigatran or treated with antiaggregant P2Y12 inhibitors such as Clopidogrel 
or Prasugrel 
 
Other criteria: 
20. Patient liable not to comply with protocol instructions and/or with treatment, in the 
investigator’s opinion 
21. Patient having taken part in a clinical trial in the preceding 2 months or taking part in a 
trial at the time of selection 
22. Patient linguistically or mentally unable to understand the nature, objectives and 
possible consequences of the trial, or refusing to patient himself/herself to its constraints 
23. Patient family member or work associate (secretary, nurse, technician,..) of the 
Investigator 
24. Patient having forfeited his / her freedom by administrative or legal award or being 
under guardianship 
Exclusion criteria before V3: 
Patients not stabilized for INR (i.e. values between 2 and 3) on at least 3 consecutive weekly 
tests performed before ECV will be excluded from the study, unless the presence of atrial 
thrombosis may be excluded with ECHO –TE (trans-esophageal echocardiograph) performed  
in the same day (before ECV) 
ECV will be performed in patients without dyskalemia 
If necessary for obtaining stabilized INR between 2 and 3, the ECV (and following visits) 
could be postponed by 7 days. 
Test Product:  
F373280  
Soft Capsules  
Dose: 
Arm with 1g of F373280 
Mode of Administration: 
Oral, one capsule each evening with dinner. 
Duration of Treatment: 
24 weeks of treatment exposure with F373280 (25 weeks if ECV postponed by 1 week) 
Reference Therapy 
Placebo soft capsules 
Placebo will be administered in the same conditions as the tested product. 
Mode of Administration: 
Oral, one capsule each evening with dinner 
Evaluation Criteria: 
Efficacy evaluation variables: 
 
Primary evaluation variable: 
- Time to first Atrial Fibrillation recurrence defined by the first episode of Atrial Fibrillation 
lasting for at least 10 minutes (Follow up of 20 weeks after  visit 3 (ECV visit) 
Handling of AF recurrences: 7-day continuous ECG (5-leads/2 or 3 channels) ambulatory 
recording (holter ECG) between visit 3 (ECV visit) and visit 4 (week 5). Then, the follow 
up will be documented using the TTEM: daily transmission from week 6 to week 8. Then, 
every two days from week 9 to week 24. 
For randomised patients with spontaneous cardioversion before ECV, the recurrence of AF 
will be assessed after visit 3 (week 5).  
Moreover, during this TTEM period, if patient experiences any AF symptoms, it should be 
recorded and documented using the TTEM.  
All ECG traces will be evaluated by a Central Reading Laboratory. 
 
Secondary evaluation variables: 
During the 7-day continuous ECG monitoring, 
• 
Numbers of AF episodes 
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• 
Duration of AF episodes 
 
Clinical parameters: 
During the whole study: 
• 
Number of recurrence of symptomatic AF episodes 
• 
EHRA score 
• 
Hospitalization for cardiovascular events 
• 
Hospitalization for thromboembolic stroke 
• 
All cause of hospitalization 
 
Cardioversion: 
• 
Assessment of spontaneous cardioversion 
• 
Assessment of successful cardioversion 
• 
Number of patients needing an other cardioversion after the initial ECV 
 
Other: 
• 
Evolution of echocardiographic parameters (from V4 to V6 and V9) (Left atrial 
diameter (mm), Left atrial area (cm²), Left atrial volume (mL), Left atrial 
volume/BSA (mL/m2), Left ventricular ejection fraction (%),Left ventricular 
volume (mL), Left ventricular volume/BSA(mL/m2, Left ventricular end diastolic 
diameter (mm), Left ventricular end diastolic volume (mL) Left ventricular end 
systolic diameter (mm), Left ventricular end systolic volume (mL)) 
• 
Evolution of omega 3 index and intra erythrocyte DHA (For this assessment 
samples will be centralized). 
 
Safety criteria: 
- Adverse events (observed and / or spontaneously reported) 
- Vital signs (Blood pressure (supine and standing), heart rate 
-  Physical examination (body weight),  
- Standard 12-lead ECG: heart rate (bpm), PR (ms), QRS (ms), QT (ms), repolarisation 
patterns (ECG not centralized). 
- Haematology: haematocrit, haemoglobin, RBC, WBC, differential count, platelets 
- Biochemistry: sodium, potassium, bicarbonate, chloride, alkaline phosphatase, gamma 
GT, albumin, total bilirubin, conjugated bilirubin, creatinin, aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), fasting glucose, total cholesterol, cholesterol 
(HDL, LDL), triglycerides, creatin phosphokinase (CPK) fibrinogen (local laboratory) 
- Coagulation parameters: Activated partial thromboplastin time (aPTT), thrombin clotting 
time (TCT), INR (local laboratory), Prothrombine Time (PT) 
Statistical Methods: 
Sample Size: 
Assuming an AF recurrence rate under placebo of 85%, a power of 80%, an alpha risk of 5% 
and a rate of not assessable patients of 15%, 76 randomised patients per group will be 
necessary to achieve, using a log-rank test of survival curves, a difference between groups of 
20%.  
Primary Efficacy Analysis 
The primary analysis, performed on the Full Analysis Set (FAS: all randomised patients with 
at least one dose of treatment and with a successful cardioversion observed at visit 3), will be 
a survival analysis using the Kaplan Meier method and Cox regression model. 
Secondary Analyses  
All secondary efficacy criteria will be described and compared using appropriate tests on the 
FAS. 
Safety Analyses 
Descriptive statistics will be performed on the Safety Set (all randomised patients with at 
least one dose of treatment)  
 
 
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STUDY FLOW-CHART 
 
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F373280 CA 201
V1
V2
V3
V4
V5
V6
V7
V8
V9
Weeks
W-4 to W-1
D1
W4
 (28 -2D/+7 D) 
W5
 (35 +/-2 D)
W8 
(56+/-7D)
W12 
(84+/-7D)
W16 
(116+/-7D)
W20 
(140+/-7D) 
W24 
(168+/-7D)
Outpatient or Hospitalization (1)
X
Informed consent
X
Demographic characteristics
X
Medico-surgical history
X
Concomitant disease
X
Concomitant treatment
X
X
X
X
X
X
X
X
X
Habits
X
Global physical examination (body weight)
X
X
X
X
X
X
X
X
Echocardiography
X
X
X
X
X
Eligibility criteria check
X
X
Blood pressure, heart rate 
X
X
X
X
X
X
X
X
X
12-Lead  ECG Recording
X
X
X
X
X
X
X
X
INR 
 
 
 (2)
X
X
X
X
X
aPTT, TCT 
X
X
X
X
X
X
X
X
Biochemistry
X
X
Hematology
X
X
Urinary pregnancy test
X
X
Red Blood Cell concentrations of DHA 
X
X
X
X
Treatment allocation
X
X
IVRS
X
X
X
X
ECV (3)
X
Drug administration 
 
 
 
 
 
 
 
 
Adverse events recording
X
X
X
X
X
X
X
X
Holter ECG 
 (4)
 
 (5)
TTEM (6)
 
 
 
 
(3) In patients with AF
(1) Outpatient or hospitalization according to clinical practice of the centre (less or more than 24 hours)
(6) TTEM everyday from week 6 to week 8. Then every 2 days from week 9 to week 24. In case of AF symptoms. In case of AF recurrence for at least 10 minutes and the patient does not 
stop  the study treatment then TTEM every 4 weeks
(2) In case of AVK introduction: INR 2 to 3 times a week, then weekly untill the ECV, then every 4 weeks after ECV.
(5) 7-day Holter ECG
(4) 24-hour Holter ECG
 
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LIST OF ABBREVIATIONS 
 
 
aPTT 
Activated partial thromboplastin time 
AE 
: 
Adverse event 
AERP 
Atrial effective refractory period 
AF 
: 
Atrial fibrillation 
ALA 
Alpha-linoleic acid 
ALT 
: 
Alanine aminotransferase 
AST 
: 
Aspartate aminotransferase 
AUC 
: 
Area under the plasma concentration versus time curve 
AUCinf 
: 
Total area under the curve extrapolated to infinity 
AVK 
Anti vitamin K 
βHCG 
: 
beta human chorionic gonadotrophin 
BLQ 
: 
Below the limit of quantification 
BMI 
: 
Body mass index 
BP 
Blood pressure 
BSA 
: 
Body Surface Area 
CEP 
Protocol evaluation committee 
CHF 
: 
Congestive heart failure 
CHMP 
: 
Committee for medicinal products for human use 
Cmax 
: 
Maximum concentration 
Cmin 
Minimum concentration 
CNALV 
: 
Clinically noteworthy abnormal laboratory value 
CPK 
Creatin phosphokinase 
CPP 
: 
Comité de protection des personnes  
CRA 
: 
Clinical research associate 
CRT 
Cardiac resynchronization therapy 
CSC 
: 
“Clinically Significant Change”, i.e., Predefined potentially clinically 
significant change leading to a potentially clinically significant value (vital 
signs) 
CV 
: 
Coefficient of variation 
DBP 
: 
Diastolic blood pressure 
DHA 
: 
Docosahexaenoic acid 
EC 
: 
Ethics committee 
ECG 
: 
Electrocardiogram 
ECHO –TE 
Trans-esophageal echocardiograph 
ECV 
: 
Electrical cardioversion 
EHRA 
European heart rhythm association 
EPA 
Eicosapentaenoic acid 
eCRF 
Electronic case report form 
FAS 
: 
Full analysis set 
Fe 
: 
Fraction of the administered drug excreted in urine 
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GCP 
: 
Good clinical practice 
GFR 
:  Glomerular Filtration Rate 
HBs 
: 
Hepatitis B antigen 
HCV 
: 
Hepatitis C virus 
HDL 
High density lipoprotein 
HF 
Heart failure 
HIV 
: 
Human immunodeficiency virus 
HR 
: 
Heart rate 
ICH 
: 
International conference on harmonisation of technical requirements for 
registration of pharmaceuticals for human use 
IDMC 
: 
Independent data monitoring committee 
INR 
International normalized ratio 
IRPF 
: 
Institut de Recherche Pierre Fabre 
IVRS 
Interactive voice response system 
LAA 
Left atrial area 
LC/MS-MS : 
Liquid chromatography with tandem mass spectrometry 
LDL 
Low density lipoprotein 
LOQ 
: 
Limit of quantification 
LVEF 
Left ventricular ejection fraction 
MedDRA 
: 
Medical dictionary for regulatory activities 
MR 
Mineralocorticoid receptor 
MR perfusion 
Magnetic Resonance perfusion 
MTD 
: 
Maximum tolerated dose 
N 
: 
Number of determinations or replicates 
NOAEL 
: 
No observed adverse effect level 
NYHA 
New York heart association 
od 
: 
Once a day 
PC 
: 
“Predefined Change”, i.e., Predefined potentially clinically significant change 
(lab or vital signs) 
PCA 
: 
PC leading to an out-of-range value (lab values) 
PFB 
: 
Pierre Fabre Biométrie 
POC 
Proof of concept 
PUFA 
: 
PolyUnsaturated fatty acid 
PK 
: 
Pharmacokinetics 
p.o. 
: 
Per os 
PP 
: 
Per protocol data set 
RBC 
: 
Red blood cells 
SAE 
: 
Serious adverse event 
SBP 
: 
Systolic blood pressure 
SD 
: 
Standard deviation 
T1/2 
: 
Terminal half-life 
T0 
: 
Time of drug administration 
Tmax 
: 
Time to reach the maximal concentration 
TCT 
Thrombin clotting time 
TEAEs 
Treatment emergent adverse events 
TTEM 
TransTelephonic ECG monitoring 
VTP 
: 
Ventricular tachypacing 
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WBC 
White blood cells 
WHO-DRUG : 
World health organization drug reference list 
 
1. INTRODUCTION AND STUDY RATIONALE 
1.1. 
TARGET PATHOLOGY AND THERAPY 
Atrial Fibrillation (AF) is a supraventricular arrhythmia characterized by uncoordinated atrial 
electric activity with consequent deterioration of atrial mechanical function. It is the most 
common sustained cardiac rhythm disorder, increasing in prevalence with age. Haemodynamic 
impairment and thromboembolic events related to AF result in significant morbidity and mortality 
[7]. 
In 2009, Decision Resources estimated that there were 7.8 million diagnosed prevalent cases of 
atrial fibrillation (AF) in US, Europe and Japan. This age-related pathology should increase to 9.4 
million cases in 2019.  
Except for the conventional class I and class III anti-arrhythmic agents, the PUFAs 
(Polyunsaturated Fatty Acids) constitute one emerging antiarrhythmic therapy. These compounds 
potently address the AF substrate by directly targeting both the electrical and the structural 
remodelling of the deficient atria. The n-3 PUFAs, essential for human, are ALA, EPA and DHA. 
First, PUFAs specifically modulate ionic channels by fastening their inactivating mode which 
renders these compounds selective for pathological situations (such as AF) without any major 
effect in normal conditions. PUFAs are “open Kv1.5 channel blockers” leading to a lengthening of 
atrial action potential duration and are “persistent Nav1.5 channel blockers” leading to 
hyperpolarization of diastolic resting potential. Second, PUFAs influence structural remodelling 
through their anti-inflammatory effects as they directly compete with arachidonic acid in the 
production of inflammatory eicosanoids. In summary, PUFAs share unique, well-tolerated 
antiarrhythmic potential by interacting with the electrical and structural remodelling during 
sustained AF. In animal studies, it was recently demonstrated that DHA is particularly effective in 
pathologic conditions such as ischemia and/or atrial fibrillation. 
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The potential anti-arrythmic effects of a PUFA was previously developed in atrial fibrillation: 
nicotinyl ester of DHA (pro-drug based on DHA delivery) were assessed in a two-week 
ventricular tachypaced canine model. Dogs were subjected to 4 weeks of medication prior to 
undergoing an electrophysiology study, and received either placebo or nicotinyl ester of DHA. 
Dogs were tachypaced at 240 beats per min for the final two weeks of the treatment plan. The 
results showed that the tested PUFA reduced the duration of atrial fibrillation (AF) induced by 
burst pacing, and the incidence of sustained AF, compared to dogs treated with the placebo [1]. 
In clinical practice, Nodari and coll assessed n-3 Polyunsaturated Fatty Acids in the prevention of 
atrial fibrillation recurrences after electrical cardioversion. All included patients were treated with 
amiodarone and a renin-angiotensin-aldosterone system inhibitor. The 199 patients were assigned 
either to placebo or n-3 PUFAs 2 g/d and then underwent direct electrical cardioversion (ECV) 4 
weeks later. The primary end point was the maintenance of sinus rhythm at 1 year after 
cardioversion. At the 1-year follow up, the maintenance of sinus rhythm was significantly higher 
in the n-3 PUFAs treated patients compared with the placebo group (hazard ratio, 0.62 [95% 
confidence interval, 0.52 to 0.72] and 0.36 [95% confidence interval, 0.26 to 0.46], respectively; p 
= 0.0001). The study concludes that in patients with persistent atrial fibrillation on amiodarone 
and a renin-angiotensin-aldosterone system inhibitor, the addition of n-3 PUFAs 2 g/d improves 
the probability of the maintenance of sinus rhythm after direct current cardioversion [2]. 
Previously, during the World Congress of Cardiology in 2006, an abstract reported the 
effectiveness of PUFA on top of traditional treatment (amiodarone, beta blockers, renin-
angiotensin-aldosterone system inhibitor) in the prevention of AF relapses in patients having 
undergone ECV. In the PUFA group, AF relapses were significantly lower than placebo group at 
one month (3.3% vs 10%; p=0.043), at 3 months (10% vs 25%; p=0.004) and at 6 months (13.3% 
vs 40%; p<0.0001) [19]. 
In contrast, in the general AF population (paroxystic atrial fibrillation and persistent atrial 
fibrillation), PUFAs failed to prove their efficacy [7] because of the absence of cardiac 
remodelling or because of a short pre-treatment duration before ECV (1 week) [8].The effect of 
PUFAs were only observed in patients with persistent AF on add on therapy and after a sufficient 
pre-treatment before ECV. Persistent AF is commonly associated to heart failure. Previous studies 
performed in heart failure population demonstrated the benefit of PUFAs on the improvement of 
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functional ventricular parameters and morbi-mortality, and on the reduction of hospitalisation [3, 
4, 5]. 
Nodari and coll [3] performed a trial in patients with a chronic heart failure (NYHA I to III and 
LVEF< 45%). After a treatment of 133 patients with PUFAs (n=67) or placebo (n=66) at a dosage 
of 5 g/day for 1 month, then 2 g/day for 11 months, the n-3 PUFAs group and the placebo group 
differed significantly (p <0.001) in regard to:  
− LVEF (increased by 10.4% and decreased by 5.0%, respectively) 
− peak VO2 (increased by 6.2% and decreased by 4.5%, respectively) 
− exercise duration (increased by 7.5% and decreased by 4.8%, respectively) 
− mean New York Heart Association functional class (decreased from 1.88+/- 0.33 to 1.61 
+/- 0.49 and increased from 1.83+/- 0.38 to 2.14 +/- 0.65, respectively).  
The hospitalization rates for HF were 6% in the n-3 PUFAs and 30% in the placebo group  
(p <0.0002). 
Moertl and coll [4] performed a dose-ranging study in patients with a more severe chronic heart 
failure (NYHA III and IV and LVEF < 35%). It was a double-blind, randomised, controlled pilot 
trial in 43 patients treated with PUFAs or placebo for 3 months (1 g/d n3-PUFA (n = 14), 4 g/d 
n3-PUFA (n = 13), or placebo (n = 16)). After treatment, left ventricular ejection fraction 
increased in a dose-dependent manner (P = 0.01 for linear trend) in the 4 g/d (baseline vs 3 
months [mean ± SD]: 24% ± 7% vs 29% ± 8%, p = 0.005) and 1 g/d treatment groups (24% ± 8% 
vs 27% ± 8%, P = 0.02). 
No changes in any investigated parameters were noted with placebo. 
Taking into account these studies performed with PUFAs, it seems that the best target for DHA is 
persistent AF in patients with heart failure. The aim of this proof of concept study is to assess in 
stand alone therapy (without association of other anti-arrhythmic treatments), the effect of 
F373280 in patients with persistent atrial fibrillation and heart failure in the maintenance of sinus 
rhythm after electrical cardioversion. 
1.2. 
INFORMATION ON THE TEST PRODUCT 
F373280 or panthenyl ester of DHA (docosahexaenoic acid) is the mono-ester of panthotenic 
alcohol and DHA, selected to be developed for the management of atrial fibrillation.  
F373280 is a prodrug of DHA. 
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A brief summary of F373280 known characteristics is presented in this section. For further details, 
please refer to the F373280 Investigator’s Brochure. [1] 
1.2.1. 
Chemical and pharmaceutical characteristics 
1.2.1.1. 
Nomenclature and structure 
Chemical name (IUPAC):  
(4Z,7Z,10Z,13Z,16Z,19Z)-3-((R)-2,4-dihydroxy-3,3-diméthylbutanamido) 
propyl 
docosa-
4,7,10,13,16,19-hexaenoate 
Structural formula: 
O
O
O
O
NNHH
O
O
OHH
O
OHH
 
Laboratory code: F373280 
Molecular formula: C31H49NO5 
Molecular mass: 515.7 
1.2.1.2. 
Physical and chemical general properties 
Appearance: Clear oily viscous liquid 
Solubilities:  
− Water: Practically insoluble 
− Alcohol: Very soluble  
− Trimethylpentane: Slightly soluble  
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1.2.2. 
Non-clinical Data 
Non-clinical data are exhaustively detailed in the Investigator’s brochure [1]. A brief summary is 
provided below. 
1.2.2.1. 
Pharmacological profile 
F373280 (mono-ester of panthotenic alcohol and DHA) is a novel pro-drug of DHA which exerts 
antiarrhythmic properties by interacting with the electrical and structural remodelling of the atria.  
Experimental investigations were conducted in HEK293 cell line transfected with human Kv1.5 
channel using the whole cell patch clamp technique to evaluate whether F373280 could block the 
sustained component of IKv1.5. F373280 concentration-dependently reduced Kv1.5 channel activity 
with an IC50 value of 13.7 µM. 
The effects of F373280 on atrial effective refractory period (AERP) were investigated in 
anesthetized pig using a conventional pacing protocol through epicardial electrodes placed on the 
left atrium. F373280 administered as a bolus and an infusion (10 mg/kg) significantly increased 
AERP (23.8 ± 2.2 ms versus -7.3 ± 11.5 ms in the presence of vehicle, P<0.05). In addition, 
F373280 was devoid of significant effect on the hemodynamic and the ECG intervals.  
Proof of the pharmacological concept was performed with a different DHA derivative named: 
Nicotinyl ester of DHA (pro-drug based on DHA delivery). Ventricular tachypacing (VTP)-
induced congestive heart failure (CHF) provides a clinically-relevant animal model of AF 
associated with structural remodelling, as is often seen clinically. It has been shown that sustained 
oral PUFA administration suppresses CHF-induced AF-promotion and fibrosis in the VTP canine 
model. Nicotinyl ester of DHA was tested in this model, at 1g/day and 5g/day, during 4 weeks, to 
prevent CHF-related atrial structural remodelling and AF promotion in dogs. Nicotinyl ester of 
DHA dose dependently reduced heart failure-induced increases in atrial fibrillation duration (989 
± 111 sec, n=5 in the presence of placebo versus 637 ± 196 sec, n=5 in the presence of 1g/kg/d 
Nicotinyl ester of DHA and 79 ± 51 sec, n=5, in the presence of 5g/kg/d Nicotinyl ester of DHA 
The protective effect of Nicotinyl ester of DHA was associated with a marked increase of plasma 
level of DHA and important incorporation of DHA in the left atrial tissue. Because F373280 
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similarly to Nicotinyl ester of DHA increases plasma level of DHA, it could be estimated that the 
compound may exert a similar protective effect [1]. 
1.2.2.2. 
Safety pharmacology 
A battery of safety pharmacology studies was performed to evaluate the effects of F373280 on the 
central nervous, cardiovascular and respiratory systems. Data of these studies are exhaustively 
detailed in the Investigator’s brochure [1]. 
No particular alerts were evidenced with F373280. 
1.2.2.3. 
Toxicology profile 
 
Concerning the toxicological data, 4-week and 26-week repeat-dose studies in rat and dog were 
performed. Compared to the high administered doses of F373280 (500 to 2000 gm/kg/day), low 
circulating concentrations of F373280 were measured.  
During these toxicity studies , no toxicity was observed in rat after 4 and 26 weeks of dosing and 
in dog after 4 weeks of dosing. A NOAEL of 2000 mg/kg/day was established in these repeat 
toxicity studies.  
During the 26-week toxicity study in dogs, the NOAEL was set at 1000 mg/kg/day based on 
changes observed on red blood cell parameters. 
Based on toxicological profiles, F373280 is considered to support the proposed clinical trial. 
 
1.2.2.4. 
Pharmacokinetic data  
According to animal studies described in the Investigator’s brochure [1], the non-clinical 
pharmacokinetic profile of F373280 is not associated with particular alerts concerning the 
proposed clinical phase IIa study. 
1.2.3. 
Clinical data 
Part A: single dose 
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6 consecutive single ascending doses were tested (0.5g, 1g, 2g, 4g, 8g and 16g) on 6 independent 
cohorts of 8 subjects (6 verum + 2 placebo). 49 subjects were treated and 48 completed the study. 
No Serious Adverse Events occurred in the course of the study. 
Regarding the reported Treatment Emergent Adverse Events (TEAEs) that were judged by the 
Investigator as having a causal relationship with the study drug administration in the absence of 
an alternative explanation, 4 were observed in the placebo group (palpitation, dizziness in 
standing position , 2 symptomatic orthostatic hypotensions without loss of consciousness) and 4 in 
the group of F373280 at the dosage of 16g (meteorism, liquid stool, symptomatic orthostatic 
hypotension and dizziness in standing position). None of these adverse events were reported in the 
groups of F373280 at the dosages of 0.5g, 1g, 2g, 4g and 8g. 
After a single administration of the different tested doses no difference between the tested product 
and placebo has been reported, regarding vital signs (heart rate, systolic blood pressure and 
diastolic blood pressure), biological parameters (related to coagulation: platelets and fibrinogen) 
and coagulation parameters (bleeding time, prothrombin time/INR, activated partial 
thromboplastin time, thrombin clotting time). Variations of these parameters were within the 
physiological ranges. 
After single oral administration of F373280 from 0.5g to 16 g in 36 young male healthy subjects 
(6 per dose level), the following was observed: 
 
- F373280: Whatever the tested dose there is no circulating F373280 in plasma: only few, 
sparse and non consecutive samples with quantifiable level of F373280 close to LOQ were 
observed. This confirm that F373280 is a prodrug. 
- Panthenol: Cmax and AUC increased with the administered dose between 0.5 and 16g. 
Panthenol concentrations were rapidly cleared from plasma with a mean terminal half-life 
around 2 hours. 
- DHA: after 0.5 and 1g, low increased in DHA plasma concentrations compared to the 
baseline levels led to a high inter-individual variability of the corresponding PK parameters. 
Plasma exposure in DHA increased with the administered dose between 2 and 16g with no 
departure from proportionality (baseline corrected parameters). 
 
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Part B: Multiple dose  
Three consecutive repeated ascending doses (1, 2 and 4g) were tested on 3 independent cohorts of 
12 subjects (9 verum + 3 placebo, double blind). 36 subjects completed the study. Each treatment 
was administered over a period of 28 days. Pharmacokinetic parameters were assessed over a 
period of 14 days.  
Among the TEAE judged by the investigator as suspected to F373280 5/9 TEAE were classified 
according the SOC in vascular system disorder with orthostatic hypotension (2 in the 1 g group, 1 
in the 2 g group and 2 in the 4 g group) and 4/9 were classified in nervous system disorder with 3 
dizziness (2 in the 2 g group and 1 in the 4 g group) and 1 migraine (in the 1 g group). These 
TEAE have already been reported with Poly Unsaturated Fatty Acids and are commonly observed 
in phase I studies. 
After a repeated administration of the different tested doses, no difference between the tested 
products and placebo was reported regarding vital signs (heart rate, systolic blood pressure and 
diastolic blood pressure), biological parameters. The assessment of coagulation parameters and 
platelet function after administration of repeated dose of F373280 did not report any bleeding 
issue. The reported changes in coagulation parameters and platelet function were within 
physiological ranges. 
After a 14-day repeated oral administration of F373280 from 1 g to 4 g, the following was 
observed: 
 Panthenol: Cmax and AUC increased with the administered dose between 1 and 4 g. No 
accumulation of panthenol in plasma was observed. 
 
 DHA: Plasma exposure increased with dose. A 2-fold accumulation in total plasma exposure 
of DHA was observed after 14 days of administration, whatever the administered dose. 
 
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1.3. 
STUDY RATIONALE 
F373280 is a new therapy based on DHA delivery (pro-drug) developed for the maintenance of 
sinus rhythm after electrical cardioversion in persistent atrial fibrillation (AF) patients with 
chronic heart failure. 
The results of a pharmacological study performed in animals evidenced that DHA reduces the 
duration of atrial fibrillation (AF) induced by burst pacing [1]. 
Moreover, the effectiveness of PUFA has been proven in the following conditions: 
- 
Prevention of atrial fibrillation recurrence in patients with persistent atrial fibrillation in 
co-administration with amiodarone (add on therapy) [2], 
- 
Improvement of ventricular functional parameters, morbi-mortality and duration of 
hospitalisation in patients with heart failure [3, 4, 5]  
Taking into account these studies, it seems that DHA might be of therapeutic interest in the 
treatment of patients with both persistent atrial fibrillation and chronic heart failure. 
This phase IIa study is designed to assess the efficacy and the safety of the investigational product 
(F373280) for maintenance of sinus rhythm after electrical cardioversion in patients with 
persistent atrial fibrillation and chronic heart failure. 
1.4. 
OVERALL RISK AND BENEFIT ASSESSMENT 
F373280 is a new pro-drug of DHA.  
DHA is a well-known long chain PUFAs with a long-term clinical experience in cardiovascular 
diseases. DHA is contained in several medicinal products such as Omacor, (1g of Omacor 
contains about 320 mg of DHA acid) marketed by Laboratoires Pierre Fabre for 
hypertriglyceridemia and as an adjuvant treatment for secondary prevention after myocardial 
infarction. According to the summary product characteristics of Omacor, [9]: 
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- The frequencies of adverse reactions are ranked according to the following: common (> 
1/100, < 1/10); uncommon (>1/1000 < 1/100); rare (>1/10000, < 1/1000); very rare ( < 1/10000), 
not known (cannot be estimated from the available data). 
- The reported adverse events are: 
• Infection and infestations 
Uncommon: gastroenteritis 
• Immune system disorders: 
Uncommon: hypersensitivity 
• Metabolism and nutrition disorders: 
Rare: hyperglycaemia 
• Nervous system disorders: 
Uncommon: dizziness, dysgeusia 
Rare: headache 
• Vascular disorders: 
Very rare: hypotension 
• Respiratory thoracic and mediastinal disorders:  
Very rare: nasal dryness 
• Gastrointestinal disorders: 
Common: dyspepsia, nausea 
Uncommon: abdominal pain, gastrointestinal disorders, gastritis, abdominal pain upper 
Rare: gastrointestinal pain 
Very rare: lower gastrointestinal haemorrhage 
• Hepatobiliary disorders:  
Rare: hepatic disorders  
• Skin and subcutaneous tissue disorders:  
Rare: acne, rash pruritic 
Very rare: urticaria 
• General disorders and administration site conditions: 
Rare: malaise sensation 
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• Investigations: 
Very rare: white blood count increased, blood lactate dehydrogenase increased 
Moderate elevation of transaminases has been reported in patients with hypertriglyceridaemia. 
Panthenol is a well-known substance with a long-term experience in medical, nutraceutic and 
cosmetic uses. According to the summary product characteristics of a product such as 
Bépanthene (tablet indicated in alopecia) which contains panthenol (100 mg), adverse event 
observed are rare cases of urticaria and erythema [10]. Panthenol is metabolised in panthotenic 
acid, i.e. B5 vitamin. 
Concerning toxicological studies performed results can support the administration of F373280 in 
the proposed clinical phase II study without particular alert [1]. 
Any safety warning was reported during a phase I study performed with F373280 administered to 
84 healthy volunteers in single dose in a range between 500 mg and 16 g or in repeated dose 
during 28 days in a range between 1g and 4g. Adverse events reported and related to study 
treatment were minor to moderate. The adverse events were palpitations, orthostatic hypotension, 
dizziness, meteorism and liquid stool. Most were reported in both groups (placebo and F373280) 
without a dose relationship. The assessment of coagulation parameters and platelet function after 
administration of repeated dose of F373280 did not report any bleeding concern: the reported 
changes in coagulation parameters and platelet function were within physiological ranges. 
Moreover, DHA has been associated with anticoagulant products in Atrial Fibrillation studies [2, 
8]. The range of PUFAs doses tested was between 2g to 3g (640 mg to 960 mg of DHA) and the 
range of study durations between 6 to 12 months. This association did not report a significant side 
effect of bleeding. 
DHA has already been used in heart failure patients in several studies without safety concern [3, 
4, 5]. The range of PUFAs doses tested was between 1g to 5g (1g of the tested PUFAs contains 
about 320 mg of DHA acid) and the range of study durations was between 3 months to 3.9 years. 
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Thus, inclusion of patients with no specific antiarrhythmic treatment is acceptable. They will 
receive an anticoagulant treatment to prevent the thrombo-embolic complications of AF 
(particularly stroke) and the adequate treatments to control the heart rate and heart failure.   
In conclusion, the overall available data allow in safe conditions the treatment of patients with 
persistent AF and chronic heart failure with F373280 in safe conditions. 
2. STUDY OBJECTIVES 
2.1. 
PRIMARY OBJECTIVE 
The primary objective of the study is to assess the efficacy of F373280 on the maintenance of 
sinus rhythm after direct electrical cardioversion in patients with persistent atrial fibrillation and 
chronic heart failure. 
2.2. 
SECONDARY OBJECTIVES 
The secondary objectives of the study are to assess: 
• the efficacy of F373280 on the efficiency of direct electrical cardioversion 
• the effect of F373280 on echocardiographic parameters 
• the safety and tolerability of F373280 
3. ETHICAL CONSIDERATIONS RELATING TO THE STUDY 
The trial is conducted according to Good Clinical Practices (CPMP/ICH/135/95), the National 
regulations and the Declaration of Helsinki and its subsequent amendments (see Appendix 17.1). 
This protocol and the informed consent form will be submitted for approval to independent local 
or national Institutional Review Boards/Ethics Committees before the study set up, according to 
national regulation. 
All the protocol amendments or critical events liable to increase the risks incurred by the patients 
or to compromise the validity of the study or patients' rights will be submitted to the coordinator 
and to the Ethics Committees. 
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After being informed orally and in writing of all potential risks and constraints of the trial, as well 
as their freedom to withdraw their participation at any time, patients will then sign a consent.  
A time of reflection will be given to the patients, before giving a written consent and starting the 
study procedures. 
The use of a placebo is in accordance with EMA Addendum to the guideline on antiarrhythmics 
on atrial fibrillation and atrial flutter (EMA/CHMP/EWP/213056/2010) [21] and is acceptable 
because the included patients will remain under the standard treatment of atrial fibrillation and 
chronic heart failure. Except antiarrythmics, they will receive anticoagulant (AVK), rate control 
treatment, chronic heart failure treatment. During the study, in case of AF recurrence that would 
require a cardioversion or an introduction of an anti-arrhythmic because of intolerable and/or 
uncomfortable clinical symptoms, patients will be withdrawn and the tested product stopped. 
These patients will be considered as treatment failure. 
In this study, patients will be carefully screened, particularly for their cardiac condition, with 
ECG, 24-hour holter monitor and echocardiographic data, and their biologic and coagulation 
condition. 
The study will be addressed only to patients requiring an ECV due to their persistent AF, in the 
following conditions: 
- 
ECV in patients not presenting a contra-indication,  
- 
Anticoagulation  with anti-vitamin K for at least 3 weeks before ECV,  
- 
ECV in patients with stabilized INR (i.e. values between 2 and 3) on at least 3 
consecutive weekly tests performed. Patients not stabilized for INR (i.e. values 
between 2 and 3) on at least 3 consecutive weekly tests performed before ECV will be 
excluded from the study, unless the presence of atrial thrombosis may be excluded 
with ECHO –TE (trans-esophageal echocardiograph) performed  in the same day 
(before ECV) 
 
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- 
Patients who do not revert to sinus rhythm or present an early relapse within the 
observation period after ECV will be withdrawn and the tested product stopped. 
During the whole study, patients will remain under medical control: visits in cardiology units will 
be scheduled at least every month. This follow up will include clinical signs, ECG, biological and 
coagulation parameters. Moreover, patient’s cardiac rhythm will be monitored between visits 
using daily, then every 2 days Trans Telephonic ECG Monitoring (TTEM) reviewed by a Central 
Reading Laboratory. 
Patients may withdraw from the study at any time without having to give a reason and can expect 
to receive regular conventional therapy. 
4. STUDY DESIGN 
4.1. 
OVERALL DESCRIPTION 
This phase IIa trial will be conducted as an international, multicentric, 24 weeks, double-blind, 
placebo-controlled, randomised, parallel group design, trial in 152 patients suffering from 
persistent atrial fibrillation and chronic heart failure. 
After a 1 to 4-week of run-in period without treatment, patients will be randomised into one of the 
following treatment groups: F373280 1g or placebo for 24 weeks.  
Nine visits are planned for the study: 
- 
Visit 1 (V1): W-4 to W-1: Selection visit (7 to 28 days before the Inclusion Visit) 
- 
Visit 2 (V2): D1: Inclusion visit (start of treatment)  
- 
Visit 3 (V3): W4 (D28 -2/+7D): cardioversion visit (outpatient or hospitalization 
according to clinical practice of the centre) (installation of the Holter ECG device) 
- 
Visit 4 (V4): W5 (D35 ± 2D): follow-up visit (removing of Holter ECG device and 
installation of the TTEM) 
- 
Visit 5 (V5): W8 (D56 ± 7D): follow-up visit 
- 
Visit 6 (V6): W12 (D84 ± 7D): follow-up visit 
- 
Visit 7 (V7): W16 (D112 ± 7D) : follow-up visit 
- 
Visit 8 (V8): W20 (D140 ± 7D): follow-up visit 
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- 
Visit 9 (V9): W24 (D168 ± 7D): final study visit 
4.2. 
DISCUSSION OF THE STUDY DESIGN 
4.2.1. 
Choice of the Study Population 
The target indication of F373280 will be the maintenance of sinus rhythm after cardioversion of 
patients with persistent atrial fibrillation and chronic heart failure. In the present proof of concept 
study, the evaluation will focus on patients within this indication. This target population is 
justified by: 
− The proved efficacy of PUFAs in patients with persistent atrial fibrillation with or 
without heart failure in co-administration with amiodarone (add on therapy) [2] 
− The proved efficacy of PUFAs on the improvement of ventricular functional parameters, 
morbi-mortality and duration of hospitalisation in patients with heart failure  [3, 4, 5] 
The study aim is to investigate the product effect in patients with: 
− early persistent atrial fibrillation history (less than one year) with a duration of a the 
current episode between 7 days to 6 months  
− a moderately abnormal moderately systolic heart failure (Left Ventricular Ejection 
Fraction (LVEF) between 30 to 45% as defined in the report from the American Society 
of Echocardiography’s Guideline). According to a sub-group analysis performed in 
patients with persistent atrial fibrillation associated to heart failure ( Nodari S. personnal 
data), PUFAs would be effective to prevent recurrence of AF after cardioversion in 
patients with moderately abnormal LVEF. 
 
− A Left Atrial Area (LAA) not severely abnormal (less than 40 cm2 as defined in the 
report from the American Society of Echocardiography’s Guideline). According to a 
sub-group analysis performed in patients with persistent atrial fibrillation associated to 
heart failure ( Nodari S. personnal data), PUFAs would not be effective to prevent 
recurrence of AF after cardioversion of patients with severely abnormal LAA. 
For the successful rate of electrical cardioversion, patients should have a stable medical 
treatment of heart failure and should not have myocardial infarction or unstable angina or 
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unstable ischemic coronaropathy (assessed by coronarography or cardiac stress test or effort 
test within 6 months before selection).  
4.2.2. 
Choice of the Study Design 
As the target indication would be the prevention of AF recurrence after ECV, the study design 
meets the requirements of EMA guideline on anti-arrhythmics on atrial fibrillation 
(EMA/CHMP/EWP/213056/2010) [21]. 
As F373280 aims to be developed as a safe treatment for the prevention of AF recurrence, it will 
not be tested as an add-on therapy during the study. To avoid any interaction with the tested 
product, anti-arhythmics class I and III will be forbidden during the study. 
The study design is defined in order to avoid methodological bias. A double blind study is 
appropriate to assess the efficacy and safety of the use of F373280 to prevent recurrence of AF 
episodes. Moreover, this study design is similar to the design of almost all trials that have assessed 
intervention for rhythm control [2, 8, 11, 12].  
According to the target indication, only patients with persistent atrial fibrillation and requiring an 
electrical cardioversion will be included in order to assess the time to first documented recurrence 
of atrial fibrillation since cardioversion. 
To confirm the persistent nature of atrial fibrillation, a 24-hour holter monitoring will be 
performed during the selection visit.  
Eligible participants will enter a selection phase in which anticoagulant treatment (anti-vitamin K) 
will be adjusted to achieve an International Normalized Ratio (INR) of 2.0 to 3.0 before electrical 
cardioversion. According to guidelines for the management of atrial fibrillation [6], anti-vitamin 
K should be given at least 3 weeks before cardioversion because of risk of thrombo-embolism due 
to post-cardioversion.  
Experimental data suggest that the maximal incorporation, of n-3 PUFAs in the myocardial cell 
membrane takes up to 28 days to occur [22]. In addition, as shown in Nodary study [2], the 
duration of pre-treatment with PUFA before cardioversion appears to be a contributing factor in 
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success.Therefore, before starting follow up for the assessment of AF recurrence, treatment with 
F373280 should be started 28 days before ECV.  
Detection of atrial fibrillation recurrence will be performed using systematic (scheduled) ECG 
recording, thus allowing detection of asymptomatic (about 50% of episodes) as well as 
symptomatic AF episodes. According to previous studies, most of atrial fibrillation recurrence 
occurred during the first days after cardioversion [11, 15]. So that, the heart rhythm will be 
closely monitored during the first week after successful cardioversion using an ambulatory 
continuous 7-day holter ECG recording in order to increase sensibility to detect asymptomatic AF 
episodes. Thereafter, to improve patient compliance, this follow up will be continued using  a 
more easy to carry and easy to use device, a TTEM.  
Finally, during the study, patients will be scheduled for a clinical visit every month (with an 
additional visit 7 days after visit 3 (ECV visit)) in order to ensure a close medical monitoring and 
to assess efficacy and safety parameters. 
4.2.3. 
Choice of the Dose  
According to a previous study in patients with atrial fibrillation [2], the tested PUFA product 
(Omacor) at the dose of 2 g (i.e. 640 mg of DHA acid) was effective in the prevention of atrial 
fibrillation after cardioversion. Moreover, PUFAs at dosage of 1g and 2g were also effective on 
the improvement of ventricular functional parameters, morbi-mortality and duration of 
hospitalisation in patients with heart failure [3, 4, 5].  
From the F373280 phase I study, after a 14-day repeated administration of F373280 (1g/day), 
observed plasma concentrations of DHA measured before treatment (Cmin) were similar to that of 
an effective dose of Omacor at 2 g/day (60 to 95mg/mL and 60 to 90mg/mL, respectively) 
(phase I study of F373280 and Salm and coll study) [16]. With regard to the rythm of 
administration, mean peak/trough fluctuation (baseline corrected) was around 0.3. This value 
supports a once-daily administration allowing a 24-hour plasma exposure in DHA.Therefore, a 
dose of 1 g daily of F373280 is considered to be appropriate to be tested in this POC study. 
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4.2.4. 
Choice of the Sample Size 
See chapter 13. 
5. STUDY POPULATION 
Each patient fulfilling all the inclusion criteria and none of the non inclusion criteria will be 
eligible. 
5.1. 
INCLUSION CRITERIA 
Demographic Characteristics and Other Baseline Characteristics: 
1. Men or women aged more than 18 years (inclusive), 
2. Patient with persistent AF between 7 days and 6 months duration for whom 
electrical cardioversion is warranted. 
3. History of first documented persistent AF less than 1 year 
4. History of ischemic or non ischemic heart failure 
5.  NYHA class I or II chronic heart failure at selection and at inclusion 
6. Reduced left ventricular ejection fraction between 30% and 45% inclusive (using the two-
dimensional echocardiography biplane Simpson’s rule) at selection and at inclusion 
7. On appropriate, stable medical treatments for heart failure, including a diuretic and/or 
angiotensin-converting 
enzyme, 
and/or 
angiotensin-receptor 
blocker 
and/or 
mineralocorticoid receptor (MR) antagonists, and/or betablockers 
8. Left atrial area ≤ 40 cm² at selection and at inclusion 
9. Patient treated or having to be treated by anti-vitamin K 
10. For female patient of child-bearing potential:  
- 
use of an effective method of contraception (hormonal contraception or intra-uterine 
device) assessed by the investigator, for at least 2 months before the selection in the 
study and agreement to go on using it during the whole duration of the study and up to 
1 month after the last dose of the study treatment or 
- 
documented as surgically sterilized 
11. For female patient of child-bearing potential: negative urine pregnancy test at inclusion 
 
Ethical /legal considerations: 
12. Having signed his/her written informed consent, 
13. Affiliated to a social security system, or is a beneficiary (if applicable in the national 
regulation), 
5.2. 
NON INCLUSION CRITERIA 
Criteria related to pathologies: 
1. History of first documented episode of persistent AF more than 1 year, 
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2. More than two successful cardioversions (electrical or pharmacological) in the last 6 months, 
3. Secondary Atrial Fibrillation due to alcohol or severe valvular heart disease (grade III to IV), 
4. NYHA class III or IV heart failure at selection or at inclusion 
5. Thyroid disease uncontrolled by treatment: TSH ± T4L ± T3L to be check in case of treatment 
for thyroid disease  
6. Myocardial infarction or unstable angina or presence of unstable ischemic coronaropathy 
assessed by coronarography or cardiac stress test (Echo stress, exercice stress test, nuclear or 
MR perfusion evaluation methods) within 6 months before selection 
7. Severe chronic kidney disease (creatinine 25 mg/L or estimated glomerular filtration rate  
< 30 mL/min) at selection 
8. Bradycardia (HR ≤ 50 bpm) 
9. Hyperkalemia or hypokalemia (K > 5.5 mEq/L or K < 3.5 mEq/L) at selection 
10. Cardiac surgery within 3 months before selection or planned during the study duration 
Criteria related to treatments: 
11. Previously ineffective pharmacological or electrical cardioversion 
12. Concomitant treatment with any anti-arrhythmic drug (within 7 days prior to selection), except 
stable dose of digoxin, beta-blockers, calcium-blockers. 
13. Previous treatment with oral amiodarone within 12 months prior to inclusion 
14. Previous treatment with intravenous amiodarone within 6 months prior to inclusion 
15. Patient requiring a cardiac resynchronization therapy (CRT) or having undergone CRT 
implantation within the last 6 months 
16. Treatment with any Polyunsaturated Fatted Acid within the last 3 months 
Dietary supplement with ω3 or ω6 according to investigator’s judgment 
18. Having undergone any form of ablation therapy for AF 
19. Patient treated with other anticoagulant treatment than antivitamin K: thrombin inhibitor such 
as Dabigatran or treated with antiaggregant P2Y12 inhibitors such as Clopidogrel or Prasugrel 
Others criteria:  
20. Patient liable not to comply with protocol instructions and/or with treatment, in the 
investigator’s opinion, 
21. Patient having taken part in a clinical trial in the preceding 2 months or taking part in a trial at 
the time of selection, 
22. Patient linguistically or mentally unable to understand the nature, objectives and possible 
consequences of the trial, or refusing to patient himself / herself to its constraints, 
23. Patient family member or work associate (secretary, nurse, technician…) of the Investigator, 
24. Patient having forfeited his / her freedom by administrative or legal award or being under 
guardianship. 
5.3. 
NUMBER OF  PATIENTS 
76 x 2 patients (taking into account 15 % of non evaluable patients). 
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5.4. 
RECRUITMENT MODALITIES 
Patients will be recruited within the medical consultation of each centre involved in the study. If 
necessary and when authorized by local and national regulation, some specific supports or tools 
will be used to improve the recruitment (announcement, mailing to general practitioners, leaflet, 
website including ClinicalTrials.gov, CRO,…). 
Before implementation, the documents will be submitted to and approved by the Ethics 
Committee. 
5.5. 
 PATIENTS IDENTIFICATION 
The patient's code will contain 7 digits: the 2 first digits corresponding to the country number, the 
following 2 digits corresponding to the centre number and the last 3 digits corresponding to the 
patient's chronological order once having signed the written informed consent. 
5.6. 
WITHDRAWAL CRITERIA 
The reasons for a patient's premature withdrawal from the study may be the following: 
• The patient's decision. A patient who wishes to withdraw from the study for any reason may 
do so at any time but must inform the investigator. In all cases, the Investigator should attempt to 
contact the patient as soon as possible for a final assessment in order to: 
− have the patient's decision written on the consent form 
− obtain the reason(s) for withdrawal and report it/them in the case report form 
− evaluate the patient's clinical condition 
− if necessary, take appropriate therapeutic measures: management of an adverse effect or 
concomitant disease, prescription of another treatment. 
• The Investigator's decision in the patient's interest. Particularly, if a serious adverse event 
occurs and is considered by the Investigator liable to threaten the health of the patient. The 
monitor will be informed by phone or fax and a letter or report explaining the withdrawal will be 
forwarded to the monitor as soon as possible. 
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• An erroneous inclusion according to the study protocol. Any inclusion not respecting 
inclusion / non inclusion criteria will immediately be withdrawn and an appropriate treatment will 
be instored by the investigator under his/her responsibility. Erroneous inclusions will not be paid 
to the investigator. 
• Patients who could not be treated with anti-vitamin K for at least 3 weeks before ECV, 
• Patients who will not stabilize INR between 2 and 3 on at least 3 consecutive weekly tests 
• Patients with only 2 consecutives INR tests between 2 and 3 in the last 3 week for whom  a 
trans-oesophagoal echocardiography can not be performed before ECV or for whom a trans-
oesophagoal echocardiography shows a thrombus in the atria.  
• Patients who will not revert to sinus rhythm or with early relapse within the observation 
period after ECV (i.e. unsuccessful ECV) will be considered to have finished follow-up. 
• An occurrence of AF recurrence that would require, at the investigator’s judgement, a 
cardioversion or an introduction of an anti-arrhythmic because of intolerable and uncomfortable 
clinical symptoms. 
5.7. 
REPLACEMENT OF PATIENTS 
Withdrawn patients will not be replaced. 
5.8. 
POST-STUDY EXCLUSION PERIOD  
Patients will not be allowed to participate to another clinical trial during 3 months following the 
study termination. 
5.9. 
STUDY CARD 
The patient will receive from the Investigating Centre at Visit 1 - Selection Visit, a personal card 
to be kept all along the study duration and providing the following information: patient's name, 
sponsor's name, study code, EUDRACT number, start date and expected end date of the study, 
complete address of the Investigating Centre with the name and phone number of the Investigator 
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and a sponsor 24H/24 phone contact number in case of emergency (French and English 
languages): 33 (0)5 63 35 25 83. 
6. STUDY TREATMENT 
The Clinical Pharmacy Department of the Institut de Recherche Pierre Fabre (IRPF) will supply 
the investigational centres with the treatment necessary for the conduct of the trial.  
6.1. 
SOURCE, PRESENTATION AND COMPOSITION OF 
 
INVESTIGATIONAL PRODUCT 
F373280 and placebo will be prepared in Soft Capsules similar presentation.  
• F373280 
Formulation of F373280, 1g, Soft Capsules: oral administration, oblong size 20, off-white, Soft 
Capsules containing: Panthenyl ester of DHA, gelatine, glycerol, titanium, dioxide, purified water. 
• Placebo 
Formulation of placebo matching tested product, Soft Capsules: oral administration, oblong size 
20, off-white, Soft Capsules containing: paraffin liquid, fish flavour, gelatine, glycerol, titanium, 
dioxide, purified water. 
 
Placebo and F373280 capsules will be packaged in opaque blisters. 
6.2. 
PACKAGING AND LABELLING 
The treatment units will be packed and labelled by the Clinical Pharmacy Department of the IRPF 
according to European Directive and local requirements. 
6.2.1. 
Packaging 
Each treatment unit will be composed of 3 cases for a 12-week treatment period. 
The Investigator will provide the patient with the treatment according to the following schedule: 
At Inclusion Visit (V2): a 12-week treatment unit will contain 3 cases, each case containing: 
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− 10 blister packs of four 1g F373280 soft capsules or placebo soft capsules each. 
At Visit 6 (V6): a 12-week treatment unit will contain 3 cases, each case containing: 
− 10 blister packs of four 1g F373280 soft capsules or placebo soft capsules each. 
6.2.2. 
Labelling 
Investigational Products will be labelled according to the following rules: 
Labelling should comply with the local requirements for Investigational Medicinal Products. 
On the treatment units and cases, the labels will bear the following indications:  
a) name and address of the sponsor 
b) protocol number, 
c) packaging batch number, 
d) the treatment number 
e) storage conditions 
f) expiry date 
g) pharmaceutical dose form 
h) route of administration 
i) quantity of dosage units 
j) direction for use 
k) legal statements:  
− “for clinical trial only”, “keep out of the reach and the sight of children”, “please return 
to your doctor any unused product”, respect the prescribed dose”. 
On the treatment unit, another label will be affixed with the mention of the investigator name and 
patient number (completed by the investigator). 
In addition, on each case, will be mentioned the case number and a detachable label will bear the 
following indications: 
− Protocol number 
− Packaging batch number 
− Expiry date 
− Case number 
− Treatment number 
On the blister pack, the label will mention the protocol number, the packaging batch number, the 
case number and the treatment number. 
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6.3. 
DISTRIBUTION TO CENTRE AND STORAGE 
The Clinical Pharmacy Department of the IRPF will supply the Investigational Centre with the 
treatment units along the study according to the need, upon request triggered by the patient’s 
selection.  
As soon as the Pharmacist or the Investigator receives the trial medication, he/she will check the 
contents and immediately acknowledges the receipt in the IVRS/IWRS. The copy of the 
acknowledgement will be kept in the Investigator’s file. The same procedure will be applied to all 
further supplies during the course of the trial. 
At the time of the delivery to the Centre, the following information will be provided: 
• Details of storage conditions that should be respected 
• And, upon request and for the 1st delivery only, a letter of release for the Investigational 
Medicinal Product from the Sponsor's Qualified Person. 
The CRA will ensure during the monitoring visits that trial medications have been received in 
good conditions and the acknowledgment of receipt has been performed adequately. 
Treatment units should remain intact until dispensation to the patients. They should be kept at 
temperature below 30°C in an appropriate lockable room only accessible to the person authorised 
to dispense them, under the responsibility of the Pharmacist or the Investigator. 
In the case of undue delay in study execution, the Pharmacist or the Investigator should ensure 
that the expiry date has not been exceeded.  
6.4. 
ALLOCATION OF TREATMENTS AND DISPENSATION TO PATIENT 
A randomisation list will be established by the Clinical Pharmacy Department of the IRPF. This 
list will be computer-generated with internal software. The randomisation methodology is 
validated by the Biometry Department before generation. 
Treatments F373280 or placebo will be balanced in a 1:1 ratio. 
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As the treatment units are prepared for 12-week treatment periods, the Investigator will have to 
allocate a treatment number at inclusion Visit and another one at Visit 6.  
For each patient, the treatment number given at Visit 6 will not be the same that the one given at 
inclusion visit (V2). 
The treatment numbers will be given through the IVRS/IWRS. 
Practically, once the patient’s eligibility is confirmed, at selection visit:  
• The Investigator: 
− Calls the vocal server  
− Answers the questions relating to the patient  
− In return, the treatment number to be allocated for the first 12-week period to the patient 
is given by the vocal server.  
• The IVRS/IWRS company: 
− Confirms this information by fax/email to the Investigator 
− Fills the “Request for Delivery of Investigational Product” form and sends it by email 
and/or fax to the Clinical Pharmacy Department of the IRPF.  
• The Clinical Pharmacy Department of the IRPF sends the corresponding treatment unit to the 
Investigator within 5 days from reception of the email request form. 
The Investigator will dispense to the patient the case which label indicates the treatment number 
and the administration period. 
At visit 5, the Investigator will contact again the IVRS/IWRS to obtain for visit 6 the treatment 
number for the last 12-week period of treatment according to the same process as described 
above. 
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6.5. 
DRUG ADMINISTRATION 
6.5.1. 
Duration of Treatment 
For a patient completing the study, the theoretical study treatment exposure will be 24 weeks, 
with F373280 or placebo. 
If the ECV is postponed by 1 week to allow INR stabilization, the treatment duration will be 25 
weeks. 
6.5.2. 
Dose Schedule 
One soft capsule of 1g of F373280 or placebo to be taken each day during 24 weeks. 
6.5.3. 
Route and Conditions of Administration 
The soft capsules are to be taken orally. One soft capsule is to be taken each evening with the 
dinner during 24 weeks.  
6.6. 
ACCOUNTABILITY ON SITE AND RETURN/DESTRUCTION OF 
 
INVESTIGATIONAL PRODUCT 
The Investigator should maintain accurate written records of drug received, dispensed, returned 
and any remaining treatment units, on the drug accountability form. These records should be made 
available for Clinical Research Associate (CRA) monitoring. The packaging of the medication 
should remain intact until just before the dispensation. 
At each visit, the Investigator will record the number of soft capsules returned by each patient 
using the appropriate page of the e-CRF. 
At the end of the study, all used and unused treatments including packaging should be noted, and 
return is organised by the CRA to the Clinical Pharmacy Department of the IRPF for destruction. 
A copy of the drug accountability form should be provided by the Investigator to the CRA. 
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6.7. 
RECALL OF INVESTIGATIONAL PRODUCTS  
In case of recall of investigational products (decided by the Competent Authorities or the 
Sponsor), the Investigator will immediately be informed by the Sponsor. 
The Investigator, in collaboration with the Sponsor representatives (Study Manager, CRA) must 
urgently: 
• Stop the delivery of the concerned investigational products to the patients. 
• Inform the concerned patients that they must immediately stop taking these investigational 
products and bring them back. 
The Study Manager/CRA organises the return of the recalled products to the Clinical Pharmacy 
Department of the IRPF, according to the Sponsor’s procedures. 
7. CONCOMITANT TREATMENTS 
Any existing concomitant treatment (Selection Visit), any new concomitant treatment or change 
in the dosage of an existing concomitant treatment during the course of the study must be noted 
on e-CRF. All treatments should be evaluated by the investigator at selection and their 
prolongation during the study or their stop should be considered. 
For all concomitant treatments taken during the study, the following information must be noted in 
the relevant section(s) of the e-CRF: 
• The name of the treatment and its form 
• The reason for prescription 
• The route of administration 
• The daily dose 
• The duration of treatment. 
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7.1. 
ANTI-VITAMIN K TREATMENT 
Anti-vitamin K should be given for at least 3 weeks before ECV and continued for the whole 
study duration. The anti-vitamin K used will be left to the decision of the each investigator 
according to his/her local practice. 
7.2. 
PROHIBITED TREATMENTS 
- 
Class I and class III antiarrhythmic treatments: 
− Class I  
- 
Class IA: Disopyramide, Procainamide, Quinidine 
- 
Class IB: Lidocaine, Mexiletine 
- 
Class IC: Flecainide, Propafenone 
 
− Class III: Dofetilide, Ibutilide, Sotalol, Amiodarone, Dronedarone.  
- 
Any Polyunsaturated Fatty Acid (PUFA) 
- 
Any anticoagulant treatment other than antivitamin K: thrombin inhibitor such as Dabigatran 
or antiaggregant P2Y12 inhibitors such as Clopidogrel or Prasugrel 
- 
Dietary supplement with Omega 3 or Omega 6 
Prohibited treatments at selection must not be prescribed for the duration of the study except in 
case of occurrence of an adverse event or AF episode that requires a corrective treatment in the 
interest of the patient’s health. 
7.3. 
AUTHORISED TREATMENTS 
Other treatments will be authorised during the study duration. 
However, if medication other than study drugs is administered at any time from the start of the 
study, details must be recorded in the case report form. During the study, patients must be asked 
whether they have been on a course of prescribed drug treatment or have taken any OTC or herbal 
drugs since the visit. 
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8. EVALUATION CRITERIA 
8.1. 
PRIMARY EFFICACY CRITERION:  
8.1.1. 
Time to the first Atrial Fibrillation Recurrence 
8.1.1.1. 
Definition 
Time to first Atrial Fibrillation recurrence is defined by the first episode of Atrial Fibrillation 
(symptomatic or not) lasting for at least 10 minutes. 
8.1.1.2. 
Schedule 
The heart rhythm follow up will be performed from the end of electrical cardioversion visit  
(visit 3) to the final study visit (visit 9).  
For randomised patients with spontaneous cardioversion before ECV, the recurrence of AF will be 
assessed after visit 3 (week 5). 
8.1.1.3. 
Evaluation Methods 
• 7-day holter monitor: 
The heart rhythm monitoring will be carried out  from visit 3 to visit 4 using a 7-day continuous 
ECG (5-leads/2 or 3 channels) ambulatory recording (holter ECG) fixed after ECV visit. 
Following holter monitoring the heart rhythm will be documented using Trans Telephonic ECG 
Monitoring (TTEM) 
• Trans Telephonic ECG Monitoring (TTEM): 
Thus, the follow up will be documented using the TTEM: daily transmission from visit 4 to visit 
6. Then, every two days from visit 6 to visit 9. 
Moreover, during this TTEM period, if patient experiences AF symptoms, it should be 
documented using the TTEM. 
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In case of AF recurrence, and provided that the patient does not required a cardioversion or an 
introduction of an anti-arrhythmic at the investigator’s judgement, he/she could be maintained in 
the study with the treatment, in order to assess a spontaneous cardioversion. For that purpose the 
patient will continue to transmit a TTEM once a week. 
The TTEM will be centralized by the Central Reading Laboratory. The patient will be requested 
to contact the Central Reading Laboratory for transmission of each stored TTEM. The TTEM will 
be validated by a trained technician, then analysed by a cardiologist. The cardiologist 
interpretation will be faxed to the site. The investigator will be asked to review and sign this 
document. 
The TTEM process will be fully described in a separate document. 
8.1.2. 
Secondary Efficacy Criteria 
8.1.2.1. 
Numbers of Atrial Fibrillation episodes in the first week following visit 3 
 
 
(ECV visit) 
8.1.2.1.1. 
Definition 
Number of Atrial Fibrillation episodes will consist in the assessment of episodes of AF with 
duration at least 10 minutes (NSup10) and of less than 10 minutes (NInf10), respectively. 
8.1.2.1.2. 
Schedule 
The heart rhythm follow up will be performed from the end of successful electrical cardioversion 
visit (visit 3) to the study visit 4.  
8.1.2.1.3. 
Evaluation Methods 
• 7-day holter monitor: 
The heart rhythm monitoring will start using a 7-day continuous ECG (5-leads/2 or 3 channels) 
ambulatory recording (holter ECG) after ECV visit from visit 3 to visit 4. 
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8.1.2.2. 
Duration of Atrial Fibrillation episodes in the first week following visit 3 
 
 
(ECV visit) 
8.1.2.2.1. 
Definition 
Duration of AF episodes will consist in the sum of duration of each AF episodes. 
8.1.2.2.2. 
Schedule 
The heart rhythm follow up will be performed from the end of successful electrical cardioversion 
visit (visit 3) to the follow up study visit (visit 4).  
8.1.2.2.3. 
Evaluation Methods 
Duration of AF episodes will be assessed using the 7-day continuous ECG (5-leads/2 or 3 
channels) ambulatory recording. 
8.1.2.3. 
Clinical parameters evaluation 
8.1.2.3.1. 
EHRA score assessment 
8.1.2.3.1.1. Definition: 
AF related symptoms will be evaluated by the EHRA (European Heart Rhythm Association) score 
[20]. The following items “during presumed arrhythmia episodes" are checked to determine the 
score: palpitation, fatigue, dizziness, dyspnea, chest pain and anxiety. 
Classification of AF-related symptoms (EHRA score) are as follows: 
• EHRA I          - ‘No symptoms’ 
• EHRA II         - ‘Mild symptoms’; normal daily activity not affected 
• EHRA III       - ‘Severe symptoms’; normal daily activity affected 
• EHRA IV       - ‘Disabling symptoms’; normal daily activity discontinued  
This classification relates exclusively to the patient-reported symptoms. 
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In addition to this score, the frequency will be classified in three groups, namely occasionally 
(less than once per month); intermediate (1/month to almost daily); and frequent at least daily. 
8.1.2.3.1.2. Schedule 
This evaluation will be performed in case of symptoms evocative of arrhythmia. 
8.1.2.3.1.3. Evaluation Methods 
This evaluation will be collected by Central Reading Laboratory during all the study period. 
8.1.2.3.2. 
Number of recurrence of symptomatic AF  
It consists of number of AF recurrence associated with a symptom (Palpitation, fatigue, dizziness, 
dyspnea, chest pain and anxiety) and confirmed by an ECG in atrial fibrillation. 
8.1.2.3.3. 
Number and duration of hospitalization 
• Number and duration of hospitalization for cardiovascular events 
− Hospitalization for AF treatment 
− Hospitalization for worsening of heart failure 
− Hospitalization for myocardial infarction 
− All cause of hospitalization 
• Number and duration of hospitalization for thromboembolic stroke  
8.1.2.4. 
Cardioversion assessment 
• Assessment of spontaneous cardioversion before visit 3 
• Assessment of successful cardioversion at visit 3 (i.e. return to sinus rhythm) 
• Shock distribution (1, 2 or 3 shocks) 
• Number of patients needing another cardioversion after initial ECV 
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8.1.2.5. 
Evolution of echocardiographic parameters 
8.1.2.5.1. 
Definition 
The following echocardiographic parameters will be assessed: Left atrial diameter (mm), Left 
atrial area (cm2), Left atrial volume (mL), Left atrial volume/BSA (mL/m2), Left ventricular 
ejection fraction (%),Left ventricular volume (mL), Left ventricular volume/BSA(mL/m2, Left 
ventricular end diastolic diameter (mm) Left ventricular end diastolic volume (mL), Left 
ventricular end systolic diameter (mm) and Left ventricular end systolic volume (mL), 
8.1.2.5.2. 
. Schedule 
The measurements will be performed at visit 1 and visit 2 to check the eligibility of the patient.  
The measurements performed at visit 4, visit 6 and visit 9 are done to follow the 
echocardiographic evolution of the patients in sinus rhythm. 
8.1.2.5.3. 
Evaluation method 
The echography evaluations will be carried out according to the recommendations for chamber 
quantification drawn up by the American Society of Echocardiography and the European 
Association of Echocardiography [23]. So, for volume measurements, the recommended method 
is to use the biplane method of discs (modified Simpson’s rule) from 2-D measurement. 
8.2. 
BIOMARKER ASSESSMENT: RED BLOOD CELL  
 
CONCENTRATIONS OF DHA 
8.2.1. 
Definition 
Because of the limited accessibility of human tissues for biopsy, red blood cell DHA contents is a 
marker for tissue DHA concentration [13], [14]. 
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8.2.2. 
Blood samples 
8.2.2.1. 
Collection schedule 
Blood samples will be collected for determination of red blood cells (RBC) concentrations of 
DHA.  
Blood samples will be performed as follows: 
• Visit 2 before treatment, visit 3, visit 6 and visit 9. 
Actual sampling times will be individually reported in the electronic Case Report Forms  
(e-CRFs). 
8.2.2.2. 
Technical handling 
Two blood samples will be collected containing EDTA. They will be gently shaken and 
centrifuged at 3000g for 15 min at room temperature, within 30 minutes after collection. Plasma 
and white blood cells will be discarded. Red blood cells will be stored at +4°C (no freezing will 
be allowed) and sent to Analytical Centre in refrigerated conditions (between +2°C and +8°C) 
within 3 weeks following collection. Analysis will be performed within 2 weeks following 
reception at the Analytical centre. 
8.2.3. 
DHA concentration measurement 
Analytical determination of RBC concentrations of DHA will be carried out by the Analytical 
Centre. 
Lipids will be extracted from red blood cells samples with a mixture of hexane/isopropanol, after 
acidification [17]. Total lipid extracts will be saponified and methylated. The fatty acid methyl 
esters (FAME) will be extracted and analyzed by Gas Chromatography. 
Identification of FAME will be based on retention times obtained for FAME prepared from fatty 
acid standards. The area under peaks will be determined using ChemStation Software (Agilent) 
and results will be expressed as % of total fatty acids. DHA concentration will be calculated using 
the internal standard and expressed as µg/g for red blood cells samples. Thus, omega-3 index will 
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be assessed. The omega-3 index represents the content of EPA plus DHA in red blood cells 
(expressed as a percent of total fatty acids). It is a biomarker considered as a new marker of risk 
for death from coronary disease [18]. 
Results of this analytical determination will be kept confidential by the dosing centre until the end 
of the study, and will be provided only at the end of the study (after database lock), in a separate 
file. 
8.3. 
SAFETY ASSESSMENT 
8.3.1. 
Adverse Events 
At selection, any concomitant disease will be reported on the e-CRF. At each further visit, the 
occurrence of adverse events (AEs) since the last visit will be based on the patient's spontaneous 
reporting, the investigator's non-leading questioning and his/her clinical evaluation. All AEs will 
be reported on the e-CRF (see section 10). 
8.3.2. 
Laboratory Investigations 
8.3.2.1. 
Schedule 
Laboratory investigations will be performed at visit 1 (before treatment) and visit 9 (end of 
treatment) or End of Treatment visit. 
Furthermore the kaliemia will be checked before electrical cardioversion at visit 3. 
The volume of blood samples complete haematology, biochemistry should not exceed 30 mL. 
8.3.2.2. 
Technical Procedures and Parameters 
The following tests will be performed: 
 
Haematology: 
Hematocrit, haemoglobin, Red blood cells (RBC) count, white blood cells 
(WBC) count, WBC differential counts (% and absolute), platelets.  
 
Chemistry: 
sodium, potassium, bicarbonate, chloride, alkaline phosphatase, gamma GT, 
albumin, total bilirubin, conjugated bilirubin, creatinin, aspartate 
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aminotransferase (AST), alanine aminotransferase (ALT), fasting glucose, 
total cholesterol, cholesterol (HDL, LDL), triglycerides, creatine 
phosphokinase (CPK), fibrinogen. 
Blood samples will be taken in the morning, in fasting conditions.  
The estimation of GFR at selection relies on the measurement of serum creatinine and the 
Cockcroft- Gault formula 
Cockcroft-Gault formula 
- with serum creatinine expressed as mg/L:  
in men: 
GFR (mL/min) = [(140-age)] x weight / 7.2 x serum creatinine in mg/L], 
 
in women: 
GFR (mL/min) = [(140-age)] x weight / 7.2 x serum creatinine in mg/L] x 0.85 
 
- with serum creatinine expressed as μmol/l: 
GFR (mL/min) = [(140-age) x weight / serum creatinine in μmol/l] x k,where k = 1.23 for men, 
1.04 for women. 
 
(weight in kg, age in years) 
Additional tests may be done at the Investigator’s discretion, in the patients’ interest. In case of 
any abnormal or clinically significant results, the Investigator will order laboratory control tests. 
8.3.3. 
Global Physical Examination 
A global physical examination including the measurement of body weight will be carried out on 
each body system at visit 1, visit 2, visit 3, visit 5, visit 6, visit 7, visit 8 and visit 9. 
The physical examination will be globally evaluated as “normal/abnormal”. Further target 
inspection will be undertaken for any abnormal finding. 
8.3.4. 
Vital Signs 
Vital signs will consist in blood pressure and heart rate at rest.  
8.3.4.1. 
Schedule 
Vital signs will be measured at each visit. 
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8.3.4.2. 
Technical Procedure and Parameters 
Systolic (SBP) and diastolic (DBP), expressed in mmHg, will be measured after at least 5 minutes 
in supine position and after 2 minutes in standing position.  
The heart rate (HR), expressed in beats per minute (bpm), will be measured by auscultation, after 
at least 5 minutes in supine position and after 2 minutes in standing position by counting the beats 
for at least 30 seconds. 
Bodyweight will be measured in  patient in underwear and with the same balance at each visit.  
8.3.5. 
Electrocardiogram (ECG)  
8.3.5.1. 
Schedule 
An electrocardiogram will be recorded at visit 1, visit 2, visit 3, visit 5, visit 6, visit 7, visit 8 and 
visit 9 using an usual standardised 12-lead cardiograph. 
8.3.5.2. 
Technical Procedure and Parameters 
• Electrocardiogram (ECG): 
The global interpretation from manual reading (normality, clinical relevance) and heart rate 
(bpm), PR (ms), QRS (ms), QT (ms), repolarisation patterns will be reported in the e-CRF. Each 
print-out will include the patient’s code, date, time, technician's initials and investigator's 
signature. 
In case of thermic paper ECG print out, a photocopy will be made by the centre to ensure safe 
filing. 
• 24 hour-Holter - ECG 
An ambulatory continuous 24-hour ECG (5-leads/2 or 3 channels) will be recorded at selection 
visit using a holter ECG, in order to confirm persistent atrial fibrillation.  
8.3.6. 
Coagulation parameters 
The assessment of coagulation will be evaluated by the following parameters: 
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− Prothrombin Time/INR (PT/INR) 
− Activated Partial Thromboplastin Time (aPTT) 
− Thrombin Clotting Time (TCT) 
During the pre-cardioversion period, if the anticoagulation by AVK should be initiated, then the 
INR monitoring will be as follow:  
− INR 2-3 times a week for the first week of treatment 
− INR weekly up to ECV, 
− INR every 4 weeks after ECV 
For patients already treated with AVK, INR monitoring will be as follow: 
− INR weekly up to ECV, 
− INR every 4 weeks after ECV 
aPTT and TCT will be performed at visit 1, visit 2, visit 3, visit 5, visit 6, visit 7, visit 8 and  
visit 9. 
Anti-coagulation by anti-vitamin K should be given at least 3 weeks before ECV and continued 
for the whole study duration. 
The quantity of blood samples collected at each time for coagulation parameters will be 2 mL. 
8.3.7. 
Concomitant Treatments 
Concomitant treatments will be evaluated at each study visit. 
Requirements relating to patient's concomitant treatments started before screening visit and 
continued throughout the trial, or started during the trial can be found in section 7.  
8.4. 
COMPLIANCE 
The patient will be reminded at each visit to bring back any remaining soft capsules, blister, case 
(used or unused) at the following visit. 
At each visit, the Investigator will record the number of supplied and remaining Soft Capsules in 
the e-CRF. 
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9. STUDY PROCEDURES 
Visit 1 - Selection Visit (Week -4 to Week -1) 
The patient considered eligible for selection by the Investigator will be informed of the 
characteristics and the consequences of the trial both verbally and by reviewing the patient's 
information sheet and consent form (see section 14.3). If he/she accepts to participate in the study, 
he/she will sign the informed consent and will keep a copy. 
The patient will be assessed for the following: 
• Demographic characteristics (gender, age, height, body surface area) 
• Personal and medico-surgical history 
• Habits (Tobacco, alcohol consumption, dietary habits including fish consumption…) 
• Cardiovascular diseases, mainly detailed history of Heart Failure and Atrial Fibrillation 
characteristics  
• Echocardiography using a two-dimensional echocardiography.  
• 12-lead ECG 
• Concomitant diseases, adverse signs or symptoms (able to be used for treatment emergent AE 
determination) 
• Concomitant treatments (authorised, disallowed) 
• Global physical examination/bodyweight 
• Vital signs 
• Biology: haematology, biochemistry, assessment of coagulation parameters: Prothrombin 
Time/INR (PT/INR), Activated Partial Thromboplastin Time (aPTT), Thrombin Clotting Time 
(TCT) 
• Biology assessment of renal function: creatinine or estimated glomerular filtration rate 
If the results of the above assessments are compatible with the selection criteria 
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• A 24-hour continuous ECG ambulatory recording (Holter ECG) device will be installed on the 
patient to monitor the patient heart rhythm. The patient will be requested to bring back the device 
after the termination of 24 hours recording. The recording will be transmitted from the 
Investigational site to the Central Reading Laboratory (CRL). The CRL will send his/her 
assessment regarding the confirmation of persistent atrial fibrillation within 2 working days to the 
Investigator. 
• The patient will enter the selection period in which anticoagulant (anti-vitamin K) will be 
adjusted to achieve an International Normalized Ratio (INR) of 2 to 3 before electrical 
cardioversion.  
At the end of the visit, the Investigator will contact the IVRS/IWRS system to confirm the patient 
selection and order the treatment delivery and organise the appointment for the next visit.  
The patient will receive from the investigational centre the study card to be kept for the duration 
of the study. 
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Visit 2 - Inclusion Visit (Day 1)  
If the patient's behaviour during the selection period and/or the result of complementary 
examinations particularly the confirmation of the presence of persistent atrial fibrillation by the 
CRL during this period, the INR and laboratory tests, are compatible with the inclusion criteria, 
the patient will be assessed for the following: 
• Adverse events 
• Concomitant treatments (authorised, disallowed) 
• Laboratory examination: red blood cell concentrations of DHA and coagulation parameters 
Prothrombin Time/INR (PT/INR), Activated Partial Thromboplastin Time (aPTT), Thrombin 
Clotting Time (TCT) 
• Global Physical examination/bodyweight 
• Vital signs 
• Echocardiography using a two-dimensional echocardiography. 
• 12-lead ECG 
• Urine pregnancy test for women of child bearing potential. 
If the results of the above assessments are compatible with the inclusion criteria, the patient will 
be included and allocated a treatment number using the IVRS/IWRS system.  
Between this Inclusion visit and the next visit (V3), the INR will be closely monitored (refer to 
paragraph 8.3.6), in order to ensure that the INR is stable, between 2 to 3 before electrical 
cardioversion. 
At the end of the visit, the Investigator will organise the appointment for the next visit and give 
the treatment to be taken during the next 4-week period. 
Visit 3 (Week 4: D28 -2/+7 days) cardioversion 
Patient will be assessed for the following criteria: 
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• Adverse events 
• Concomitant treatments (authorised, disallowed) 
• Laboratory examination: Red Blood Cell concentrations of DHA, Prothrombin Time/INR 
(PT/INR), Activated Partial Thromboplastin Time (aPTT), Thrombin Clotting Time (TCT) 
• Global Physical examination /bodyweight 
• Vital signs  
• 12-lead ECG 
• Electrocardioversion (ECV): ECV has to be scheduled 4 weeks after randomization and after 
target international normalized ratio levels will be stabilized (between 2 and 3) on at least 3 
consecutive weekly tests in patients with AF. Patients not stabilized for INR (i.e. values between 2 
and 3) on at least 3 consecutive weekly tests performed before ECV will be excluded from the 
study, unless the presence of atrial thrombosis may be excluded with ECHO –TE (trans-
esophageal echocardiograph) performed  in the same day (before ECV). ECV will be performed 
in the morning, with the patient in the fasting state and without dyskalemia. Anesthesia will be 
induced and patients will be cardioverted with administration of a synchronized, biphasic current. 
The initial shock will be set at 100 J if the body weight is less than 70 kg and at 150 J for higher 
body weights. Successful cardioversion will be defined as recovery of sinus rhythm lasting at least 
1 minute after the shock. If unsuccessful, a second 200-J shock, and eventually a third 200-J 
shock, will be administered. Failure of ECV is defined as the persistence of AF after the third 
attempt at cardioversion. After the procedure, patients will be monitored on telemetry for at least 
6 hours before discharge. Patients who will not revert to sinus rhythm or with early relapse within 
the observation period after ECV will be withdrawn from the study and will be considered to have 
finished their follow-up. 
At the end of the visit, a 7-day continuous ECG (5-leads/2 or 3 channels) ambulatory recording 
(holter ECG) will be installed on the patient in order to monitor the patient heart rhythm after 
ECV.  
At the end of the visit, the Investigator will organise the appointment for the next visit and give 
the treatment to be taken during the next 4-week period. 
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Visit 4 (Week 5: D35 ± 2 days) 
After removal of the continuous ECG ambulatory device, the patient will be assessed for the 
following criteria: 
• Assessment of Adverse Events 
• Concomitant treatments (authorised, disallowed) 
• Vitals Signs 
• Echocardiography using a two-dimensional echocardiography 
At the end of the visit, the patient will be given the TTEM device (Trans Telephonic ECG 
Monitoring) for cardiac monitoring. The patient will be clearly instructed on the frequency and 
modalities of transmission. The patient will be requested to performed daily transmission from 
week 6 to week 8, then every 2 days from week 9 to week 24. Moreover, in case of AF symptoms 
additional transmission may be performed. 
Visit 5 (Week 8: D56 ± 7 days) – Visit 6 (Week 12: D84 ± 7 days) - Visit 7 (Week 16: D112 ± 
7 days) - Visit 8 (Week 20: D140 ± 7 days) 
Patient will be assessed for the following criteria: 
• Adverse events 
• Concomitant treatments (authorised, disallowed) 
• Laboratory examination: Prothrombin Time/INR (PT/INR), Activated Partial Thromboplastin 
Time (aPTT), Thrombin Clotting Time (TCT). However, in case of discontinuation of 
anticoagulation after ECV, the monitoring of INR, aPTT and TCT should be stopped. 
• Global Physical examination/bodyweight  
• Vital signs  
• 12-lead ECG 
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• The cardiac monitoring will be continued using a TTEM device (Trans Telephonic ECG 
Monitoring). The device will be given to the patient who will be requested to performed daily 
transmission from week 6 to week 8, then every 2 days from week 9 to week 24. Moreover, in 
case of AF symptoms additional transmission may be performed. 
The Investigator will collect all the cases, blisters and any unused soft capsules and count the 
unused capsules for each 4-week treatment period. 
At the end of the visit, the Investigator will organise the appointment for the next visit and give 
the treatment to be taken during the next 4-week treatment period. 
In addition: 
- at visit 5, the investigator will contact the IVRS/IWRS to obtain another treatment unit to be 
dispensed at visit 6 for the last 12-week period. 
- at visit 6, an echocardiography will be performed and, the red blood cell concentration of DHA 
will be measured.  
End-of-Study Visit - Visit 9 (Week 24: D168 ± 7 days) 
 Patient will be assessed for the following: 
• Adverse events 
• Concomitant treatments (authorised, disallowed) 
• Global Physical examination/bodyweight 
• Vital signs 
• 12-lead ECG 
• Laboratory examination: haematology, biochemistry, assessment of coagulation parameters: 
Prothrombin Time/INR (PT/INR), Activated Partial Thromboplastin Time (aPTT), Thrombin 
Clotting Time (TCT). Red blood cell concentration of DHA. 
• Urine pregnancy test for women of childbearing potential 
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• Echocardiography using a two-dimensional echocardiography 
The Investigator will collect all the cases, blisters and any unused soft capsules and count the 
unused soft capsules. 
10. ADVERSE EVENTS: DEFINITION AND REPORTING 
10.1. 
ADVERSE EVENTS 
10.1.1. Definition of Adverse Events 
An adverse event is any adverse change from the patient's baseline condition, i.e. any subjective 
signs and symptoms or change in a concomitant disease present at the Selection Visit considered 
or not related to the treatment. 
This includes intercurrent signs, symptoms, illnesses and significant deviations from baseline for 
vital signs and laboratory values, which may occur during the course of the clinical study. 
All laboratory tests for which abnormal results are collected after study treatment initiation should 
be repeated until the values return to normal or to a stable status. Abnormal results are defined as 
those falling out of the laboratory normal ranges and that are clinically significant. The frequency 
of such checks should be defined by the Investigator according to the degree of abnormality. 
In all cases, the aetiology should, as much as possible, be identified and Pierre Fabre Médicament 
notified. 
10.1.2. Grading of Adverse Events 
Adverse or intercurrent events are graded as follows: 
• Mild: awareness of signs or symptoms, but easily tolerated 
• Moderate: uncomfortable enough to cause interference with usual activity 
• Severe: incapacity with inability to work or do usual activity. 
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10.1.3. Reporting of Adverse Events 
The records of adverse events in the electronic Case Report Form (e-CRF) describe the nature 
(diagnosis, signs and symptoms), severity, onset date, stop date, outcome and actions taken, and 
relationship to study treatment (in the Investigator's opinion). It must be specified whether the 
event is serious or not. 
10.2. 
SERIOUS ADVERSE EVENTS (SAE) 
10.2.1. Definition 
A serious adverse event (SAE) includes, but is not necessarily restricted to any event which: 
• Results in death (whatever may be the cause) 
• Is life-threatening 
• Results in persistent or significant disability/incapacity 
• Requires the patient's hospitalisation or prolongation of current hospitalisation * 
• Is a congenital anomaly or birth defect. 
Other events such as cancer, and any additional adverse experience or abnormal laboratory values 
occurring during the study period, defined by the protocol as serious or which the Investigator 
considers significant enough, or that suggest a significant hazard, contra-indications, side effect or 
precaution, must be handled as serious adverse events. 
Any overdosage meeting a seriousness criteria should be reported as a SAE (see section 10.3). 
Any pregnancy occurring during/after exposure to the study drug(s) should be reported on the 
SAE notification form (see section 10.4). 
* any hospitalisation, or prolongation of hospitalisation due to the circumstances listed below: 
− planned (as per protocol) medical/surgical procedure, 
− preparation for routine health assessment/procedure (e.g. routine colonoscopy), 
− planned medical/surgical admission (planned prior to entry into study trial, appropriate 
documentation required), 
− administrative or social reasons (e.g. lack of housing, economic inadequacy, care-giver 
respite, family circumstances) 
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will not be reported as a SAE. 
10.2.2. Reporting of SAE 
All serious adverse events, according to the above-mentioned definitions and regardless of 
treatment or relationship to study drug, must be recorded by the Investigator as soon as he/she is 
informed of the event. 
The Investigator must notify the Sponsor of this event by sending, within 24 hours, the 
"Notification of serious adverse event" form ("first notification") (see appendix 17.2) with all the 
available information about the event, to the Sponsor's representative: 
Marlène GUIRAUD, Pharm D 
INSTITUT DE RECHERCHE PIERRE FABRE,  
Centre de R&D Pierre Fabre – BP 13562 
3 Avenue Hubert Curien 
31035 TOULOUSE Cedex 1 
Phone: +33 5 35 50 63 48 
Fax: + 33 5 34 50 65 92 
Email: marlene.guiraud@pierre-fabre.com 
In case of non-inclusion the reporting period ends when the non-inclusion is documented. 
10.2.3. Follow-up of SAE 
The Investigator must draw-up a specific clinical report and use the "Notification of serious 
adverse event" form ("follow-up") (see appendix 17.2) and collect the results of the carried out 
examinations and the reports of hospitalisation. 
The serious adverse events must be followed up until resolution or stabilisation. 
10.2.4. SAE Occurring After the Study 
Any SAE occurring during 30 days following the end of the study for the patient should be 
notified to the Sponsor. 
Must also be notified to the Sponsor any event occurring at any time after the end of the study for 
the patient which may be related to the study treatment in the Investigator's opinion. 
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10.3. 
REPORTING OF OVERDOSAGE TO THE SPONSOR 
For the purpose of this trial an overdosage will be defined as any dose exceeding the planned 
prescribed dose of the study drug or the administration of any dose of an associated product that is 
considered both excessive and medically important. 
In the absence of seriousness criteria, the overdosage, and associated adverse event if any, are 
reported only on the Adverse Event page of the CRF. If the definition of seriousness criteria is 
met, the SAE notification form must be also transmitted to the sponsor. 
10.4. 
REPORTING OF PREGNANCY TO THE SPONSOR 
Pregnancies discovered in the period in between the informed consent form signed but before any 
study drug exposure are not to be reported to the sponsor unless associated to a seriousness 
criteria (e.g. serious adverse event study-protocol related procedure). If pregnancy is confirmed, 
the women must not be administered the study drug and be withdrawn immediately from the 
study.  
If pregnancy is suspected while the patient is receiving study treatment, the study drug(s) should 
be discontinued immediately until the result of the pregnancy testing is known. If pregnancy is 
confirmed, then the study treatment is permanently discontinued in an appropriate manner and the 
patient is discontinued from the study.  
The investigators must report to the sponsor any pregnancy which occurs during or after the 
patient has been exposed to the study drug and until 30 days after the last study drug 
administration. The investigator must immediately notify the sponsor using the SAE notification 
form and also report the pregnancy on the AE page of the e-CRF. 
Women who become pregnant after exposure to the study drug must be followed by the 
investigator until the completion/termination of the pregnancy. If the pregnancy goes to term, the 
outcome will have to be reported to the sponsor (baby's healthy status). 
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10.5. 
SPONSOR'S RESPONSIBILITIES FOR SAFETY REPORTING 
 
PURPOSES 
Sponsor will submit expedited and periodic reports to both Competent Authorities and Ethics 
Committees per corporate standard operating procedures as regards to the EU directive 
2001/20/EC taking into account local specific requirements. 
11. DATA COLLECTION AND STUDY MONITORING 
11.1. 
DATA COLLECTION 
11.1.1. Case Report Form 
An electronic Case Report Forms (e-CRF) will be used to record all patient data required by the 
protocol except the central ECG (Holter ECG, TTEM) and DHA data which will be transferred 
from vendors to the subcontractor as electronic data files and which will be loaded into the study 
database.  
The e-CRF should be fully validated, compliant with ICH-GCP requirements and European 
regulations and include a traceability system for data corrections and deletions (audit trail). 
Prior to the start of the study, the Investigator will complete a "Delegation of significant study-
related duties" form. The signature and initials of all personal in charge of e-CRF completion 
should be recorded on this form. Each person involved in e-CRF completion, review, correction 
and / or validation will be trained and will have an individual login and access code to the e-CRF. 
Training sessions will be held by the subcontractor for all participants who will use this tool. An 
e-CRF user manual will be available for investigators and CRAs.  
All the information included into the e-CRF will be recorded from source documents onto the e-
CRF by an authorised person. 
The Investigator is responsible for the management and accuracy of the information on the  
e-CRF. At each monitoring visit, the e-CRF(s) should be at the CRA's disposition for review and 
validation. 
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At the end of the study, a CD-ROM containing the pdf version of all e-CRF (including audit-trail) 
will be sent by the subcontractor to the Sponsor and to the investigational sites for archiving. The 
subcontractor must store all study data for at least 15 years after the end of the study and ensure 
their legibility and accessibility during all the storage period. 
11.1.2. Source Documents 
A source document is an original record or certified copy of an original record of clinical findings, 
observations or any other medical or paramedical activities performed during the clinical trial, 
necessary for the transcription and the verification of the collected data. 
Source documents along with all other trial-related documents (copies of all "informed consent" 
forms, e-CRFs CD-ROM, drug inventories and any correspondence related to the study) must be 
kept in the investigator's file throughout the study, and then, must be stored in the study centre's 
archives for a period of at least 15 years or as per local legal requirements, whatever is the 
longest.  
For further details see section 15.2. 
11.2. 
STUDY MONITORING 
11.2.1. Monitoring visits 
On-site visits will be carried out by a representative of the Sponsor's staff (Study Manager or 
CRA) prior to study initiation and at regular intervals (every 4 to 6 weeks) throughout the study. 
Additional visits and communication by telephone fax or meeting may be performed if necessary. 
Any site visit performed by the Sponsor's representatives will be recorded in the Investigator's 
study file. 
11.2.1.1. 
Site Preselection Visit 
Before selecting a centre for the study, a visit will be carried out by the CRA and/or the Study 
Manager to ensure that the Investigator has the necessary capacities (availability, patient's 
recruitment, environment), technical means and staff to carry out the study. 
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11.2.1.2. 
Initiation Visit 
Before the start of the study at all investigation sites, an initiation visit will be carried out by the 
CRA to check at the latest that: 
• The Investigator: 
− has received the technical protocol, administrative and financial agreement signed by all 
parties 
− has received the written statement of the Ethics Committee approval and the list of its 
members and their functions 
• The original dated and signed curriculum vitae of the investigator(s) has been collected 
• Laboratory normal ranges have been collected  
• All study materials are available on the study site 
• All participants agree with the monitoring procedures and know the study procedures 
• All participants are aware of a possible audit or inspection 
The CRA has also to provide training on the study protocol requirements and study specific 
procedures. 
11.2.1.3. 
Follow-up Visits 
Throughout the study, regular follow-up visits will be carried out by the CRA to check 
compliance with GCP, patient’s informed consents, strict application of the protocol, conformity 
of the data entered on the e-CRF with the source documents and ensure its correct completion, 
adverse events reporting, proper retention, storage and management of the study medication, as 
well as the source and other trial-related documents. 
11.2.1.4. 
Closing Visit 
At the end of the study, a final visit will be carried out by the CRA to: 
• Verify that the e-CRFs CD-ROM with pdf files are correctly stored 
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• Control the accountability of intact and used treatment units and return them to the Clinical 
Pharmacy Department of the IRPF for destruction 
• Obtain the last data clarifications and/or solutions if any 
• Collect the patient's consent forms in sealed envelopes,  
• Make an on-site review of all study documentation and complete it if necessary 
• And finally, remind the Investigator of his regulatory obligations, study document archiving 
process and duration. 
11.2.2. Direct Access to Source Documents 
In accordance to the requirements of the GCP, all Sponsor representatives (Study Manager, CRA 
and Auditors) have to be given a direct access to all source and study data to perform quality 
monitoring/audit, thus ensuring accuracy and completeness of data).  
Investigators are reminded that all Sponsor representatives keep professional confidentiality with 
regards to the patient data. 
11.3. 
INDEPENDENT DATA MONITORING COMMITTEE 
An Independent Data Monitoring Committee (IDMC) will be established to assess at intervals the 
progress of the clinical trial, the compliance with the inclusion criteria, the quality of follow up, 
the quality of measures of primary end point, the safety data and to recommend to the Sponsor 
whether to continue, modify, or to stop the study.  
The IDMC operating procedures will be described in an independent document.  
12. DATA MANAGEMENT  
All clinical data related to the study will be collected and saved in a computerised database by the 
Data Management Department of the subcontractor and under the supervision of the Data 
Manager of Pierre Fabre Biometry (PFB) according to the following procedures.  
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12.1. DATA ENTRY 
All required data will be collected by the Investigator or authorised designee (duly identified into 
the delegation task list) on a e-CRF.  
The e-CRF used for this study will be developed and maintained by the Data Management 
Department of the subcontractor and approved by the Sponsor.  
Electronic data (Holter ECG, TTEM and DHA) will be transferred by the 3rd party vendor 
according to the specifications given by the Data Manager of the subcontractor. These data will be 
captured and handled in accordance with the European GCP ICH E6 guideline. 
12.2. 
DATA CLEANING 
The subcontractor will define in the Data Validation Plan for reviewing and querying data, 
descriptions of both manual and electronic edit checks. Upon Sponsor approval, the subcontractor 
will program the checks.  
The subcontractor will review the data over the course of the study, working with the Sponsor to 
identify data inconsistencies. The Investigator will be asked to resolve queries by making changes 
directly into the e-CRF.  
12.3. 
DATA CODING 
Adverse events, concomitant diseases, medical/surgical histories will be coded by the 
subcontractor using the MedDRA dictionary (latest version in use). 
Concomitant medication will be coded by the subcontractor using the WHO-DRUG dictionary 
(latest version in use).  
The Sponsor Clinical Development Physician will validate coding. 
12.4. 
DATA STORAGE 
The computer data files, as well as their modifications, will be archived by the subcontractor and 
kept available upon request of the Sponsor. 
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12.5. 
DATABASE LOCK 
The validated database will be locked by the subcontractor upon request of the Data Manager of 
PFB following the completion of all steps required, i.e.: data entry and check of all data, 
resolution of all queries, validation of the coding, Clinical and Products Safety databases 
reconciliation and validation committee.  
Then, the subcontractor will transfer the locked database in SAS format to the Data Manager of 
PFB who assume storage on the PFB secured server. 
13. STATISTICAL ANALYSIS 
After the database lock and the randomisation code release, the statistical analysis will be 
performed by Pierre Fabre Biométrie (PFB) or under the supervision of the statistician of PFB 
using SAS® software, according to the Statistical Analysis Plan (SAP) approved by the Validation 
Committee. 
13.1. 
GENERAL CONSIDERATIONS 
The main objective of the study is to assess the efficacy of F373280 versus placebo on the 
maintenance of sinus rhythm after direct electrical cardioversion in patients with persistent atrial 
fibrillation and chronic heart failure. 
Only the primary analysis of the primary efficacy criterion, on which is based the sample size 
justification, may lead to a causal interpretation. All other statistical results are to be regarded 
within a descriptive perspective. 
The statistical significance level of the various two sided tests of all analyses will be 5 %. 
13.2. 
SAMPLE SIZE 
Assuming an AF recurrence rate of 85% under placebo and 65% under active group, i.e. a 
clinically relevant difference ∆ of 20%, a sample size of 64 evaluable patients per group is 
required to achieve, using a log-rang test of survival curves with a 80 % power and a 5 % two-
sided significance level. 
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According to the previous assumptions and assuming a rate of not assessable patients of 15%, a 
minimum of 76  patients will have to be randomised per group. 
13.3. PROTOCOL DEVIATIONS 
Prior to the database lock and the randomisation code release, the Validation Committee members 
will review the protocol deviations and will classify them as either minor or major. A protocol 
deviation will be considered major when it is likely to bias significantly the treatment effect 
estimate based on the primary efficacy criterion. 
Patients with major deviation(s) will be excluded from the Per Protocol data set (see section 13.4). 
A listing of all protocol deviations will be provided for all randomised patients, including the type 
(major/minor) of protocol deviations according to the decisions made by the members of the 
Validation Committee. 
The number and percentage of patients with major protocol deviations will be tabulated by 
treatment group and type of major protocol deviations on the Full Analysis Set defined in section 
13.4. 
13.4. DATA SETS ANALYSED 
The following 2 data sets will be analysed (as defined by the Validation Committee):  
 
• The Safety Set composed of all randomised patients having received at least one dose of the 
study treatment. This data set will be used to perform analyses of Safety 
• The Full Analysis Set (FAS) composed of all randomised patients having received at least one 
dose of the study treatment and with a successful cardioversion observed at visit 3. This data set 
will be used to perform analyses of Efficacy.  
• The Per Protocol Set (PP) which is the subset of the Full Analysis Set composed of all patients 
with a primary efficacy criteria available and without any major protocol deviation or other source 
of bias for primary criteria analyses. 
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13.5. 
HANDLING OF DROPOUTS AND MISSING DATA 
13.5.1. Dropouts 
The number of patients who withdraw from the study after their randomisation will be provided 
by treatment group for all treated patients (Safety Set). All withdrawn patients will be further 
described regarding their time to dropout and reasons for withdrawal. 
13.5.2. Repositioning of Visits 
No repositioning of visits will be done. 
13.5.3. Missing Data 
Missing values will not be substituted by estimated values, but considered as missing in statistical 
analysis. 
13.6. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Before the first trial drug intake, patient’s background, medical and surgical history, demographic 
data and disease characteristics will be described by treatment group on the Safety Set. 
- Quantitative parameters will be described by treatment group and overall using the 
following: number of patients, number of missing data, mean, standard deviation, 
minimum, median and maximum values. 
- Qualitative parameters will be described by treatment group and overall using 
frequencies. 
Concomitant diseases, as well as medical and surgical histories will be tabulated descriptively by  
treatment group and overall using the MedDRA codes of System Organ Classes and preferred 
terms. 
If more than 10% of patients are excluded from the FAS and PP set, the description of patients by 
treatment group at selection and inclusion will be repeated on the FAS and PP set for all 
parameters. 
No statistical test of comparability of treatment groups at baseline will be performed.  
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13.7. 
EFFICACY ANALYSIS  
13.7.1. Primary Criterion  
13.7.1.1. 
Primary Analysis 
The primary criteria, time to first recurrence, will be analysed using the Kaplan Meier method and 
compared with the Log rank test. Hazard ratios and 95% confidence intervals will be estimated 
with the Cox regression model. 
The primary analysis will be performed on the FAS. 
13.7.1.2. 
Supportive Analysis 
The primary analysis will be repeated on the PP set. 
13.7.2. Secondary Criteria 
All secondary analyses will be performed on the FAS. If more than 10% of patients are excluded 
from the PP set, the secondary analyses will be repeated on the PP set.  
13.7.2.1. Numbers of Atrial Fibrillation Episodes 
Both the numbers of AF episodes (symptomatic or not) lasting for at least 10 minutes and with 
duration less than 10 minutes (NSup10 and NInf10) will be described by treatment group and 
compared by the chi-square test (or CMH test adjusted for centre) or Fisher’s exact Test. 
13.7.2.2. Duration of Atrial Fibrillation Episodes 
The duration of all AF Episodes will be described by treatment group and compared using the 
Student t (or using an ANOVA with treatment and centres effects) or Wilcoxon test. 
13.7.2.3. Time to first AF recurrence less than 10 minutes or symtomatic 
The time to the first AF recurrence less than 10 minutes and the time to the first symptomatic AF 
recurrence will be analysed as the primary analysis.  
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13.7.2.4. Clinical parameters evaluation 
The EHRA score will be described by treatment group and analysed using a chi-squared test (or 
CMH test adjusted for centre) or Fisher’s exact Test.  
The frequency of presumed arrhythmia will be described by treatment group. 
The number of recurrence of symptomatic AF, of hospitalizations (for cardiovascular events, for 
thromboembolic stroke and for all causes), of spontaneous cardioversion, of successful 
cardioversion (including number of shocks distribution) and the number of patients needing 
cardioversion after initial ECV will be described by treatment group and compared using a chi-
square test or a Fisher Test (if the numbers are relevant).  
The duration of hospitalizations for cardiovascular events, for thromboembolic stroke and for any 
cause will be described by treatment group and compared using the Student t (or using an 
ANOVA with treatment and centre effects) or Wilcoxon test. 
The echocardiographic parameters values will be described at each time (V1, V2, V4, V6 and V9) 
and changes described from V4 to V9 and from V2 to V9. 
13.7.2.5. Biomarker analysis: red blood cell concentrations of DHA 
Values and changes from baseline for red blood cell concentration of DHA will be performed by 
treatment group and assessment time. 
13.8. 
SAFETY ANALYSIS 
The Safety Set will be used to perform all analyses of the safety criteria. 
13.8.1. Adverse Events 
Any adverse event having been reported during the study for a given patients will be classified by 
preferred term and corresponding system organ class using the MedDRA terminology. 
Adverse events will be classified as: 
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• Treatment emergent adverse events, i.e., any adverse event which occurs or worsens on study 
treatment during the randomised period. 
• Or non treatment emergent adverse events, i.e., any adverse event which occurs during the 
run-in period (before V2) or is reported as concomitant disease with the same intensity. 
For each study period, any patient with at least one reported adverse event will be classified as a 
patient: 
• With at least one adverse event 
• With at least one treatment emergent adverse event 
• With one TEAE 
• With two TEAE 
• With at least three TEAE 
• With at least one related TEAE 
• With an adverse event leading to the study treatment discontinuation (definitive or 
temporary) 
• With an adverse event leading to withdrawal 
• With at least one serious adverse event. 
• 
Numbers and percentages of patient with at least one reported treatment emergent adverse 
event will be tabulated by treatment group: 
• By system organ class 
• By system organ class and preferred term 
• By system organ class and preferred term, taking into consideration its most severe 
intensity 
• And by system organ class and preferred term, taking into consideration the most severe 
relationship to the study treatment. 
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Recurring adverse events (i.e., adverse events classified with the same preferred term) for a given 
patient will only be counted once and only their most severe intensity or most severe relationship 
to the study treatment will be tabulated. 
"The number and percentage of patient with at least one most common (reported in 1% patients in 
any group) drug related TE AE ("not excluded or unassessable") will be tabulated by Preferred 
Term and Treatment group in decreasing order for the treatment group (for all patient). 
The number and percentage of patients with at least one reported most common treatment 
emergent adverse event will also be plotted by treatment group. This graphical representation will 
highlight the frequencies of the most severe intensities reported by system organ class and 
preferred term. 
Serious adverse events will also be described on an individual basis: treatment group, patient's 
code, sex and age, Investigator's reported term, preferred term, time of onset according to the time 
of the first study treatment administration, duration, action taken regarding the study treatment 
administration, use of a corrective treatment, outcome and relationship to the study treatment in 
the Investigator’s opinion. 
13.8.2. Clinical Laboratory Evaluation  
For each laboratory parameter, data will be tabulated by treatment group and assessment time. 
The absolute changes post-trial drug administration - baseline (the baseline value being the value 
measured on the last blood sample collected before the first trial drug administration) will be 
calculated and tabulated by parameter, treatment group and post-trial drug administration 
assessment time. Results of retests performed post-trial drug administration will not be analysed 
and tabulated. They will only be displayed in individual data listings. 
For all blood laboratory parameters, scatter plots highlighting individual results will display the 
baseline and week 24 of the laboratory measurements for each patient by locating the point 
defined by the baseline value on the abscissa and respectively week 24 value in the ordinate. Each 
treatment group will be identified differently. The first bisecting line (45° line), the lines of lower 
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and upper normal range, the lines of PSC range and CNALV range added on the plots (see 
Appendix 17.3). 
For all blood laboratory parameters, shift tables will be provided to depict the numbers of  patients 
with post-trial drug administration variations at each assessment time as compared to the baseline 
values (measured on the last blood sample collected before the first trial drug administration) by 
treatment group. A 3-point scale (low, normal, high) will be used as defined by the normal ranges 
in use in the laboratory in charge of the assays. 
Clinically noteworthy abnormal laboratory values (CNALV) (see in Appendix 17.3) will be 
identified and described on an individual basis. If relevant, five separate individual data listings by 
treatment group will be provided: 
• CNALV for haemoglobin (including corresponding individual results of erythrocytes and 
haematocrit) 
• CNALV for neutrophils or leucocytes (including corresponding individual results of 
basophils, eosinophils, lymphocytes and monocytes) 
• CNALV for platelets (including corresponding individual results of erythrocytes and 
leucocytes) 
• CNALV for liver function parameters (including corresponding individual results of 
gamma-GT) 
• CNALV for serum creatinine  
13.8.3. Global Physical Examination 
Recorded data of the global physical examination performed will not be tabulated as any 
abnormal findings post-randomisation should be reported as AEs (if clinically significant). 
Physical examination assessments will be provided in the listings of individual data. 
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13.8.4. Vital Signs, Physical Findings and Other Observations Related to Safety 
13.8.4.1. 
Vital Sign Measurements Over Time 
For each parameter (systolic blood pressure, diastolic blood pressure and heart rate in supine and 
standing positions), descriptive statistics over time of values and changes from baseline will be 
tabulated by treatment group and assessment time. 
13.8.4.2. 
Body weight 
Descriptive statistics over time of values and changes from baseline will be tabulated by treatment 
group and assessment time. 
13.8.4.3. 
Individual Patient Changes 
The number and percentage of patient with at least one Predefined Potentially Clinically 
Significant Change (PSC) and with at least one PSC Leading to Clinically Significant Value 
(PSCV) will be tabulated by treatment group (see Table 1 in Appendix 17.3).  
According to the pharmacological drug profile mentioned previously in this Protocol, the changes 
from baseline to the maximum and/or minimum post-baseline value could be categorized and 
tabulated by treatment group with frequencies and decreasing cumulative percentages. 
If there is a signal of a drug effect toward one direction rather than the other, additionally shift 
tables of variations from baseline to the maximum or minimum post-baseline value could be also 
provided (see Table 2 to 4 in Appendix 17.3). 
An individual data listing of patients with symptomatic or asymptomatic orthostatic hypotension 
will be provided by treatment group (see Table 5 in Appendix 17.3). 
13.8.5. ECG 
Frequencies on the clinical interpretation (normal, abnormal CS or NCS) will be presented by 
treatment group and assessment time. Individual tabulated data for ECG abnormalities will be also 
displayed. 
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13.8.6. Coagulation parameters 
Scatter plots highlighting individual results for coagulation parameters (prothrombin time/INR, 
activated partial thromboplastin time and thrombin clotting time) before and after study treatment 
administration will be produced. 
13.9. CONCOMITANT TREATMENTS 
Concomitant treatments will be tabulated by treatment group within a descriptive perspective. 
They will be classified by therapeutic area according to the WHO-DRUG dictionary using the 
"anatomical therapeutic chemical" (ATC) classification on the safety set. 
13.10. 
COMPLIANCE 
 
The percentage of compliance will be described by treatment group using the quantity 
 
100
_
_
_
(%)
×
=
n
consumptio
l
Theoretica
n
consumptio
actual
Estimated
Compliance
 
 
 
with: Estimated actual consumption = number of tablets provided at the start of study (Visit 2) – 
number of tablets returned at the end of study (Visit 9) 
Theoretical consumption = number of days of treatment intake planned between the start and the 
end of study (168 days ± 7days). 
 
13.11. 
INTERIM ANALYSIS AND DATA MONITORING 
No interim analysis is planned. 
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14. GENERAL ETHICAL CONSIDERATIONS  
14.1. 
ETHICAL CONDITIONS 
This study is performed in accordance with the principles stated in the Declaration of Helsinki 
(1964) and subsequent amendments and in accordance with the Good Clinical Practice Guideline 
(CPMP/ICH/135/95). 
14.2. 
ETHICS COMMITTEE AND LEGAL REQUIREMENTS 
All the documents required by National Regulations and any other informative documents that 
may be requested are submitted for review to an Ethics Committee whose procedures and 
operations meet the GCP and National Legal Requirements. 
Depending on National Regulations, the application is submitted to the Ethics Committee by the 
Sponsor (or representative) or by the Investigator. 
A copy of the formal written approval from the Ethics Committee is provided to the Sponsor 
(directly by the Ethics Committee or via the Investigator) with a list of names and qualifications 
of its members. 
The request for authorisation by the Competent Authority or its notification if required (depending 
on National Regulations) is carried out by the Sponsor. 
The screening of patients does not start before the approval of the Ethics Committee has been 
obtained and the study authorised by the Competent Authority or notified to the Competent 
Authority (depending on National Regulations). 
14.3. 
PATIENT'S INFORMATION LEAFLET AND INFORMED CONSENT 
 
FORM 
An information must be given to the patients before their decision to participate or abstain from 
participation. 
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This information is based on the elements set out in the Declaration of Helsinki and the ICH GCP 
Guidelines. It must also describe the measures taken to safeguard patient’s privacy and protection 
of personal data, according to European Directive 95/46 EC or other local regulation. 
Restraints and risks must be explained, as well as the right to discontinue participation in the 
study at any stage, without affecting their further relationship with the Investigator and/or their 
future care. 
The written information and consent form must be submitted to the patient with an oral 
explanation. It must be agreed and signed by the patient before any study-related procedure starts. 
This information and consent procedure is under the Investigator’s responsibility. 
The information and consent document are made in triplicate: the original copy is kept by the 
Investigator, one copy is given to the patient and the last copy is kept by the Clinical Quality 
Assurance Unit of the Sponsor in a sealed envelope at the end of study. 
Specific areas of the Sponsor’s copy are not triplicated to avoid the reading of the patient’s 
surname (except the first 3 letters), first name, address and signature.  
If any information becomes available during the trial that may be relevant to the patient’s 
willingness to keep on participating in the trial, an updated written informed consent must be 
submitted to the patient to confirm  agreement to continue participating. 
14.4. 
PERSONAL DATA PROTECTION 
All information from this study (excluding data from the informed consent) is entered into a 
computer under the Sponsor’s responsibility in accordance with the French law, "Loi 
Informatique et Libertés" (January 6, 1978, and subsequent amendments) and with the European 
Directive 95/46/CE. 
14.5. 
INSURANCE POLICY 
In accordance with the provisions of the law and the GCP, the Sponsor Pierre Fabre Médicament, 
has an insurance policy intended to guarantee against possible damage resulting from the research. 
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The studies and/or experiments performed on behalf of the Sponsor Pierre Fabre Médicament, are 
specifically and expressly guaranteed. 
It is advisable to underline that non compliance with the Research Legal Conditions is a cause for 
guarantee exclusion. 
15. ADMINISTRATIVE PROCEDURES 
15.1. 
PROTOCOL AMENDMENT 
Neither the Investigator nor the Sponsor may alter the protocol without the authorisation of the 
other party.  
All changes to the protocol are subject to an amendment which must be dated and signed by both 
parties and must appear as an amendment to the protocol. 
Substantial amendments are submitted for approval / authorisation to the Ethics Committees and 
Competent Authorities 
Urgent amendments are submitted for approval / authorisation to the Ethics Committees and 
Competent Authorities, but could be implemented immediately under specific conditions defined 
with the Sponsor. 
15.2. 
SOURCE DOCUMENTS, INVESTIGATOR'S FILE STORAGE 
The Investigator: 
• Keeps all trial-related documents in appropriate file folders. Records of patient, original 
informed consent forms, source documents, a CD Rom containing a pdf copy of e-CRF, drug 
inventory, Ethics Committees and Sponsor correspondence pertaining to the study must be kept 
on file. 
• Retains all documents relating to the screening (consent and investigation results) of all 
patients included in the trial or not 
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• Retains a list of the patient’s names, addresses (and/or number of medical file), code numbers 
to allow checking of data reported on e-CRFs with those from source documents 
• Authorises direct access to source documents for monitoring, audits and inspections 
• The trial-related documents must be retained as strictly confidential at the Investigator’s site 
for at least 15 years or according to local requirements, whatever is the longest after the 
completion or discontinuation of the trial (European Directive 2003/63/EC). 
15.3. 
END OF THE STUDY 
15.3.1. Definition of the End of Study 
The end of study is the last visit of the last patient undergoing the trial. 
Any change to this definition during the study, for whatever reason, must be notified as a 
substantial amendment. 
15.3.2. Early Study Termination 
15.3.2.1. 
Early Study Termination Decided by the Sponsor 
The Sponsor may discontinue the study at any time for any of the following reasons: 
• Lack of recruitment 
• Deviations from good clinical practice and/or regulations 
• Poor product safety 
• New information that could jeopardise the patient’s safety 
• Stopping of the development … 
15.3.2.2. 
Early Study Termination Decided by the Competent Authorities 
The Competent Authorities may suspend or prohibit a study if it considers that the conditions of 
authorisation are not being met or has doubt about the safety or scientific validity of the study. 
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15.4. 
AUDIT 
The 
Sponsor 
is 
responsible 
for 
making 
sure 
that 
both 
his 
representatives 
(Study Manager, CRA, ...) and the Investigator fulfil the requirements as specified by the GCP 
Guideline.  
An audit can be organised internally at Pierre Fabre Médicament and at the investigational site 
where the e-CRFs are matched against source documents. 
All study documentation must be directly accessible to auditors. 
The practical conditions for the audit are discussed between the Investigator and the Clinical 
Quality Assurance Department. 
Oral information about the audit results are given to the Investigator. 
15.5. INSPECTION 
The Health Authorities may inspect any investigation site or the Sponsor in the course of the study 
or after its completion, to verify the conduct of the study and quality of the data. The Investigator 
must provide to the inspectors direct access to study documents. 
15.6. CONFIDENTIALITY 
The present materials (protocol and related documentation, e-CRF, Investigator's Brochure) 
contain confidential information.  
Except if agreed to in writing with the Study Manager, the investigators must hold such 
information confidential, and must not disclose it to others (except where required by Applicable 
Law). 
15.7. CLINICAL STUDY REPORT 
Data analysis, and clinical study report writing are under the Sponsor’s responsibility.  
Upon completion of the data analysis, a final report, including a review of the objectives and 
methods, a presentation and discussion of the results are drawn up according to ICH Guidelines 
(Structure and Content of Clinical Study Reports, ICH-E3, CPMP/ICH/137/95). 
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The report is a clinical and statistical integrated report. It must be signed by the Sponsor's 
representative(s) and the Coordinating Investigator. 
15.8. STUDY RESULTS COMMUNICATION 
Upon completion of the study, the global results of the Research are communicated to the 
investigator. According to the Local Regulation, the patient can ask the Investigator for the 
results. 
15.9. STUDY RESULTS PUBLICATION 
The information and data collected during the conduct of this clinical study are considered 
confidential and are used by the Sponsor in connection with the development of the study drug. 
This information may be disclosed if deemed necessary by the Sponsor. 
To allow use of the information derived from this clinical study and to insure compliance with 
Current Regulations, the Investigator must provide the Sponsor with complete test results and all 
data collected during the study.  
Only the Sponsor may make study information available to physicians and to Regulatory 
Agencies, except as required by Current Regulations. 
All the results of this study including data, reports, discoveries and inventions resulting from the 
study, are the property of the Sponsor. 
In the event the Sponsor chooses to publish study data, the manuscript must be provided to the 
author(s) at least 30 days prior to the expected date of submission to the intended publisher. 
The investigator(s) can reserve the right to publish or present study data; if so, the manuscript or 
abstract must be provided to the Sponsor for review at least 30 days prior to the expected date of 
submission to the intended publisher or of planned presentation. 
In addition, if necessary, (the) investigator(s) shall withhold publication for an additional 60 days, 
to allow the filing of a patent application, or to allow the Sponsor to take any measures he deems 
appropriate to establish and preserve his proprietary rights. 
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It is agreed that publication of study results by each site shall be made only as part of a 
publication of the study results obtained by all sites performing the protocol, once the study is 
completed and finalised.  
The authors list is agreed by all investigators prior to publication. The names of the authors are 
provided according to their participation in the design of the protocol as well as their recruitment 
of eligible and analysable patients. 
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16. REFERENCES 
 
[1] 
F373280 INVESTIGATOR'S BROCHURE, version October 2012 
 
[2] 
NODARI S., TRIGGIONAI M., CAMPIA U., MANERBA A., MILESI G., CESANA 
M.B., GHEORGHIADE M., DEI CAS L. 
n-3 Polyunsaturated Fatty Acids in the prevention of atrial Fibrillation Recurrences after 
electrical cardioversion. A prospective, Randomised study 
Circulation, 2011; 124:1100-1106 
 
[3] 
NODARI S., TRIGGIANI M., CAMPIA U., MANERBA A., MILESI G., CESANA 
M B., GHEORGHIADE M., DEI CAS L. 
Effects of n-3 polyunsaturated fatty acids on left ventricular function and functional 
capacity in patients with dilated cardiomyopathy 
J. Am. Coll. Cardiol. 2011;57;870-879 
 
[4] 
MOERTL D., HAMMER A., STEINER S., HUTULEAC R., VONBANK K., 
BERGER R. 
Dose-dependant effects of omega-3-polyunsaturated fatty acids on systolic left ventricular 
function, endothelial function, and markers of inflammation in chronic heart failure of non 
ischemic origin: A double-blind, placebo-controlled, 3-arm study  
American Heart Journal 2011; 161:915.e1-915.e9 - volume 161, number 5 
 
[5] 
GISSI-HF INVESTIGATORS 
Effects of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GSSI-
HF Trial): a randomised, double-blind, placebo-controlled trial 
The lancet on line - August 2008 
 
[6] 
CAMM A.J., KIRCHHOF P., LIP G.Y., SCHOTTEN U., SAVELIEVA I., ERNST S., 
VAN GELDER I.C., AL-ATTAR N., HINDRICKS G., PRENDERGAST B., 
HEIDBUCHEL H., ALFIERI O., ANGELINI A., ATAR D., COLONNA P., DE 
CATERINA R., DE SUTTER J., GOETTE A., GORENEK B., HELDAL M., 
HOHLOSER S.H., KOLH P., LE HEUZEY J.Y., PONIKOWSKI P., RUTTEN F.H. 
Guidelines for the management of atrial fibrillation: the Task Force for the Management of 
Atrial Fibrillation of the European Society of Cardiology (ESC). 
European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery,  
Eur Heart J. 2010 Oct;31(19):2369-429 
 
 
[7] 
KOWEY PR, REIFFEL JA, ELLENBOGEN KA, NACCARELLI GV, PRATT CM. 
Efficacy and safety of prescription omega-3 fatty acids for the prevention of recurrent 
symptomatic atrial fibrillation: a randomised controlled trial. 
JAMA. 2010;304:2363–2372. 
 
 
 
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[8] 
BIANCONI L., CALO L., MENNUNI M., SANTINI L., MOROSETTI P., 
AZZOLINI P., BARBATO G., BISCIONE F., ROMANO P., SANTINI M.  
N-3 polyunsaturated fatty acids for the prevention of arrhythmia recurrence after electrical 
cardioversion of chronic persistent atrial fibrillation: a randomised, double-blind, 
multicentre study  
Europace (2011) 13, 174-181 
 
[9] 
OMACOR® SUMMARY PRODUCT CARACTERISTICS (SPC) dated 17/02/2012 
 
[10] 
BEPANTHENE ® SUMMARY PRODUCT CARACTERISTICS (SPC) 
 
[11] 
TOUBOUL P, BRUGADA J, CAPUCCI A, CRIJNS HJ, EDVARDSSON N, 
 
HOHNLOSER SH.  
Dronedarone for prevention of atrial fibrillation: a dose-ranging study.  
Eur Heart J 2003;24(16):1481-7. 
 
[12] LE HEUZEY JY AND ALL.  
A Short-Term, Randomised, Double-Blind, Parallel-Group Study to Evaluate the Efficacy 
and Safety of Dronedarone versus Amiodarone in Patients with Persistent Atrial 
Fibrillation: The DIONYSOS Study. 
J Cardiovasc Electrophysiol. 
 
[13] METCALF G.R., JAMES J.M., GIBSON A.R., EDWARDS J., STUBBERFIELD J., 
STUKLIS R., YOUNG D.G., ROBERTS-THOMSON K. & CLELAND G.L.M.L. & 
OKEN H. 
Effects of fish-oil supplementation on myocardial fatty acids in humans.  
Am J Clin Nutr (2007); 85 : 1225. 
 
[14] ARTERBURN M.L. & OKEN H. 
Distribution, interconversion and dose response of n-3 fatty acids in humans.  
Am J Clin Nutr (2006);83 : 1469-1473S. 
 
[15] TIELEMAN RG, VAN GELDER IC, CRIJNS HJ, DE KAM PJ, VAN DEN BERG 
MP, HAAKSMA J, VAN DER WOUDE HJ, AND ALLESSIE MA. 
Early recurrences of atrial fibrillation after electrical cardioversion: a result of 
fibrillation-induced electrical remodelling of the atria? 
J. Am. Coll. Cardiol. 1998;31;167-173 
 
[16] 
SALM P, TAYLOR PJ, KOSTNER K 
Simultaneous quantification of total eicosapentaenoic acid, docosahexaenoic acid and 
arachidonic acid in plasma by high-performance liquid chromatography-tandem mass 
spectrometry.  
Biomed Chromatogr 2011 Jun;25(6):652-9. 
 
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[17] LEGRAND P., SCHMITT B., MOUROT J., CATHELINE D., CHESNEAU G., 
MIREAUX M., KERHOAS N., WEILL P. 
The consumption of food products from linseed-fed animals maintains erythrocyte omega-3 
fatty acids in obese human 
Lipids, 2010, 45, 11-19. 
 
[18] HARRIS WS, VON SCHACKY C. 
The Omega-3 Index: a new risk factor for death from coronary heart disease? 
Prev Med. 2004 Jul; 39(1):212-20 
 
[19] ABSTRACT: P5161 . 
NODARI S, MANERBA A., MADURERI A., BERLINGHIERI N., PULCINI E., 
FRATTINI S., METRA M, DEI CAS L. 
Effects of Polyunsaturated Fatty Acids n-3 (PUFA n-3) in the prophylaxis of atrial 
fibrillation relapses after external electric cardioversion 
World Congress of Cardiology 2006, 2-6 September, Barcelona – Spain 
 
[20] 
KIRCHHOF P., AURICCHIO A., BAX J., CRIJNS H., CAMM J., DIENER HC., 
 
GOETTE A., HINDRICKS G., HOHNLOSER S., KAPPENBERGER L., KUCK 
 
KH., LIP HYG., OLSSON B., MEINERTZ T., PRIORI S., RAVENS U., 
 
STEINBECK G., SVERHAGE E., TIJSSEN J., VINCENT A., BREITHARDT G. 
 
Outcome parameters from a consensus conference organized by the German Atrial 
 
Fibrillation Competence NETwork and the European Heart Rhythm Association. 
 
Europace 2007, 9, 1006-1023 
 
[21] 
EUROPEAN MEDICINES AGENCY 
 
Addendum to the guideline on antiarrhythmics on atrial fibrillation and atrial flutter. 
 
EMA/CHMA/EWP/213056/2010 
 
[22] 
OWEN AJ, PETER-PRZYBOROWSKA BA, HOY AJ, MCLENNAN PL. 
Dietary fish oil dose- and time-response effects on cardiac phospholipid fatty acid 
composition. 
Lipids. 2004;39:955–961 
 
[23] 
ROBERTO M. LANG, MICHELLE BIERIG, RICHARD B. DEVEREUX, FRANK 
A. FLACHSKAMPF*, ELYSE FOSTER, PATRICIA A. PELLIKKA, MICHAEL H. 
PICARD, MARY J. ROMAN, JAMES SEWARD, JACK SHANEWISE, SCOTT 
SOLOMON, KIRK T. SPENCER, MARTIN ST. JOHN SUTTON, WILLIAM 
STEWART. 
 
Recommendations for chamber quantification 
 
Eur J Echocardiography (2006) 7, 79-108 
 
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17. APPENDICES 
 
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17.1. DECLARATION OF HELSINKI 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
ETHICAL PRINCIPLES FOR MEDICAL RESEARCH INVOLVING 
HUMAN SUBJECTS 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 29th WMA 
General Assembly, Tokyo, Japan, October 1975 35th WMA General Assembly, Venice, Italy, October 1983 41st 
WMA General Assembly, Hong Kong, September 1989 48th WMA General Assembly, Somerset West, Republic of 
South Africa, October 1996 52nd WMA General Assembly, Edinburgh, Scotland, October 2000 53th WMA General 
Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 55th WMA General Assembly, Tokyo 
2004 (Note of Clarification on Paragraph 30 added) 59th WMA General Assembly, Seoul, October 2008 
 
A. INTRODUCTION  
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of 
ethical principles for medical research involving human subjects, including research on identifiable 
human material and data. The Declaration is intended to be read as a whole and each of its constituent 
paragraphs should not be applied without consideration of all other relevant paragraphs.  
2. Although the Declaration is addressed primarily to physicians, the WMA encourages other participants 
in medical research involving human subjects to adopt these principles.  
3. It is the duty of the physician to promote and safeguard the health of patients, including those who are 
involved in medical research. The physician's knowledge and conscience are dedicated to the fulfilment 
of this duty.   
4. The Declaration of Geneva of the WMA binds the physician with the words, “The health of my patient 
will be my first consideration,” and the International Code of Medical Ethics declares that, “A physician 
shall act in the patient's best interest when providing medical care.”  
5. Medical progress is based on research that ultimately must include studies involving human subjects. 
Populations that are underrepresented in medical research should be provided appropriate access to 
participation in research.  
6. In medical research involving human subjects, the well-being of the individual research subject must 
take precedence over all other interests.  
7. The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic interventions 
(methods, procedures and treatments). Even the best current interventions must be evaluated continually 
through research for their safety, effectiveness, efficiency, accessibility and quality.  
8. In medical practice and in medical research, most interventions involve risks and burdens.  
9. Medical research is subject to ethical standards that promote respect for all human subjects and protect 
their health and rights. Some research populations are particularly vulnerable and need special 
protection. These include those who cannot give or refuse consent for themselves and those who may be 
vulnerable to coercion or undue influence.  
10. Physicians should consider the ethical, legal and regulatory norms and standards for research involving 
human subjects in their own countries as well as applicable international norms and standards. No 
national or international ethical, legal or regulatory requirement should reduce or eliminate any of the 
protections for research subjects set forth in this Declaration.  
 
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B. PRINCIPLES FOR ALL MEDICAL RESEARCH  
11. It is the duty of physicians who participate in medical research to protect the life, health, dignity, 
integrity, right to self-determination, privacy, and confidentiality of personal information of research 
subjects.  
12. Medical research involving human subjects must conform to generally accepted scientific principles, be 
based on a thorough knowledge of the scientific literature, other relevant sources of information, and 
adequate laboratory and, as appropriate, animal experimentation. The welfare of animals used for 
research must be respected.   
13. Appropriate caution must be exercised in the conduct of medical research that may harm the 
environment.  
14. The design and performance of each research study involving human subjects must be clearly described 
in a research protocol. The protocol should contain a statement of the ethical considerations involved 
and should indicate how the principles in this Declaration have been addressed. The protocol should 
include information regarding funding, sponsors, institutional affiliations, other potential conflicts of 
interest, incentives for subjects and provisions for treating and/or compensating subjects who are 
harmed as a consequence of participation in the research study. The protocol should describe 
arrangements for post-study access by study subjects to interventions identified as beneficial in the 
study or access to other appropriate care or benefits.   
15. The research protocol must be submitted for consideration, comment, guidance and approval to a 
research ethics committee before the study begins. This committee must be independent of the 
researcher, the sponsor and any other undue influence. It must take into consideration the laws and 
regulations of the country or countries in which the research is to be performed as well as applicable 
international norms and standards but these must not be allowed to reduce or eliminate any of the 
protections for research subjects set forth in this Declaration. The committee must have the right to 
monitor ongoing studies. The researcher must provide monitoring information to the committee, 
especially information about any serious adverse events. No change to the protocol may be made 
without consideration and approval by the committee.  
16. Medical research involving human subjects must be conducted only by individuals with the appropriate 
scientific training and qualifications. Research on patients or healthy volunteers requires the 
supervision of a competent and appropriately qualified physician or other health care professional. The 
responsibility for the protection of research subjects must always rest with the physician or other health 
care professional and never the research subjects, even though they have given consent.  
17. Medical research involving a disadvantaged or vulnerable population or community is only justified if 
the research is responsive to the health needs and priorities of this population or community and if 
there is a reasonable likelihood that this population or community stands to benefit from the results of 
the research.   
18. Every medical research study involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and communities involved in the research in 
comparison with foreseeable benefits to them and to other individuals or communities affected by the 
condition under investigation.  
19. Every clinical trial must be registered in a publicly accessible database before recruitment of the first 
subject.  
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20. Physicians may not participate in a research study involving human subjects unless they are confident 
that the risks involved have been adequately assessed and can be satisfactorily managed. Physicians 
must immediately stop a study when the risks are found to outweigh the potential benefits or when 
there is conclusive proof of positive and beneficial results.  
21. Medical research involving human subjects may only be conducted if the importance of the objective 
outweighs the inherent risks and burdens to the research subjects.  
22. Participation by competent individuals as subjects in medical research must be voluntary. Although it 
may be appropriate to consult family members or community leaders, no competent individual may be 
enrolled in a research study unless he or she freely agrees.  
23. Every precaution must be taken to protect the privacy of research subjects and the confidentiality of 
their personal information and to minimize the impact of the study on their physical, mental and social 
integrity.   
24. In medical research involving competent human subjects, each potential subject must be adequately 
informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional 
affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort 
it may entail, and any other relevant aspects of the study. The potential subject must be informed of the 
right to refuse to participate in the study or to withdraw consent to participate at any time without 
reprisal. Special attention should be given to the specific information needs of individual potential 
subjects as well as to the methods used to deliver the information. After ensuring that the potential 
subject has understood the information, the physician or another appropriately qualified individual 
must then seek the potential subject’s freely-given informed consent, preferably in writing. If the 
consent cannot be expressed in writing, the non-written consent must be formally documented and 
witnessed.  
25. For medical research using identifiable human material or data, physicians must normally seek consent 
for the collection, analysis, storage and/or reuse. There may be situations where consent would be 
impossible or impractical to obtain for such research or would pose a threat to the validity of the 
research. In such situations the research may be done only after consideration and approval of a 
research ethics committee.   
26. When seeking informed consent for participation in a research study the physician should be 
particularly cautious if the potential subject is in a dependent relationship with the physician or may 
consent under duress. In such situations the informed consent should be sought by an appropriately 
qualified individual who is completely independent of this relationship.  
27. For a potential research subject who is incompetent, the physician must seek informed consent from the 
legally authorized representative. These individuals must not be included in a research study that has 
no likelihood of benefit for them unless it is intended to promote the health of the population 
represented by the potential subject, the research cannot instead be performed with competent persons, 
and the research entails only minimal risk and minimal burden.   
28. When a potential research subject who is deemed incompetent is able to give assent to decisions about 
participation in research, the physician must seek that assent in addition to the consent of the legally 
authorized representative. The potential subject’s dissent should be respected.  
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29. Research involving subjects who are physically or mentally incapable of giving consent, for example, 
unconscious patients, may be done only if the physical or mental condition that prevents giving 
informed consent is a necessary characteristic of the research population. In such circumstances the 
physician should seek informed consent from the legally authorized representative. If no such 
representative is available and if the research cannot be delayed, the study may proceed without 
informed consent provided that the specific reasons for involving subjects with a condition that renders 
them unable to give informed consent have been stated in the research protocol and the study has been 
approved by a research ethics committee. Consent to remain in the research should be obtained as soon 
as possible from the subject or a legally authorized representative.  
30. Authors, editors and publishers all have ethical obligations with regard to the publication of the results 
of research. Authors have a duty to make publicly available the results of their research on human 
subjects and are accountable for the completeness and accuracy of their reports. They should adhere to 
accepted guidelines for ethical reporting. Negative and inconclusive as well as positive results should 
be published or otherwise made publicly available. Sources of funding, institutional affiliations and 
conflicts of interest should be declared in the publication. Reports of research not in accordance with 
the principles of this Declaration should not be accepted for publication.  
 
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE  
31. The physician may combine medical research with medical care only to the extent that the research is 
justified by its potential preventive, diagnostic or therapeutic value and if the physician has good 
reason to believe that participation in the research study will not adversely affect the health of the 
patients who serve as research subjects.   
32. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the 
best current proven intervention, except in the following circumstances:  
• 
The use of placebo, or no treatment, is acceptable in studies where no current proven intervention 
exists; or  
• 
Where for compelling and scientifically sound methodological reasons the use of placebo is 
necessary to determine the efficacy or safety of an intervention and the patients who receive 
placebo or no treatment will not be subject to any risk of serious or irreversible harm.  Extreme 
care must be taken to avoid abuse of this option.  
33. At the conclusion of the study, patients entered into the study are entitled to be informed about the 
outcome of the study and to share any benefits that result from it, for example, access to interventions 
identified as beneficial in the study or to other appropriate care or benefits.  
34. The physician must fully inform the patient which aspects of the care are related to the research. The 
refusal of a patient to participate in a study or the patient’s decision to withdraw from the study must 
never interfere with the patient-physician relationship.  
35. In the treatment of a patient, where proven interventions do not exist or have been ineffective, the 
physician, after seeking expert advice, with informed consent from the patient or a legally authorized 
representative, may use an unproven intervention if in the physician's judgement it offers hope of 
saving life, re-establishing health or alleviating suffering. Where possible, this intervention should be 
made the object of research, designed to evaluate its safety and efficacy. In all cases, new information 
should be recorded and, where appropriate, made publicly available.  
 
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17.2. SAE REPORT FORM 
 
 
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N O T I F I C A T I O N  O F  S E R I O U S  A D V E R S E  E V E N T  ( S A E )  O R  P R E G N A N C Y    
TO PIERRE FABRE PRODUCT SAFETY DEPARTMENT 
 
TO BE TRANSMITTED TO THE MONITOR BY FAX WITHIN 24H : M. GUIRAUD  .............. Fax n° +33 5 34 50 65 92 
Transmission date  
 
 
  
 
  
 
 
 
(ddmmyyyy) 
Country :  
........................................
 
 
 
   SAE N° 
 
 
 
                      FIRST NOTIFICATION           FOLLOW-UP   
 
 SUBJECT CHARACTERISTICS  
 
     Surname    
 
 
 
          First name 
 
 
Birth date  
 
 
 
 
 
 
 
 
  
 
 
Gender 
 
1=M,    2=F 
   Height 
 
 
 
cm 
 Weight 
 
 
 
 
 
kg 
 
 
 DESCRIPTION OF THE EVENT 
The serious adverse event resulted in : 
 Death (whatever may be the cause) 
 Hospitalisation (*) or extension thereof 
 Life threatening 
 Invalidity or disability 
 
 Congenital abnormality or abnormal pregnancy outcome 
 Cancer 
 Other  (any other serious clinical or laboratory event 
     according to the investigator or the protocol, overdosage 
      meeting seriousness criteria, suicide attempts) 
Other fact to be notified : 
 Pregnancy exposure 
Nature of the event (if clinical nature, indicate the diagnosis or the major symptom) : 
........................................................................................................................................................................................................... 
........................................................................................................................................................................................................... 
........................................................................................................................................................................................................... 
AE onset date  |__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
 
Seriousness onset date  |__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
 
Summary description (if clinical cause, significant history, progression of event, available laboratory results, etc...) : 
 
 
 
 
 
 
(*) Except hospitalisations with durations and goals planned in the protocol 
 
 THE SAE IN RELATION TO THE TRIAL 
                                                      TREATMENT NUMBER         |___|___|___|___|___|___| 
• Time of occurrence of SAE 
 
 During the selection or run-in period 
 
 During the administration phase of the study treatment 
 
 After the administration phase of the study treatment 
• Date of first study treatment administration 
• Date of last study treatment administration 
   before the occurence of SAE 
|__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
 
|__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
• Was the blind broken ?       Yes         No          Not applicable 
   If yes, or if this is an open study, drug(s) administered : 
 
 
 
 
 
  Conditions of administration (cycles(s), daily dose(s), route(s) of administration, etc..) :  
 
 
 
 
 
 
 
 
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Transmission date 
 
 
  
 
  
 
 
 
  (ddmmyyyy) 
Country : ............................................ 
 
 
 
  SAE N° 
 
 
 
                     FIRST NOTIFICATION           FOLLOW-UP   
 
 CONCOMITANT MEDICATION SINCE TRIAL INITIATION and UP UNTIL THE OCCURRENCE OF THE SAE 
     (EXCEPT THE TREATMENTS GIVEN FOR THE SAE)  
 
INN or trade name 
 
 
Daily dose 
 
Start date 
(ddmmyy) 
Ongoing at 
occurence of the 
event 
 
Stop date 
(ddmmyy) 
Route of 
admin. 
 
Indication 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 MEASURES TAKEN FOLLOWING THE SAE 
• Study treatment 
 
 No change 
 
 Dosage modification, specify :……………………………..….      Modification Date : 
 
 Temporarily discontinued                                                       Readministration date : 
 
 Withdrawn                                                                                                  End date : 
 
 Not applicable 
 
 
 
 
 ____/____/_____ 
 ____/____/_____ 
 ____/____/_____ 
• The event led to : 
 
 Prescription of corrective or symptomatic treatments (specify names and dosages) : 
 
 
 
 Discontinuation of concomitant treatments (specify names) : 
 
 
 
 Others, specify : 
 
 
 OUTCOME 
         Not recovered/Not resolved                  Recovering/Resolving               Recovered/Resolved 
         Recovered/Resolved with sequelae     Fatal                                          Unknown 
 
                In case of death, has an autopsy been conducted ?       Yes         No 
 
 INVESTIGATOR CAUSALITY ASSESSMENT (investigator’s assessment to be done as soon as possible) 
 Not Suspected                          Suspected                    Insufficient data 
comments : ............................................................................................................................................................. 
 
Enclose in the notification the results of carried out examinations, reports of hospitalisation, etc... 
 
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17.3. PREDEFINED LIMITS OF LABORATORY AND VITAL SIGN 
POTENTIALLY CLINICALLY SIGNIFICANT CHANGES AND VALUES  
 
List of Predefined Potentially Clinically Significant Change For Laboratory Values(¤) 
 
 
PARAMETERS 
UNIT 
PSC 
 
 
 
Decrease 
Increase 
MUSCLE 
Creatine  Phosphokinase 
U / l 
- 
236 
KIDNEY 
Creatinine 
Urea 
Uric acid 
Phosphate 
Calcium 
µmol/l 
mmol/l 
µmol/l 
mmol/l 
mmol/l 
- 
- 
- 
0.39 
0.30 
35 
3.2 
119 
0.39 
0.30 
ELECTROLYTES 
Sodium 
Potassium 
Chloride 
Bicarbonate 
mmol/l 
mmol/l 
mmol/l 
mmol/l 
8 
1.1 
8 
7 
8 
1.1 
7 
8 
METABOLISM/ 
NUTRITIONAL 
Glucose (random) 
Albumin 
Protein 
Cholesterol 
HDL cholesterol 
LDL cholesterol 
Triglycerides 
mmol/l 
g/l 
g/l 
mmol/l 
mmol/l 
mmol/l 
mmol/l 
3 
6 
11 
- 
0.91 
2.17 
- 
3.7 
6 
10 
1.97 
0.85 
2.04 
2.91 
ERYTHROCYTES 
Erythrocyte count 
Haemoglobin 
Haematocrit 
MCV  
MCH (Fe) 
MCHC (Fe) 
T/l 
g/l 
1 
fl 
fmol 
mmol/l 
0.7 
20 
0.06 
7 
0.19 
2 
0.7 
- 
0.06 
7 
0.19 
2 
LEUKOCYTES 
Leukocyte count 
G/l 
4.2 
3.8 
DIFFERENTIAL 
COUNT 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
G/l 
G/l 
G/l 
G/l 
G/l 
3.47 
1.76 
- 
- 
- 
3.19 
1.63 
0.49 
0.41 
0.14 
URINE 
Specific gravity 
pH 
- 
- 
0.017 
2 
0.015 
2 
LIVER 
Total bilirubin 
ASAT (SGOT) 
ALAT (SGPT) 
Gamma GT 
Alkaline phosphatase 
µmol/l 
U/l 
U/l 
U/l 
U/l 
- 
- 
- 
- 
-- 
10 
N x (23/36) 
N x (28/45) 
N x (25/38) 
N x (30/95) 
 
N = upper limit of normal range 
 
(¤) Delta-limits from « Routine Laboratory Tests in Clinical Trials » W. Leigh Thompson, Rocco 
L. Brunelle, Gregory G. Enas, Patrick J. Simpson and Randy L. Walker Lilly Research 
Laboratories, Lilly Corporate Centre, Indianapolis, Indiana in « Clinical Trials and Tribulations » 
1988. 
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Definition of Clinically Noteworthy Abnormal Laboratory Values (CNALV) 
 
 
PARAMETERS 
CNALV 
HAEMOGLOBIN 
 
• Decrease of at least 2g/dl and value < 10 g/dl whatever the baseline 
value 
• If missing baseline : value <10g/dl 
NEUTROPHILS 
• < 1 500/mm3 whatever the baseline value 
WBC 
(if missing value for neutrophils) 
• < 3 000/mm3 whatever the baseline value 
PLATELETS 
• < 100 000/mm3 whatever the baseline value 
SERUM CREATININE 
• Increase of at least 30 % as compared to baseline value and 
value > 150 µmol/l whatever the baseline value 
• If missing baseline : value > 150 µmol/l 
LIVER FUNCTION TESTS 
 
 
ALAT 
 
 If normal baseline :  
 
 
•ALAT > 2 N 
 If abnormal baseline : 
→if baseline value ≤ 2.5 N : 
  
• increase of at least 100 % as compared to baseline value 
→ if baseline value > 2.5 N :  
 
 
• value > 5 N 
and/or 
ASAT 
 
  If normal baseline :  
 
 
• ASAT > 2 N 
  If abnormal baseline : 
→ if baseline value ≤ 2.5 N : 
  
• increase of at least 100 % as compared to baseline value 
→ if baseline value > 2.5 N :  
 
 
• value > 5 N 
and/or 
Alkaline phosphatase (AP) 
 
  If normal baseline :  
 
 
• AP > 1.25 N 
  If abnormal baseline :  
 
 
• AP > 2 N 
and/or 
Total bilirubin (TB) 
  If normal baseline :  
 
 
• TB > 1.5 N 
  If abnormal baseline :  
 
 
• TB > 2 N 
N=upper limit of normal range 
International consensus Meeting. International Journal of Clinical Pharmacology, Therapy and Toxicology, 1990;28:317-322 
Standardisation of definitions and criteria of causality assessment of adverse drug reactions: drugs-induced liver disorders: report 
of an Standardisation of definitions and criteria of causality assessment of adverse drug reactions: drugs-induced cytopenia. 
International Journal of Clinical Pharmacology, Therapy and Toxicology, 1991;29:75-81 
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Cardiovascular Safety 
 
Table 1: Predefined Limits for Potentially Clinically Significant Changes (PSC) and PSC 
Leading to Clinically Significant Values (PSCV) 
 
Parameter 
PSC 
PSCV 
SBP 
Increase ≥ 20 mmHg 
Decrease ≥ 20 mmHg 
SBP ≥ 160 mmHg and increase ≥ 20 mmHg 
SBP ≤ 90 mmHg and decrease ≥ 20 mmHg 
DBP 
Increase ≥ 10 mmHg 
Decrease ≥ 10 mmHg 
DBP ≥ 100 mmHg and increase ≥ 10 mmHg 
DBP ≤ 50 mmHg and decrease ≥ 10 mmHg 
HR 
Increase ≥ 10 bpm 
Decrease ≥ 10 bpm 
HR ≥ 110 bpm and increase ≥ 10 bpm 
HR ≤ 50 bpm and decrease ≥ 10 bpm 
 
Table 2: Predefined Classes for changes from Baseline to the Maximum (and/ or Minimum) 
Post-baseline Value 
Classes of Change from Baseline to the Maximum 
Post-baseline Value 
Classes of Change from Baseline to the 
Minimum Post-baseline Value 
SBP  mmHg 
DBP  mmHg 
HR bpm 
SBP  mmHg 
DBP  mmHg 
HR bpm 
All 
All 
All 
All 
All 
All 
≥  0 
≥  0 
≥  0 
≤  0 
≤  0 
≤  0 
>  0 
>  0 
>  0 
<  0 
<  0 
<  0 
≥ 10 
≥  5 
≥ 10 
≤ -10 
≤ - 5 
≤ -10 
≥ 20 
≥ 10 
≥ 20 
≤ -20 
≤ -10 
≤ -20 
≥ 30 
≥ 15 
≥ 30 
≤ -30 
≤ -15 
≤ -30 
≥ 40 
≥ 20 
 
≤ -40 
≤ -20 
 
 
≥ 25 
 
 
≤ -25 
 
 
≥ 30 
 
 
≤ -30 
 
 
Table 3: Classes for Vital Signs Maximum or Minimum Values 
Classes  for  the Maximum Post-baseline Value 
for each parameter 
Classes  for  the Minimum Post-baseline Value 
for each parameter 
SBP  mmHg 
DBP  mmHg 
HR bpm 
SBP  mmHg 
DBP  mmHg 
HR bpm 
< 120 
< 80 
≤ 50 
≤ 90 
≤ 50 
≤ 50 
[120 ;140[ 
[80;90[ 
]50 ;75[ 
[90 ;120[ 
[50;80[ 
]50 ;75[ 
[140;160[ 
 [90;100[ 
[75;100[ 
[120;140[ 
 [80;90[ 
[75;100[ 
≥ 160 
≥ 100 
≥ 100 
≥ 140 
≥ 90 
≥ 100 
 
Table 4: Classes for Maximum or Minimum of BP in its entirety 
Classification of Maximum Values for Blood 
Pressure (mmHg) 
Classification of Minimum Values Blood 
Pressure (mmHg) 
SBP < 140 and DBP < 90 
SBP > 90 and DBP > 50 
SBP [140;160[ and DBP < 100 
or DBP [90;100[ and SBP < 160 
SBP ≤  90 or DBP ≤  50 
SBP ≥ 160 or DBP ≥ 100 
 
 
Table 5: Definition of orthostatic hypotension 
Orthostatic Hypotension * 
SBP Decrease ≥ 20 mmHg or DBP Decrease ≥ 10 mmHg between supine and standing positions 
* Consensus Committee of the American Autonomic Society and the American Academy of Neurolog :Consensus statement on the definition of 
orthostatic hypotension, pure autonomic failure and multiple system atrophy. Neurology 1996;46:1470-3. 
 
 
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16.1.1.2. 
Protocol and appendices 
                    (version 2: 15 January 2013) 
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F 373280 CA 2 01 
 
 
 
 
 
 
 
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Pierre Fabre Médicament 
Represented by: Institut de Recherche Pierre Fabre 
45, Place Abel Gance 
F-92100 Boulogne 
 
CLINICAL STUDY PROTOCOL 
 
Efficacy and safety study of F373280 for maintenance of sinus rhythm after 
electrical cardioversion in patients with persistent Atrial Fibrillation and 
Chronic Heart Failure. 
International, multicentric, randomised, double-blind, placebo controlled study 
F373280 / Soft Capsules / 1g  
 
Pierre Fabre Study Code: 
EudraCT Number: 
 
Sponsor's Representative: 
 
 
 
 
 
 
 
 
 
Study Coordinating Investigator 
F 373280 CA 2 01  
2012 – 003487 - 48 
 
Marlène GUIRAUD, Pharm D  
INSTITUT DE RECHERCHE PIERRE FABRE - 
Centre de R&D Pierre Fabre - BP 13562  
3 avenue Hubert Curien  
31035 TOULOUSE Cédex 1 
Phone: +33 5 34 50 63 48  
Fax:+33 5 34 50 65 92  
E-mail:marlene.guiraud@pierre-fabre.com  
 
Pr Savina NODARI 
Section of Cardiology  
Department of Experimental and Applied Sciences 
University of Brescia 
BRESCIA, ITALY 
Phone: +39 030 3996 587 - Fax: +39 030 3700 359 
E-mail: savinanodari@gmail.com  
 
Version 2– 15 JAN 2013 
 
The information contained in this document is confidential and is the property of the Sponsor, Pierre Fabre 
Medicament. This information is given for the needs of the study and must not be disclosed without prior written 
consent of the Sponsor Pierre Fabre Medicament. Persons to whom this information is given for the needs of the 
study must be informed that it is confidential and must not be disclosed. 
 
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SPONSOR PERSONNEL 
PIERRE FABRE MEDICAMENT 
represented by 
Institut de Recherche Pierre Fabre 
 
Clinical Study Manager (Monitor) 
Marlène GUIRAUD, Pharm D 
Phone: +33 5 34 50 63 48 
Fax: + 33 5 34 50 65 92 
E-mail: marlene.guiraud@pierre-
fabre.com 
Institut de Recherche Pierre Fabre 
Centre de R&D Pierre Fabre 
BP 13 562 
3, Avenue Hubert Curien 
31035 TOULOUSE Cedex 1 
 
Head of Therapeutic Area 
Alain DELARUE, MD 
Phone: + 33 5 34 50 61 88 
Fax: +33 5 34 50 65 92 
E-mail: alain.delarue@pierre-
fabre.com 
Institut de Recherche Pierre Fabre 
Centre de R&D Pierre Fabre 
BP 13 562 
3, Avenue Hubert Curien 
31035 TOULOUSE Cedex 1 
 
Clinical Development Physician 
Richard ROCHE, MD 
Phone: +33 5 34 50 61 94 
Fax: +33 5 34 50 65 92 
E-mail: richard.roche@pierre-
fabre.com 
Institut de Recherche Pierre Fabre 
Centre de R&D Pierre Fabre 
BP 13 562 
3, Avenue Hubert Curien 
31035 TOULOUSE Cedex 1 
 
 
 
 
 
 
 
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CONTRACT RESEARCH ORGANISATIONS 
 
 
 
 
For Feasibility, Monitoring and Regulatory issues: 
Pharmaceutical Service Network (PSN) 
Rufino Gonzalez 
28 037 Madrid - SPAIN 
Phone: +34 91 375 6930 - Fax: +34 91 375 6931 
E-mail: www.psnglobal.org 
 
 
For Centralised Randomisation and Electronic Case Report Form 
S-Clinica 
6, Chaussée de Boondael 
B-1050 Brussels - BELGIUM 
Phone: +32 2 645 0567 - Fax: +32 2 645 0569 
E-mail: irena.seredina@s-clinica.com 
 
 
 
For Centralised Reading of Holder ECG and TTEM and equipment supply: 
Biomedical System 
1945 Chaussée de Wavre 
B-1160 Brussels - BELGIUM 
Phone: +32 2 661 20 70 - Fax: +32 2 661 20 71 
E-mail: sjacobs@biomedsys.com 
 
 
 
For intra erythrocyte DHA dosage 
Agrocampus Ouest 
Laboratoire de Biochimie 
65 rue de Saint Brieuc – CS 84215 
35042 RENNES Cedex - FRANCE 
Phone: +33 2 23 48 55 49 - Fax: +33 2 23 48 55 50 
E-mail: daniel.catheline@agrocampus-ouest.fr 
 
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Protocol F 373280 CA 2 01 
COUNTRY COORDINATING  INVESTIGATOR  
SIGNATURE FORM 
Protocol Version 2 – 15 JAN 2013 
 
 
Country: …………………….. 
 
Country Coordinating Investigator:  
"Name"  
Date:   
 
 
 
 
 
 
Signature:  
 
 
 
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Protocol F 373280 CA 2 01 
INVESTIGATOR SIGNATURE FORM 
Protocol Version 2 – 15 JAN 2013 
 
 
 
By my signature below, I, Dr / Pr "                                         ", hereby confirm that I agree: 
♦ to conduct the trial described in the protocol F 373280 CA 2 01, dated 15 January 2013 in 
compliance with GCP, with applicable regulatory requirements and with the protocol 
agreed upon by the Sponsor Pierre Fabre Médicament and given approval / favourable* 
opinion by the Ethics Committee; 
♦ to document the delegation of significant study-related tasks and to notify the Sponsor of 
changes in site personnel involved in the study; 
♦ to comply with the procedure for data recording and reporting; 
♦ to allow monitoring, auditing and inspection; 
♦ to retain the trial-related essential documents until the Sponsor informs that these documents 
are no longer needed. 
Furthermore, I hereby confirm that I will have and will use the available adequate resources, 
personnel and facilities for conduct this trial. 
 
I have been informed that certain regulatory authorities require the Sponsor Pierre Fabre 
Médicament to obtain and supply details about the investigator’s ownership interest in the 
Sponsor or the study drug, and more generally about his/her financial relationships with the 
Sponsor. The Sponsor will use and disclose the information solely for the purpose of complying 
with regulatory requirements. 
Hence I agree: 
♦ to supply the Sponsor with any information regarding ownership interest and financial 
relationships with the Sponsor (including those of my spouse and dependent children); 
♦ to promptly update this information if any relevant changes occur during the course of the 
study and for 1 year following completion of the study; 
♦ that the Sponsor may disclose this information about such ownership interests and financial 
relationships to regulatory authorities. 
* To be adapted  
 
Date:  
Signature:  
 
 
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TABLE OF CONTENTS OF CLINICAL STUDY PROTOCOL 
 
1. 
INTRODUCTION AND STUDY RATIONALE ................................................................ 21 
1.1. 
TARGET PATHOLOGY AND THERAPY ........................................................................ 21 
1.2. 
INFORMATION ON THE TEST PRODUCT .................................................................... 23 
1.2.1. 
Chemical and pharmaceutical characteristics .................................................................... 24 
1.2.1.1. 
Nomenclature and structure ............................................................................................ 24 
1.2.1.2. 
Physical and chemical general properties ...................................................................... 24 
1.2.2. 
Non-clinical Data .............................................................................................................. 25 
1.2.2.1. 
Pharmacological profile ................................................................................................. 25 
1.2.2.2. 
Safety pharmacology ...................................................................................................... 26 
1.2.2.3. 
Toxicology profile .......................................................................................................... 26 
1.2.2.4. 
Pharmacokinetic data ..................................................................................................... 26 
1.2.3. 
Clinical data ....................................................................................................................... 26 
1.3. 
STUDY RATIONALE ......................................................................................................... 29 
1.4. 
OVERALL RISK AND BENEFIT ASSESSMENT ............................................................ 29 
2. 
STUDY OBJECTIVES ......................................................................................................... 32 
2.1. 
PRIMARY OBJECTIVE ..................................................................................................... 32 
2.2. 
SECONDARY OBJECTIVES ............................................................................................. 32 
3. 
ETHICAL CONSIDERATIONS RELATING TO THE STUDY .................................... 32 
4. 
STUDY DESIGN ................................................................................................................... 34 
4.1. 
OVERALL DESCRIPTION ................................................................................................ 34 
4.2. 
DISCUSSION OF THE STUDY DESIGN .......................................................................... 35 
4.2.1. 
Choice of the Study Population ......................................................................................... 35 
4.2.2. 
Choice of the Study Design ............................................................................................... 36 
4.2.3. 
Choice of the Dose ............................................................................................................ 37 
4.2.4. 
Choice of the Sample Size ................................................................................................. 38 
5. 
STUDY POPULATION ........................................................................................................ 38 
5.1. 
INCLUSION CRITERIA ..................................................................................................... 38 
5.2. 
NON INCLUSION CRITERIA ........................................................................................... 38 
5.3. 
NUMBER OF  PATIENTS .................................................................................................. 39 
5.4. 
RECRUITMENT MODALITIES ........................................................................................ 40 
5.5. 
PATIENTS IDENTIFICATION .......................................................................................... 40 
5.6. 
WITHDRAWAL CRITERIA ............................................................................................... 40 
5.7. 
REPLACEMENT OF PATIENTS ....................................................................................... 41 
5.8. 
POST-STUDY EXCLUSION PERIOD .............................................................................. 41 
5.9. 
STUDY CARD ..................................................................................................................... 41 
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6. 
STUDY TREATMENT ......................................................................................................... 42 
6.1. 
SOURCE, PRESENTATION AND COMPOSITION OF  INVESTIGATIONAL 
PRODUCT ........................................................................................................................... 42 
6.2. 
PACKAGING AND LABELLING ..................................................................................... 42 
6.2.1. 
Packaging .......................................................................................................................... 42 
6.2.2. 
Labelling ............................................................................................................................ 43 
6.3. 
DISTRIBUTION TO CENTRE AND STORAGE .............................................................. 44 
6.4. 
ALLOCATION OF TREATMENTS AND DISPENSATION TO PATIENT ................... 44 
6.5. 
DRUG ADMINISTRATION ............................................................................................... 46 
6.5.1. 
Duration of Treatment ....................................................................................................... 46 
6.5.2. 
Dose Schedule ................................................................................................................... 46 
6.5.3. 
Route and Conditions of Administration ........................................................................... 46 
6.6. 
ACCOUNTABILITY ON SITE AND RETURN/DESTRUCTION OF  
INVESTIGATIONAL PRODUCT ...................................................................................... 46 
6.7. 
RECALL OF INVESTIGATIONAL PRODUCTS ............................................................. 47 
7. 
CONCOMITANT TREATMENTS ..................................................................................... 47 
7.1. 
ANTI-VITAMIN K TREATMENT ..................................................................................... 48 
7.2. 
PROHIBITED TREATMENTS ........................................................................................... 48 
7.3. 
AUTHORISED TREATMENTS ......................................................................................... 48 
8. 
EVALUATION CRITERIA ................................................................................................. 49 
8.1. 
PRIMARY EFFICACY CRITERION: ................................................................................ 49 
8.1.1. 
Time to the first Atrial Fibrillation Recurrence ................................................................. 49 
8.1.1.1. 
Definition ........................................................................................................................ 49 
8.1.1.2. 
Schedule ......................................................................................................................... 49 
8.1.1.3. 
Evaluation Methods ........................................................................................................ 49 
8.1.2. 
Secondary Efficacy Criteria .............................................................................................. 50 
8.1.2.1. 
Numbers of Atrial Fibrillation episodes in the first week following visit 3   (ECV 
visit) ................................................................................................................................ 50 
8.1.2.2. 
Duration of Atrial Fibrillation episodes in the first week following visit 3   (ECV 
visit) ................................................................................................................................ 51 
8.1.2.3. 
Clinical parameters evaluation ....................................................................................... 51 
8.1.2.4. 
Cardioversion assessment ............................................................................................... 52 
8.1.2.5. 
Evolution of echocardiographic parameters ................................................................... 53 
8.2. 
BIOMARKER ASSESSMENT: RED BLOOD CELL   CONCENTRATIONS OF 
DHA ..................................................................................................................................... 53 
8.2.1. 
Definition ........................................................................................................................... 53 
8.2.2. 
Blood samples ................................................................................................................... 54 
8.2.2.1. 
Collection schedule ........................................................................................................ 54 
8.2.2.2. 
Technical handling ......................................................................................................... 54 
8.2.3. 
DHA concentration measurement ..................................................................................... 54 
8.3. 
SAFETY ASSESSMENT .................................................................................................... 55 
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8.3.1. 
Adverse Events .................................................................................................................. 55 
8.3.2. 
Laboratory Investigations .................................................................................................. 55 
8.3.2.1. 
Schedule ......................................................................................................................... 55 
8.3.2.2. 
Technical Procedures and Parameters ............................................................................ 55 
8.3.3. 
Global Physical Examination ............................................................................................ 56 
8.3.4. 
Vital Signs ......................................................................................................................... 56 
8.3.4.1. 
Schedule ......................................................................................................................... 57 
8.3.4.2. 
Technical Procedure and Parameters.............................................................................. 57 
8.3.5. 
Electrocardiogram (ECG) .................................................................................................. 57 
8.3.5.1. 
Schedule ......................................................................................................................... 57 
8.3.5.2. 
Technical Procedure and Parameters.............................................................................. 57 
8.3.6. 
Coagulation parameters ..................................................................................................... 58 
8.3.7. 
Concomitant Treatments ................................................................................................... 58 
8.4. 
COMPLIANCE .................................................................................................................... 58 
9. 
STUDY PROCEDURES ....................................................................................................... 59 
10. ADVERSE EVENTS: DEFINITION AND REPORTING ............................................... 64 
10.1. ADVERSE EVENTS ........................................................................................................... 64 
10.1.1. Definition of Adverse Events ............................................................................................ 64 
10.1.2. Grading of Adverse Events ............................................................................................... 65 
10.1.3. Reporting of Adverse Events ............................................................................................ 65 
10.2. SERIOUS ADVERSE EVENTS (SAE) .............................................................................. 65 
10.2.1. Definition ........................................................................................................................... 65 
10.2.2. Reporting of SAE .............................................................................................................. 66 
10.2.3. Follow-up of SAE ............................................................................................................. 67 
10.2.4. SAE Occurring After the Study ......................................................................................... 67 
10.3. REPORTING OF OVERDOSAGE TO THE SPONSOR ................................................... 67 
10.4. REPORTING OF PREGNANCY TO THE SPONSOR ...................................................... 67 
10.5. SPONSOR'S RESPONSIBILITIES FOR SAFETY REPORTING  PURPOSES ............... 68 
11. DATA COLLECTION AND STUDY MONITORING ..................................................... 68 
11.1. DATA COLLECTION ......................................................................................................... 68 
11.1.1. Case Report Form .............................................................................................................. 68 
11.1.2. Source Documents ............................................................................................................. 69 
11.2. STUDY MONITORING ...................................................................................................... 70 
11.2.1. Monitoring visits ............................................................................................................... 70 
11.2.1.1. Site Preselection Visit .................................................................................................... 70 
11.2.1.2. Initiation Visit ................................................................................................................. 70 
11.2.1.3. Follow-up Visits ............................................................................................................. 71 
11.2.1.4. Closing Visit ................................................................................................................... 71 
11.2.2. Direct Access to Source Documents ................................................................................. 71 
11.3. INDEPENDENT DATA MONITORING COMMITTEE ................................................... 72 
12. DATA MANAGEMENT ...................................................................................................... 72 
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12.1. DATA ENTRY ..................................................................................................................... 72 
12.2. DATA CLEANING ............................................................................................................. 72 
12.3. DATA CODING .................................................................................................................. 73 
12.4. DATA STORAGE ............................................................................................................... 73 
12.5. DATABASE LOCK ............................................................................................................. 73 
13. STATISTICAL ANALYSIS ................................................................................................. 73 
13.1. GENERAL CONSIDERATIONS ........................................................................................ 74 
13.2. SAMPLE SIZE ..................................................................................................................... 74 
13.3. PROTOCOL DEVIATIONS ................................................................................................ 74 
13.4. DATA SETS ANALYSED .................................................................................................. 75 
13.5. HANDLING OF DROPOUTS AND MISSING DATA ..................................................... 75 
13.5.1. Dropouts ............................................................................................................................ 75 
13.5.2. Repositioning of Visits ...................................................................................................... 75 
13.5.3. Missing Data ...................................................................................................................... 75 
13.6. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ............................... 76 
13.7. EFFICACY ANALYSIS ...................................................................................................... 76 
13.7.1. Primary Criterion ............................................................................................................... 76 
13.7.1.1. Primary Analysis ............................................................................................................ 76 
13.7.1.2. Supportive Analysis ....................................................................................................... 76 
13.7.2. Secondary Criteria ............................................................................................................. 77 
13.7.2.1. Numbers of Atrial Fibrillation Episodes ........................................................................ 77 
13.7.2.2. Duration of Atrial Fibrillation Episodes ......................................................................... 77 
13.7.2.3. Time to first AF recurrence less than 10 minutes or symtomatic .................................. 77 
13.7.2.4. Clinical parameters evaluation ....................................................................................... 77 
13.7.2.5. Biomarker analysis: red blood cell concentrations of DHA ........................................... 78 
13.8. SAFETY ANALYSIS .......................................................................................................... 78 
13.8.1. Adverse Events .................................................................................................................. 78 
13.8.2. Clinical Laboratory Evaluation ......................................................................................... 80 
13.8.3. Global Physical Examination ............................................................................................ 81 
13.8.4. Vital Signs, Physical Findings and Other Observations Related to Safety ....................... 81 
13.8.4.1. Vital Sign Measurements Over Time ............................................................................. 81 
13.8.4.2. Body weight ................................................................................................................... 81 
13.8.4.3. Individual Patient Changes ............................................................................................. 82 
13.8.5. ECG ................................................................................................................................... 82 
13.8.6. Coagulation parameters ..................................................................................................... 82 
13.9. CONCOMITANT TREATMENTS ..................................................................................... 82 
13.10. COMPLIANCE .................................................................................................................... 83 
13.11. INTERIM ANALYSIS AND DATA MONITORING ........................................................ 83 
14. GENERAL ETHICAL CONSIDERATIONS .................................................................... 83 
14.1. ETHICAL CONDITIONS ................................................................................................... 83 
14.2. ETHICS COMMITTEE AND LEGAL REQUIREMENTS ................................................ 83 
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14.3. PATIENT'S INFORMATION LEAFLET AND INFORMED CONSENT  FORM ........... 84 
14.4. PERSONAL DATA PROTECTION ................................................................................... 85 
14.5. INSURANCE POLICY ........................................................................................................ 85 
15. ADMINISTRATIVE PROCEDURES ................................................................................ 85 
15.1. PROTOCOL AMENDMENT .............................................................................................. 85 
15.2. SOURCE DOCUMENTS, INVESTIGATOR'S FILE STORAGE ..................................... 86 
15.3. END OF THE STUDY ......................................................................................................... 86 
15.3.1. Definition of the End of Study .......................................................................................... 86 
15.3.2. Early Study Termination ................................................................................................... 87 
15.3.2.1. Early Study Termination Decided by the Sponsor ......................................................... 87 
15.3.2.2. Early Study Termination Decided by the Competent Authorities.................................. 87 
15.4. AUDIT .................................................................................................................................. 87 
15.5. INSPECTION ....................................................................................................................... 88 
15.6. CONFIDENTIALITY .......................................................................................................... 88 
15.7. CLINICAL STUDY REPORT ............................................................................................. 88 
15.8. STUDY RESULTS COMMUNICATION .......................................................................... 88 
15.9. STUDY RESULTS PUBLICATION ................................................................................... 88 
16. REFERENCES ...................................................................................................................... 90 
17. APPENDICES ....................................................................................................................... 93 
17.1. DECLARATION OF HELSINKI ........................................................................................ 94 
17.2. SAE REPORT FORM .......................................................................................................... 98 
17.3. PREDEFINED LIMITS OF LABORATORY AND VITAL SIGN POTENTIALLY 
CLINICALLY SIGNIFICANT CHANGES AND VALUES ............................................ 101 
 
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SYNOPSIS 
 
Name of Sponsor: 
Pierre Fabre Médicament represented by the Institut de Recherche Pierre Fabre (IRPF) 
Name of Finished Product: 
Not applicable 
Name of Active Substance:  
F373280 (Panthenyl-Ester of DHA) 
Title of the Study: 
Efficacy and safety study of F373280 for maintenance of sinus rhythm after electrical 
cardioversion in patients with persistent Atrial Fibrillation and Chronic Heart Failure. 
 
Abbreviated Title: 
Not applicable 
Study Coordinating Investigator: 
Pr Savina NODARI 
 
Study Centres: 
International, multicentric 
Publication / Rationale: 
F373280 is a new therapy based on DHA delivery (pro-drug) developed for the maintenance 
of sinus rhythm after electrical cardioversion in persistent atrial fibrillation (AF) patients with 
chronic heart failure. 
The results of a pharmacological study performed in animals evidenced that DHA reduces the 
duration of Atrial Fibrillation (AF) induced by burst pacing.[1] 
Moreover, the effectiveness of PUFA (PolyUnsaturated Fatty Acid) has been proven in the 
following conditions: 
− 
prevention of Atrial Fibrillation recurrence in patients with persistent Atrial 
Fibrillation, in co-administration with amiodarone (add on therapy) [2]  
− 
Improvement of ventricular functional parameters, morbi-mortality and duration 
of hospitalisation in patients with heart failure [3, 4, 5] 
Taking into account these studies, it seems that DHA might be of therapeutic interest in the 
treatment of patients with both persistent atrial fibrillation and chronic heart failure. 
This phase IIa study is designed to assess the efficacy and the safety of the investigational 
product (F373280) for maintenance of sinus rhythm after electrical cardioversion (ECV) in 
patients with persistent atrial fibrillation and chronic heart failure. 
Planned Study Period: 
January 2013 –  April 2014 
Clinical Phase: IIa 
 
Objectives: 
Primary: 
- Efficacy of F373280 on the maintenance of sinus rhythm after direct electrical 
cardioversion in patients with persistent atrial fibrillation and chronic heart failure 
Secondary: 
- Efficacy of F373280 on the efficiency of direct electrical  cardioversion 
- Effect of F373280 on echocardiographic parameters 
- Safety and tolerability of F373280 
Methodology: 
- International, multicentre, randomised, double-blind, placebo-controlled 
- Selection period 
- Start of treatment 4 weeks before ECV 
• 
Condition to ECV:  
− 
INR 2-3 (anti-vitamin K should be given at least 3 weeks before ECV) 
− 
No spontaneous cardioversion before ECV 
- Follow-up 20 weeks after visit 3  (ECV visit) 
• 
Condition: successful ECV or spontaneous CV 
- Cardiac monitoring: 
• 
7-days continuous ECG ambulatory recording (Holter ECG)  between visit 3 (ECV 
visit) and visit 4  (week 5) in patients with sinusal rhythm 
• 
TTEM: daily transmission from week 6 to week 8; then every two days from week 
9 to week 24, and in case of AF symptoms 
- Treatment duration: 24 weeks 
Study Schedule 
9 visits will be scheduled: 
- V1/ W-4 to W-1: selection visit (7 to 28 days before the inclusion visit)  
- V2/ D1: Inclusion visit (start of treatment) 
- V3/ W4 (D28 -2/+7 days): cardioversion visit (Outpatient or hospitalization according to 
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clinical practice of the centre) (installation of the Holter device) 
- V4/ W5 (D35± 2 days): follow-up visit (removing of the Holter device and installation of 
the TTEM) 
- V5/ W8 (D56± 7 days): follow-up visit 
- V6/ W12 (D84 ± 7 days): follow-up visit 
- V7/ W16 (D112 ± 7 days): follow-up visit 
- V8/ W20 (D140 ± 7 days): follow-up visit 
- V9/ W24 (D168 ± 7 days): final study visit 
 
Number of  Patients: 
76 x 2 patients  
Diagnosis and Criteria for Inclusion: 
Inclusion Criteria: 
Demographic Characteristics and Other Baseline Characteristics: 
1. 
Men or women aged more than 18 years (inclusive), 
2. 
Patients with persistent AF between 7 days and 6 months duration for whom electrical 
cardioversion is warranted. 
3. 
History of first documented persistent AF less than 1 year 
4. 
History of ischemic or non ischemic heart failure  
5. 
NYHA class I or II chronic heart failure at selection and at inclusion 
6. 
Reduced left ventricular ejection fraction between 30% and 45% inclusive (using the 
two-dimensional echocardiography biplane Simpson’s rule) ) at selection and at 
inclusion 
7. 
On appropriate, stable medical treatments for heart failure, including a diuretic and/or 
angiotensin-converting enzyme, and/or angiotensin-receptor blocker and/or 
mineralocorticoid receptor (MR) antagonists, and/or betablockers 
8. 
Left atrial area ≤ 40 cm² ) at selection and at inclusion 
9. 
Patients treated or having to be treated by anti-vitamin K 
10. For female patient of child-bearing potential:  
- 
use of an effective method of contraception (hormonal contraception or intra-
uterine device) assessed by the investigator, for at least 2 months before the 
selection in the study, and agreement to go on using it during the whole duration of 
the study and up to 1 month after the last dose of the study treatment 
- 
documented as surgically sterilized 
11. For female patient of child-bearing potential: negative urine pregnancy test at inclusion 
Ethical /legal considerations: 
12. Having signed his/her written informed consent, 
13. Affiliated to a social security system, or is beneficiary (if applicable in the national 
regulation) 
 
Non-Inclusion Criteria: 
Criteria related to pathologies: 
1. 
History of first documented episode of persistent AF more than 1 year 
2. 
More than two successful cardioversions (electrical or pharmacological) in the last 6 
months 
3. 
Secondary Atrial Fibrillation due to alcohol or severe valvular heart disease (grade III to 
IV) 
4. 
NYHA class III or IV heart failure at selection or at inclusion 
5. 
Thyroid disease uncontrolled by treatment: TSH ± T4L ± T3L to be checked in case of 
treatment for thyroid disease 
6. 
Myocardial infarction or unstable angina or presence of unstable ischemic 
coronaropathy assessed by coronarography or cardiac stress test (Echo stress, exercice 
stress test, nuclear or MR perfusion evaluation methods) within 6 months before 
selection 
7. 
Severe chronic kidney disease (creatinine ≥ 25 mg/L or estimated glomerular filtration 
rate < 30 mL/min) at selection 
8. 
Bradycardia (HR ≤ 50 bpm) 
9. 
Hyperkalemia or hypokalemia (K>5.5 mEq/L or K < 3.5 mEq/L) at selection  
10. Cardiac surgery within 3 months before selection or planned during the study duration 
 
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Criteria related to treatments: 
11. Previously ineffective pharmacological or electrical cardioversion 
12. Concomitant treatment with any anti-arrhythmic drug (within 7 days prior to selection), 
except stable dose of digoxin, betablockers, calcium-blockers 
13. Previous treatment with oral amiodarone within 12 months prior to inclusion 
14. Previous treatment with intravenous amiodarone within 6 months prior to inclusion 
15. Patient requiring a cardiac resynchronization therapy (CRT) or having undergone CRT 
implantation within the last 6 months  
16. Treatment with any Polyunsaturated Fatty Acid (PUFA) within the last 3 months 
17. Dietary supplement with ω3 or ω6 according to investigator’s judgement 
18. Having undergone any form of ablation therapy for AF 
19. Patient treated with other anticoagulant treatment than antivitamin K: thrombin inhibitor 
such as Dabigatran or treated with antiaggregant P2Y12 inhibitors such as Clopidogrel 
or Prasugrel 
 
Other criteria: 
20. Patient liable not to comply with protocol instructions and/or with treatment, in the 
investigator’s opinion 
21. Patient having taken part in a clinical trial in the preceding 2 months or taking part in a 
trial at the time of selection 
22. Patient linguistically or mentally unable to understand the nature, objectives and 
possible consequences of the trial, or refusing to patient himself/herself to its constraints 
23. Patient family member or work associate (secretary, nurse, technician,..) of the 
Investigator 
24. Patient having forfeited his / her freedom by administrative or legal award or being 
under guardianship 
25. Breastfeeding female patient 
 
Exclusion criteria before V3: 
Patients not stabilized for INR (i.e. values between 2 and 3) on at least 3 consecutive weekly 
tests performed before ECV will be excluded from the study, unless the presence of atrial 
thrombosis may be excluded with ECHO –TE (trans-esophageal echocardiograph) performed  
in the same day (before ECV) 
ECV will be performed in patients without dyskalemia 
If necessary for obtaining stabilized INR between 2 and 3, the ECV (and following visits) 
could be postponed by 7 days. 
Test Product:  
F373280  
Soft Capsules  
Dose: 
Arm with 1g of F373280 
Mode of Administration: 
Oral, one capsule each evening with dinner. 
Duration of Treatment: 
24 weeks of treatment exposure with F373280 (25 weeks if ECV postponed by 1 week) 
Reference Therapy 
Placebo soft capsules 
Placebo will be administered in the same conditions as the tested product. 
Mode of Administration: 
Oral, one capsule each evening with dinner 
Evaluation Criteria: 
Efficacy evaluation variables: 
 
Primary evaluation variable: 
- Time to first Atrial Fibrillation recurrence defined by the first episode of Atrial Fibrillation 
lasting for at least 10 minutes (Follow up of 20 weeks after  visit 3 (ECV visit) 
Handling of AF recurrences: 7-day continuous ECG (5-leads/2 or 3 channels) ambulatory 
recording (holter ECG) between visit 3 (ECV visit) and visit 4 (week 5). Then, the follow 
up will be documented using the TTEM: daily transmission from week 6 to week 8. Then, 
every two days from week 9 to week 24. 
For randomised patients with spontaneous cardioversion before ECV, the recurrence of AF 
will be assessed after visit 3 (week 5).  
Moreover, during this TTEM period, if patient experiences any AF symptoms, it should be 
recorded and documented using the TTEM.  
All ECG traces will be evaluated by a Central Reading Laboratory. 
 
Secondary evaluation variables: 
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During the 7-day continuous ECG monitoring, 
• 
Numbers of AF episodes 
• 
Duration of AF episodes 
 
Clinical parameters: 
During the whole study: 
• 
Number of recurrence of symptomatic AF episodes 
• 
EHRA score 
• 
Hospitalization for cardiovascular events 
• 
Hospitalization for thromboembolic stroke 
• 
All cause of hospitalization 
 
Cardioversion: 
• 
Assessment of spontaneous cardioversion 
• 
Assessment of successful cardioversion 
• 
Number of patients needing an other cardioversion after the initial ECV 
 
Other: 
• 
Evolution of echocardiographic parameters (from V4 to V6 and V9) (Left atrial 
diameter (mm), Left atrial area (cm²), Left atrial volume (mL), Left atrial 
volume/BSA (mL/m2), Left ventricular ejection fraction (%),Left ventricular 
volume (mL), Left ventricular volume/BSA(mL/m2, Left ventricular end diastolic 
diameter (mm), Left ventricular end diastolic volume (mL) Left ventricular end 
systolic diameter (mm), Left ventricular end systolic volume (mL)) 
• 
Evolution of omega 3 index and intra erythrocyte DHA (For this assessment 
samples will be centralized). 
 
Safety criteria: 
- Adverse events (observed and / or spontaneously reported) 
- Vital signs (Blood pressure (supine and standing), heart rate 
-  Physical examination (body weight),  
- Standard 12-lead ECG: heart rate (bpm), PR (ms), QRS (ms), QT (ms), repolarisation 
patterns (ECG not centralized). 
- Haematology: haematocrit, haemoglobin, RBC, WBC, differential count, platelets 
- Biochemistry: sodium, potassium, bicarbonate, chloride, alkaline phosphatase, gamma 
GT, albumin, total bilirubin, conjugated bilirubin, creatinin, aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), fasting glucose, total cholesterol, cholesterol 
(HDL, LDL), triglycerides, creatin phosphokinase (CPK) fibrinogen (local laboratory) 
- Coagulation parameters: Activated partial thromboplastin time (aPTT), thrombin clotting 
time (TCT), INR (local laboratory), Prothrombine Time (PT) 
Statistical Methods: 
Sample Size: 
Assuming an AF recurrence rate under placebo of 85%, a power of 80%, an alpha risk of 5% 
and a rate of not assessable patients of 15%, 76 randomised patients per group will be 
necessary, using a log-rank test of survival curves, a difference between groups of 20%.  
Primary Efficacy Analysis 
The primary analysis, performed on the Full Analysis Set (FAS: all randomised patients with 
at least one dose of treatment and with a successful cardioversion observed at visit 3), will be 
a survival analysis using the Kaplan Meier method and Cox regression model. 
Secondary Analyses  
All secondary efficacy criteria will be described and compared using appropriate tests on the 
FAS. 
Safety Analyses 
Descriptive statistics will be performed on the Safety Set (all randomised patients with at 
least one dose of treatment)  
 
 
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STUDY FLOW-CHART 
 
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F373280 CA 201
V1
V2
V3
V4
V5
V6
V7
V8
V9
Weeks
W-4 to W-1
D1
W4
 (28 -2D/+7 D) 
W5
 (35 +/-2 D)
W8 
(56+/-7D)
W12 
(84+/-7D)
W16 
(112+/-7D)
W20 
(140+/-7D) 
W24 
(168+/-7D)
Outpatient or Hospitalization (1)
X
Informed consent
X
Demographic characteristics
X
Medico-surgical history
X
Concomitant disease
X
Concomitant treatment
X
X
X
X
X
X
X
X
X
Habits
X
Global physical examination (body weight)
X
X
X
X
X
X
X
X
Echocardiography
X
X
X
X
X
Eligibility criteria check
X
X
Blood pressure, heart rate 
X
X
X
X
X
X
X
X
X
12-Lead  ECG Recording
X
X
X
X
X
X
X
X
INR 
 
 
 (2)
X
X
X
X
X
aPTT, TCT 
X
X
X
X
X
X
X
X
Biochemistry
X
X
Hematology
X
X
X
X
Urinary pregnancy test
X
X
Red Blood Cell concentrations of DHA 
X
X
X
X
Treatment allocation
X
X
IVRS
X
X
X
X
ECV (3)
X
Drug administration 
 
 
 
 
 
 
 
 
Adverse events recording
X
X
X
X
X
X
X
X
Holter ECG 
 (4)
 
 (5)
TTEM (6)
 
 
 
 
(3) In patients with AF
(1) Outpatient or hospitalization according to clinical practice of the centre (less or more than 24 hours)
(6) TTEM everyday from week 6 to week 8. Then every 2 days from week 9 to week 24. In case of AF symptoms. In case of AF recurrence for at least 10 minutes and the patient does not 
stop  the study treatment then TTEM every 4 weeks
(2) In case of AVK introduction: INR 2 to 3 times a week, then weekly untill the ECV, then every 4 weeks after ECV.
(5) 7-day Holter ECG
(4) 24-hour Holter ECG
 
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LIST OF ABBREVIATIONS 
 
aPTT 
Activated partial thromboplastin time 
AE 
: 
Adverse event 
AERP 
Atrial effective refractory period 
AF 
: 
Atrial fibrillation 
ALA 
Alpha-linoleic acid 
ALT 
: 
Alanine aminotransferase 
AST 
: 
Aspartate aminotransferase 
AUC 
: 
Area under the plasma concentration versus time curve 
AUCinf 
: 
Total area under the curve extrapolated to infinity 
AVK 
Anti vitamin K 
βHCG 
: 
beta human chorionic gonadotrophin 
BLQ 
: 
Below the limit of quantification 
BMI 
: 
Body mass index 
BP 
Blood pressure 
BSA 
: 
Body Surface Area 
CEP 
Protocol evaluation committee 
CHF 
: 
Congestive heart failure 
CHMP 
: 
Committee for medicinal products for human use 
Cmax 
: 
Maximum concentration 
Cmin 
Minimum concentration 
CNALV 
: 
Clinically noteworthy abnormal laboratory value 
CPK 
Creatin phosphokinase 
CPP 
: 
Comité de protection des personnes  
CRA 
: 
Clinical research associate 
CRT 
Cardiac resynchronization therapy 
CSC 
: 
“Clinically Significant Change”, i.e., Predefined potentially clinically significant 
change leading to a potentially clinically significant value (vital signs) 
CV 
: 
Coefficient of variation 
DBP 
: 
Diastolic blood pressure 
DHA 
: 
Docosahexaenoic acid 
EC 
: 
Ethics committee 
ECG 
: 
Electrocardiogram 
ECHO –TE 
Trans-esophageal echocardiograph 
ECV 
: 
Electrical cardioversion 
EHRA 
European heart rhythm association 
EPA 
Eicosapentaenoic acid 
eCRF 
Electronic case report form 
FAS 
: 
Full analysis set 
Fe 
: 
Fraction of the administered drug excreted in urine 
GCP 
: 
Good clinical practice 
GFR 
:  Glomerular Filtration Rate 
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HBs 
: 
Hepatitis B antigen 
HCV 
: 
Hepatitis C virus 
HDL 
High density lipoprotein 
HF 
Heart failure 
HIV 
: 
Human immunodeficiency virus 
HR 
: 
Heart rate 
ICH 
: 
International conference on harmonisation of technical requirements for 
registration of pharmaceuticals for human use 
IDMC 
: 
Independent data monitoring committee 
INR 
International normalized ratio 
IRPF 
: 
Institut de Recherche Pierre Fabre 
IVRS 
Interactive voice response system 
LAA 
Left atrial area 
LC/MS-MS : 
Liquid chromatography with tandem mass spectrometry 
LDL 
Low density lipoprotein 
LOQ 
: 
Limit of quantification 
LVEF 
Left ventricular ejection fraction 
MedDRA 
: 
Medical dictionary for regulatory activities 
MR 
Mineralocorticoid receptor 
MR perfusion 
Magnetic Resonance perfusion 
MTD 
: 
Maximum tolerated dose 
N 
: 
Number of determinations or replicates 
NOAEL 
: 
No observed adverse effect level 
NYHA 
New York heart association 
od 
: 
Once a day 
PC 
: 
“Predefined Change”, i.e., Predefined potentially clinically significant change (lab 
or vital signs) 
PCA 
: 
PC leading to an out-of-range value (lab values) 
PFB 
: 
Pierre Fabre Biométrie 
POC 
Proof of concept 
PUFA 
: 
PolyUnsaturated fatty acid 
PK 
: 
Pharmacokinetics 
p.o. 
: 
Per os 
PP 
: 
Per protocol data set 
RBC 
: 
Red blood cells 
SAE 
: 
Serious adverse event 
SBP 
: 
Systolic blood pressure 
SD 
: 
Standard deviation 
T1/2 
: 
Terminal half-life 
T0 
: 
Time of drug administration 
Tmax 
: 
Time to reach the maximal concentration 
TCT 
Thrombin clotting time 
TEAEs 
Treatment emergent adverse events 
TTEM 
TransTelephonic ECG monitoring 
VTP 
: 
Ventricular tachypacing 
WBC 
White blood cells 
WHO-DRUG : 
World health organization drug reference list 
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1. INTRODUCTION AND STUDY RATIONALE 
1.1. 
TARGET PATHOLOGY AND THERAPY 
Atrial Fibrillation (AF) is a supraventricular arrhythmia characterized by uncoordinated atrial 
electric activity with consequent deterioration of atrial mechanical function. It is the most 
common sustained cardiac rhythm disorder, increasing in prevalence with age. Haemodynamic 
impairment and thromboembolic events related to AF result in significant morbidity and mortality 
[7]. 
In 2009, Decision Resources estimated that there were 7.8 million diagnosed prevalent cases of 
atrial fibrillation (AF) in US, Europe and Japan. This age-related pathology should increase to 9.4 
million cases in 2019.  
Except for the conventional class I and class III anti-arrhythmic agents, the PUFAs 
(Polyunsaturated Fatty Acids) constitute one emerging antiarrhythmic therapy. These compounds 
potently address the AF substrate by directly targeting both the electrical and the structural 
remodelling of the deficient atria. The n-3 PUFAs, essential for human, are ALA, EPA and DHA. 
First, PUFAs specifically modulate ionic channels by fastening their inactivating mode which 
renders these compounds selective for pathological situations (such as AF) without any major 
effect in normal conditions. PUFAs are “open Kv1.5 channel blockers” leading to a lengthening of 
atrial action potential duration and are “persistent Nav1.5 channel blockers” leading to 
hyperpolarization of diastolic resting potential. Second, PUFAs influence structural remodelling 
through their anti-inflammatory effects as they directly compete with arachidonic acid in the 
production of inflammatory eicosanoids. In summary, PUFAs share unique, well-tolerated 
antiarrhythmic potential by interacting with the electrical and structural remodelling during 
sustained AF. In animal studies, it was recently demonstrated that DHA is particularly effective in 
pathologic conditions such as ischemia and/or atrial fibrillation. 
The potential anti-arrythmic effects of a PUFA was previously developed in atrial fibrillation: 
nicotinyl ester of DHA (pro-drug based on DHA delivery) were assessed in a two-week 
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ventricular tachypaced canine model. Dogs were subjected to 4 weeks of medication prior to 
undergoing an electrophysiology study, and received either placebo or nicotinyl ester of DHA. 
Dogs were tachypaced at 240 beats per min for the final two weeks of the treatment plan. The 
results showed that the tested PUFA reduced the duration of atrial fibrillation (AF) induced by 
burst pacing, and the incidence of sustained AF, compared to dogs treated with the placebo [1]. 
In clinical practice, Nodari and coll assessed n-3 Polyunsaturated Fatty Acids in the prevention of 
atrial fibrillation recurrences after electrical cardioversion. All included patients were treated with 
amiodarone and a renin-angiotensin-aldosterone system inhibitor. The 199 patients were assigned 
either to placebo or n-3 PUFAs 2 g/d and then underwent direct electrical cardioversion (ECV) 4 
weeks later. The primary end point was the maintenance of sinus rhythm at 1 year after 
cardioversion. At the 1-year follow up, the maintenance of sinus rhythm was significantly higher 
in the n-3 PUFAs treated patients compared with the placebo group (hazard ratio, 0.62 [95% 
confidence interval, 0.52 to 0.72] and 0.36 [95% confidence interval, 0.26 to 0.46], respectively; p 
= 0.0001). The study concludes that in patients with persistent atrial fibrillation on amiodarone 
and a renin-angiotensin-aldosterone system inhibitor, the addition of n-3 PUFAs 2 g/d improves 
the probability of the maintenance of sinus rhythm after direct current cardioversion [2]. 
Previously, during the World Congress of Cardiology in 2006, an abstract reported the 
effectiveness of PUFA on top of traditional treatment (amiodarone, beta blockers, renin-
angiotensin-aldosterone system inhibitor) in the prevention of AF relapses in patients having 
undergone ECV. In the PUFA group, AF relapses were significantly lower than placebo group at 
one month (3.3% vs 10%; p=0.043), at 3 months (10% vs 25%; p=0.004) and at 6 months (13.3% 
vs 40%; p<0.0001) [19]. 
In contrast, in the general AF population (paroxystic atrial fibrillation and persistent atrial 
fibrillation), PUFAs failed to prove their efficacy [7] because of the absence of cardiac 
remodelling or because of a short pre-treatment duration before ECV (1 week) [8].The effect of 
PUFAs were only observed in patients with persistent AF on add on therapy and after a sufficient 
pre-treatment before ECV. Persistent AF is commonly associated to heart failure. Previous studies 
performed in heart failure population demonstrated the benefit of PUFAs on the improvement of 
functional ventricular parameters and morbi-mortality, and on the reduction of hospitalisation [3, 
4, 5]. 
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Nodari and coll [3] performed a trial in patients with a chronic heart failure (NYHA I to III and 
LVEF< 45%). After a treatment of 133 patients with PUFAs (n=67) or placebo (n=66) at a dosage 
of 5 g/day for 1 month, then 2 g/day for 11 months, the n-3 PUFAs group and the placebo group 
differed significantly (p <0.001) in regard to:  
− LVEF (increased by 10.4% and decreased by 5.0%, respectively) 
− peak VO2 (increased by 6.2% and decreased by 4.5%, respectively) 
− exercise duration (increased by 7.5% and decreased by 4.8%, respectively) 
− mean New York Heart Association functional class (decreased from 1.88+/- 0.33 to 1.61 
+/- 0.49 and increased from 1.83+/- 0.38 to 2.14 +/- 0.65, respectively).  
The hospitalization rates for HF were 6% in the n-3 PUFAs and 30% in the placebo group  
(p <0.0002). 
Moertl and coll [4] performed a dose-ranging study in patients with a more severe chronic heart 
failure (NYHA III and IV and LVEF < 35%). It was a double-blind, randomised, controlled pilot 
trial in 43 patients treated with PUFAs or placebo for 3 months (1 g/d n3-PUFA (n = 14), 4 g/d 
n3-PUFA (n = 13), or placebo (n = 16)). After treatment, left ventricular ejection fraction 
increased in a dose-dependent manner (P = 0.01 for linear trend) in the 4 g/d (baseline vs 3 
months [mean ± SD]: 24% ± 7% vs 29% ± 8%, p = 0.005) and 1 g/d treatment groups (24% ± 8% 
vs 27% ± 8%, P = 0.02). 
No changes in any investigated parameters were noted with placebo. 
Taking into account these studies performed with PUFAs, it seems that the best target for DHA is 
persistent AF in patients with heart failure. The aim of this proof of concept study is to assess in 
stand alone therapy (without association of other anti-arrhythmic treatments), the effect of 
F373280 in patients with persistent atrial fibrillation and heart failure in the maintenance of sinus 
rhythm after electrical cardioversion. 
1.2. 
INFORMATION ON THE TEST PRODUCT 
F373280 or panthenyl ester of DHA (docosahexaenoic acid) is the mono-ester of panthotenic 
alcohol and DHA, selected to be developed for the management of atrial fibrillation.  
F373280 is a prodrug of DHA. 
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A brief summary of F373280 known characteristics is presented in this section. For further details, 
please refer to the F373280 Investigator’s Brochure. [1] 
1.2.1. 
Chemical and pharmaceutical characteristics 
1.2.1.1. 
Nomenclature and structure 
Chemical name (IUPAC):  
(4Z,7Z,10Z,13Z,16Z,19Z)-3-((R)-2,4-dihydroxy-3,3-diméthylbutanamido) 
propyl 
docosa-
4,7,10,13,16,19-hexaenoate 
Structural formula: 
O
O
O
O
NNHH
O
O
OHH
O
OHH
 
Laboratory code: F373280 
Molecular formula: C31H49NO5 
Molecular mass: 515.7 
1.2.1.2. 
Physical and chemical general properties 
Appearance: Clear oily viscous liquid 
Solubilities:  
− Water: Practically insoluble 
− Alcohol: Very soluble  
− Trimethylpentane: Slightly soluble  
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1.2.2. 
Non-clinical Data 
Non-clinical data are exhaustively detailed in the Investigator’s brochure [1]. A brief summary is 
provided below. 
1.2.2.1. 
Pharmacological profile 
F373280 (mono-ester of panthotenic alcohol and DHA) is a novel pro-drug of DHA which exerts 
antiarrhythmic properties by interacting with the electrical and structural remodelling of the atria.  
Experimental investigations were conducted in HEK293 cell line transfected with human Kv1.5 
channel using the whole cell patch clamp technique to evaluate whether F373280 could block the 
sustained component of IKv1.5. F373280 concentration-dependently reduced Kv1.5 channel activity 
with an IC50 value of 13.7 µM. 
The effects of F373280 on atrial effective refractory period (AERP) were investigated in 
anesthetized pig using a conventional pacing protocol through epicardial electrodes placed on the 
left atrium. F373280 administered as a bolus and an infusion (10 mg/kg) significantly increased 
AERP (23.8 ± 2.2 ms versus -7.3 ± 11.5 ms in the presence of vehicle, P<0.05). In addition, 
F373280 was devoid of significant effect on the hemodynamic and the ECG intervals.  
Proof of the pharmacological concept was performed with a different DHA derivative named: 
Nicotinyl ester of DHA (pro-drug based on DHA delivery). Ventricular tachypacing (VTP)-
induced congestive heart failure (CHF) provides a clinically-relevant animal model of AF 
associated with structural remodelling, as is often seen clinically. It has been shown that sustained 
oral PUFA administration suppresses CHF-induced AF-promotion and fibrosis in the VTP canine 
model. Nicotinyl ester of DHA was tested in this model, at 1g/day and 5g/day, during 4 weeks, to 
prevent CHF-related atrial structural remodelling and AF promotion in dogs. Nicotinyl ester of 
DHA dose dependently reduced heart failure-induced increases in atrial fibrillation duration (989 
± 111 sec, n=5 in the presence of placebo versus 637 ± 196 sec, n=5 in the presence of 1g/kg/d 
Nicotinyl ester of DHA and 79 ± 51 sec, n=5, in the presence of 5g/kg/d Nicotinyl ester of DHA 
The protective effect of Nicotinyl ester of DHA was associated with a marked increase of plasma 
level of DHA and important incorporation of DHA in the left atrial tissue. Because F373280 
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similarly to Nicotinyl ester of DHA increases plasma level of DHA, it could be estimated that the 
compound may exert a similar protective effect [1]. 
1.2.2.2. 
Safety pharmacology 
A battery of safety pharmacology studies was performed to evaluate the effects of F373280 on the 
central nervous, cardiovascular and respiratory systems. Data of these studies are exhaustively 
detailed in the Investigator’s brochure [1]. 
No particular alerts were evidenced with F373280. 
1.2.2.3. 
Toxicology profile 
 
Concerning the toxicological data, 4-week and 26-week repeat-dose studies in rat and dog were 
performed. Compared to the high administered doses of F373280 (500 to 2000 gm/kg/day), low 
circulating concentrations of F373280 were measured.  
During these toxicity studies , no toxicity was observed in rat after 4 and 26 weeks of dosing and 
in dog after 4 weeks of dosing. A NOAEL of 2000 mg/kg/day was established in these repeat 
toxicity studies.  
During the 26-week toxicity study in dogs, the NOAEL was set at 1000 mg/kg/day based on 
changes observed on red blood cell parameters. 
Based on toxicological profiles, F373280 is considered to support the proposed clinical trial. 
 
1.2.2.4. 
Pharmacokinetic data  
According to animal studies described in the Investigator’s brochure [1], the non-clinical 
pharmacokinetic profile of F373280 is not associated with particular alerts concerning the 
proposed clinical phase IIa study. 
1.2.3. 
Clinical data 
Part A: single dose 
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6 consecutive single ascending doses were tested (0.5g, 1g, 2g, 4g, 8g and 16g) on 6 independent 
cohorts of 8 subjects (6 verum + 2 placebo). 49 subjects were treated and 48 completed the study. 
No Serious Adverse Events occurred in the course of the study. 
Regarding the reported Treatment Emergent Adverse Events (TEAEs) that were judged by the 
Investigator as having a causal relationship with the study drug administration in the absence of 
an alternative explanation, 4 were observed in the placebo group (palpitation, dizziness in 
standing position , 2 symptomatic orthostatic hypotensions without loss of consciousness) and 4 in 
the group of F373280 at the dosage of 16g (meteorism, liquid stool, symptomatic orthostatic 
hypotension and dizziness in standing position). None of these adverse events were reported in the 
groups of F373280 at the dosages of 0.5g, 1g, 2g, 4g and 8g. 
After a single administration of the different tested doses no difference between the tested product 
and placebo has been reported, regarding vital signs (heart rate, systolic blood pressure and 
diastolic blood pressure), biological parameters (related to coagulation: platelets and fibrinogen) 
and coagulation parameters (bleeding time, prothrombin time/INR, activated partial 
thromboplastin time, thrombin clotting time). Variations of these parameters were within the 
physiological ranges. 
After single oral administration of F373280 from 0.5g to 16 g in 36 young male healthy subjects 
(6 per dose level), the following was observed: 
 
- F373280: Whatever the tested dose there is no circulating F373280 in plasma: only few, 
sparse and non consecutive samples with quantifiable level of F373280 close to LOQ were 
observed. This confirm that F373280 is a prodrug. 
- Panthenol: Cmax and AUC increased with the administered dose between 0.5 and 16g. 
Panthenol concentrations were rapidly cleared from plasma with a mean terminal half-life 
around 2 hours. 
- DHA: after 0.5 and 1g, low increased in DHA plasma concentrations compared to the 
baseline levels led to a high inter-individual variability of the corresponding PK parameters. 
Plasma exposure in DHA increased with the administered dose between 2 and 16g with no 
departure from proportionality (baseline corrected parameters). 
 
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Part B: Multiple dose  
Three consecutive repeated ascending doses (1, 2 and 4g) were tested on 3 independent cohorts of 
12 subjects (9 verum + 3 placebo, double blind). 36 subjects completed the study. Each treatment 
was administered over a period of 28 days. Pharmacokinetic parameters were assessed over a 
period of 14 days.  
Among the TEAE judged by the investigator as suspected to F373280 5/9 TEAE were classified 
according the SOC in vascular system disorder with orthostatic hypotension (2 in the 1 g group, 1 
in the 2 g group and 2 in the 4 g group) and 4/9 were classified in nervous system disorder with 3 
dizziness (2 in the 2 g group and 1 in the 4 g group) and 1 migraine (in the 1 g group). These 
TEAE have already been reported with Poly Unsaturated Fatty Acids and are commonly observed 
in phase I studies. 
After a repeated administration of the different tested doses, no difference between the tested 
products and placebo was reported regarding vital signs (heart rate, systolic blood pressure and 
diastolic blood pressure), biological parameters. The assessment of coagulation parameters and 
platelet function after administration of repeated dose of F373280 did not report any bleeding 
issue. The reported changes in coagulation parameters and platelet function were within 
physiological ranges. 
After a 14-day repeated oral administration of F373280 from 1 g to 4 g, the following was 
observed: 
 Panthenol: Cmax and AUC increased with the administered dose between 1 and 4 g. No 
accumulation of panthenol in plasma was observed. 
 
 DHA: Plasma exposure increased with dose. A 2-fold accumulation in total plasma exposure 
of DHA was observed after 14 days of administration, whatever the administered dose. 
 
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1.3. 
STUDY RATIONALE 
F373280 is a new therapy based on DHA delivery (pro-drug) developed for the maintenance of 
sinus rhythm after electrical cardioversion in persistent atrial fibrillation (AF) patients with 
chronic heart failure. 
The results of a pharmacological study performed in animals evidenced that DHA reduces the 
duration of atrial fibrillation (AF) induced by burst pacing [1]. 
Moreover, the effectiveness of PUFA has been proven in the following conditions: 
- 
Prevention of atrial fibrillation recurrence in patients with persistent atrial fibrillation in 
co-administration with amiodarone (add on therapy) [2], 
- 
Improvement of ventricular functional parameters, morbi-mortality and duration of 
hospitalisation in patients with heart failure [3, 4, 5]  
Taking into account these studies, it seems that DHA might be of therapeutic interest in the 
treatment of patients with both persistent atrial fibrillation and chronic heart failure. 
This phase IIa study is designed to assess the efficacy and the safety of the investigational product 
(F373280) for maintenance of sinus rhythm after electrical cardioversion in patients with 
persistent atrial fibrillation and chronic heart failure. 
1.4. 
OVERALL RISK AND BENEFIT ASSESSMENT 
F373280 is a new pro-drug of DHA.  
DHA is a well-known long chain PUFAs with a long-term clinical experience in cardiovascular 
diseases. DHA is contained in several medicinal products such as Omacor, (1g of Omacor 
contains about 320 mg of DHA acid) marketed by Laboratoires Pierre Fabre for 
hypertriglyceridemia and as an adjuvant treatment for secondary prevention after myocardial 
infarction. According to the summary product characteristics of Omacor, [9]: 
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- The frequencies of adverse reactions are ranked according to the following: common (> 
1/100, < 1/10); uncommon (>1/1000 < 1/100); rare (>1/10000, < 1/1000); very rare ( < 1/10000), 
not known (cannot be estimated from the available data). 
- The reported adverse events are: 
• Infection and infestations 
Uncommon: gastroenteritis 
• Immune system disorders: 
Uncommon: hypersensitivity 
• Metabolism and nutrition disorders: 
Rare: hyperglycaemia 
• Nervous system disorders: 
Uncommon: dizziness, dysgeusia 
Rare: headache 
• Vascular disorders: 
Very rare: hypotension 
• Respiratory thoracic and mediastinal disorders:  
Very rare: nasal dryness 
• Gastrointestinal disorders: 
Common: dyspepsia, nausea 
Uncommon: abdominal pain, gastrointestinal disorders, gastritis, abdominal pain upper 
Rare: gastrointestinal pain 
Very rare: lower gastrointestinal haemorrhage 
• Hepatobiliary disorders:  
Rare: hepatic disorders  
• Skin and subcutaneous tissue disorders:  
Rare: acne, rash pruritic 
Very rare: urticaria 
• General disorders and administration site conditions: 
Rare: malaise sensation 
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• Investigations: 
Very rare: white blood count increased, blood lactate dehydrogenase increased 
Moderate elevation of transaminases has been reported in patients with hypertriglyceridaemia. 
Panthenol is a well-known substance with a long-term experience in medical, nutraceutic and 
cosmetic uses. According to the summary product characteristics of a product such as 
Bépanthene (tablet indicated in alopecia) which contains panthenol (100 mg), adverse event 
observed are rare cases of urticaria and erythema [10]. Panthenol is metabolised in panthotenic 
acid, i.e. B5 vitamin. 
Concerning toxicological studies performed results can support the administration of F373280 in 
the proposed clinical phase II study without particular alert [1]. 
Any safety warning was reported during a phase I study performed with F373280 administered to 
84 healthy volunteers in single dose in a range between 500 mg and 16 g or in repeated dose 
during 28 days in a range between 1g and 4g. Adverse events reported and related to study 
treatment were minor to moderate. The adverse events were palpitations, orthostatic hypotension, 
dizziness, meteorism and liquid stool. Most were reported in both groups (placebo and F373280) 
without a dose relationship. The assessment of coagulation parameters and platelet function after 
administration of repeated dose of F373280 did not report any bleeding concern: the reported 
changes in coagulation parameters and platelet function were within physiological ranges. 
Moreover, DHA has been associated with anticoagulant products in Atrial Fibrillation studies [2, 
8]. The range of PUFAs doses tested was between 2g to 3g (640 mg to 960 mg of DHA) and the 
range of study durations between 6 to 12 months. This association did not report a significant side 
effect of bleeding. 
DHA has already been used in heart failure patients in several studies without safety concern [3, 
4, 5]. The range of PUFAs doses tested was between 1g to 5g (1g of the tested PUFAs contains 
about 320 mg of DHA acid) and the range of study durations was between 3 months to 3.9 years. 
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Thus, inclusion of patients with no specific antiarrhythmic treatment is acceptable. They will 
receive an anticoagulant treatment to prevent the thrombo-embolic complications of AF 
(particularly stroke) and the adequate treatments to control the heart rate and heart failure.   
In conclusion, the overall available data allow in safe conditions the treatment of patients with 
persistent AF and chronic heart failure with F373280 in safe conditions. 
2. STUDY OBJECTIVES 
2.1. 
PRIMARY OBJECTIVE 
The primary objective of the study is to assess the efficacy of F373280 on the maintenance of 
sinus rhythm after direct electrical cardioversion in patients with persistent atrial fibrillation and 
chronic heart failure. 
2.2. 
SECONDARY OBJECTIVES 
The secondary objectives of the study are to assess: 
• the efficacy of F373280 on the efficiency of direct electrical cardioversion 
• the effect of F373280 on echocardiographic parameters 
• the safety and tolerability of F373280 
3. ETHICAL CONSIDERATIONS RELATING TO THE STUDY 
The trial is conducted according to Good Clinical Practices (CPMP/ICH/135/95), the National 
regulations and the Declaration of Helsinki and its subsequent amendments (see Appendix 17.1). 
This protocol and the informed consent form will be submitted for approval to independent local 
or national Institutional Review Boards/Ethics Committees before the study set up, according to 
national regulation. 
All the protocol amendments or critical events liable to increase the risks incurred by the patients 
or to compromise the validity of the study or patients' rights will be submitted to the coordinator 
and to the Ethics Committees. 
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After being informed orally and in writing of all potential risks and constraints of the trial, as well 
as their freedom to withdraw their participation at any time, patients will then sign a consent.  
A time of reflection will be given to the patients, before giving a written consent and starting the 
study procedures. 
The use of a placebo is in accordance with EMA Addendum to the guideline on antiarrhythmics 
on atrial fibrillation and atrial flutter (EMA/CHMP/EWP/213056/2010) [21] and is acceptable 
because the included patients will remain under the standard treatment of atrial fibrillation and 
chronic heart failure. Except antiarrythmics, they will receive anticoagulant (AVK), rate control 
treatment, chronic heart failure treatment. During the study, in case of AF recurrence that would 
require a cardioversion or an introduction of an anti-arrhythmic because of intolerable and/or 
uncomfortable clinical symptoms, patients will be withdrawn and the tested product stopped. 
These patients will be considered as treatment failure. 
In this study, patients will be carefully screened, particularly for their cardiac condition, with 
ECG, 24-hour holter monitor and echocardiographic data, and their biologic and coagulation 
condition. 
The study will be addressed only to patients requiring an ECV due to their persistent AF, in the 
following conditions: 
- 
ECV in patients not presenting a contra-indication,  
- 
Anticoagulation  with anti-vitamin K for at least 3 weeks before ECV,  
- 
ECV in patients with stabilized INR (i.e. values between 2 and 3) on at least 3 
consecutive weekly tests performed. Patients not stabilized for INR (i.e. values 
between 2 and 3) on at least 3 consecutive weekly tests performed before ECV will be 
excluded from the study, unless the presence of atrial thrombosis may be excluded 
with ECHO –TE (trans-esophageal echocardiograph) performed  in the same day 
(before ECV) 
 
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- 
Patients who do not revert to sinus rhythm or present an early relapse within the 
observation period after ECV will be withdrawn and the tested product stopped. 
During the whole study, patients will remain under medical control: visits in cardiology units will 
be scheduled at least every month. This follow up will include clinical signs, ECG, biological and 
coagulation parameters. Moreover, patient’s cardiac rhythm will be monitored between visits 
using daily, then every 2 days Trans Telephonic ECG Monitoring (TTEM) reviewed by a Central 
Reading Laboratory. 
Patients may withdraw from the study at any time without having to give a reason and can expect 
to receive regular conventional therapy. 
4. STUDY DESIGN 
4.1. 
OVERALL DESCRIPTION 
This phase IIa trial will be conducted as an international, multicentric, 24 weeks, double-blind, 
placebo-controlled, randomised, parallel group design, trial in 152 patients suffering from 
persistent atrial fibrillation and chronic heart failure. 
After a 1 to 4-week of run-in period without treatment, patients will be randomised into one of the 
following treatment groups: F373280 1g or placebo for 24 weeks.  
Nine visits are planned for the study: 
- 
Visit 1 (V1): W-4 to W-1: Selection visit (7 to 28 days before the Inclusion Visit) 
- 
Visit 2 (V2): D1: Inclusion visit (start of treatment)  
- 
Visit 3 (V3): W4 (D28 -2/+7D): cardioversion visit (outpatient or hospitalization 
according to clinical practice of the centre) (installation of the Holter ECG device) 
- 
Visit 4 (V4): W5 (D35 ± 2D): follow-up visit (removing of Holter ECG device and 
installation of the TTEM) 
- 
Visit 5 (V5): W8 (D56 ± 7D): follow-up visit 
- 
Visit 6 (V6): W12 (D84 ± 7D): follow-up visit 
- 
Visit 7 (V7): W16 (D112 ± 7D) : follow-up visit 
- 
Visit 8 (V8): W20 (D140 ± 7D): follow-up visit 
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- 
Visit 9 (V9): W24 (D168 ± 7D): final study visit 
4.2. 
DISCUSSION OF THE STUDY DESIGN 
4.2.1. 
Choice of the Study Population 
The target indication of F373280 will be the maintenance of sinus rhythm after cardioversion of 
patients with persistent atrial fibrillation and chronic heart failure. In the present proof of concept 
study, the evaluation will focus on patients within this indication. This target population is 
justified by: 
− The proved efficacy of PUFAs in patients with persistent atrial fibrillation with or 
without heart failure in co-administration with amiodarone (add on therapy) [2] 
− The proved efficacy of PUFAs on the improvement of ventricular functional parameters, 
morbi-mortality and duration of hospitalisation in patients with heart failure  [3, 4, 5] 
The study aim is to investigate the product effect in patients with: 
− early persistent atrial fibrillation history (less than one year) with a duration of a the 
current episode between 7 days to 6 months  
− a moderately abnormal moderately systolic heart failure (Left Ventricular Ejection 
Fraction (LVEF) between 30 to 45% as defined in the report from the American Society 
of Echocardiography’s Guideline). According to a sub-group analysis performed in 
patients with persistent atrial fibrillation associated to heart failure ( Nodari S. personnal 
data), PUFAs would be effective to prevent recurrence of AF after cardioversion in 
patients with moderately abnormal LVEF. 
 
− A Left Atrial Area (LAA) not severely abnormal (less than 40 cm2 as defined in the 
report from the American Society of Echocardiography’s Guideline). According to a 
sub-group analysis performed in patients with persistent atrial fibrillation associated to 
heart failure ( Nodari S. personnal data), PUFAs would not be effective to prevent 
recurrence of AF after cardioversion of patients with severely abnormal LAA. 
For the successful rate of electrical cardioversion, patients should have a stable medical 
treatment of heart failure and should not have myocardial infarction or unstable angina or 
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unstable ischemic coronaropathy (assessed by coronarography or cardiac stress test or effort 
test within 6 months before selection).  
4.2.2. 
Choice of the Study Design 
As the target indication would be the prevention of AF recurrence after ECV, the study design 
meets the requirements of EMA guideline on anti-arrhythmics on atrial fibrillation 
(EMA/CHMP/EWP/213056/2010) [21]. 
As F373280 aims to be developed as a safe treatment for the prevention of AF recurrence, it will 
not be tested as an add-on therapy during the study. To avoid any interaction with the tested 
product, anti-arhythmics class I and III will be forbidden during the study. 
The study design is defined in order to avoid methodological bias. A double blind study is 
appropriate to assess the efficacy and safety of the use of F373280 to prevent recurrence of AF 
episodes. Moreover, this study design is similar to the design of almost all trials that have assessed 
intervention for rhythm control [2, 8, 11, 12].  
According to the target indication, only patients with persistent atrial fibrillation and requiring an 
electrical cardioversion will be included in order to assess the time to first documented recurrence 
of atrial fibrillation since cardioversion. 
To confirm the persistent nature of atrial fibrillation, a 24-hour holter monitoring will be 
performed during the selection visit.  
Eligible participants will enter a selection phase in which anticoagulant treatment (anti-vitamin K) 
will be adjusted to achieve an International Normalized Ratio (INR) of 2.0 to 3.0 before electrical 
cardioversion. According to guidelines for the management of atrial fibrillation [6], anti-vitamin 
K should be given at least 3 weeks before cardioversion because of risk of thrombo-embolism due 
to post-cardioversion.  
Experimental data suggest that the maximal incorporation, of n-3 PUFAs in the myocardial cell 
membrane takes up to 28 days to occur [22]. In addition, as shown in Nodary study [2], the 
duration of pre-treatment with PUFA before cardioversion appears to be a contributing factor in 
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success.Therefore, before starting follow up for the assessment of AF recurrence, treatment with 
F373280 should be started 28 days before ECV.  
Detection of atrial fibrillation recurrence will be performed using systematic (scheduled) ECG 
recording, thus allowing detection of asymptomatic (about 50% of episodes) as well as 
symptomatic AF episodes. According to previous studies, most of atrial fibrillation recurrence 
occurred during the first days after cardioversion [11, 15]. So that, the heart rhythm will be 
closely monitored during the first week after successful cardioversion using an ambulatory 
continuous 7-day holter ECG recording in order to increase sensibility to detect asymptomatic AF 
episodes. Thereafter, to improve patient compliance, this follow up will be continued using  a 
more easy to carry and easy to use device, a TTEM.  
Finally, during the study, patients will be scheduled for a clinical visit every month (with an 
additional visit 7 days after visit 3 (ECV visit)) in order to ensure a close medical monitoring and 
to assess efficacy and safety parameters. 
4.2.3. 
Choice of the Dose  
According to a previous study in patients with atrial fibrillation [2], the tested PUFA product 
(Omacor) at the dose of 2 g (i.e. 640 mg of DHA acid) was effective in the prevention of atrial 
fibrillation after cardioversion. Moreover, PUFAs at dosage of 1g and 2g were also effective on 
the improvement of ventricular functional parameters, morbi-mortality and duration of 
hospitalisation in patients with heart failure [3, 4, 5].  
From the F373280 phase I study, after a 14-day repeated administration of F373280 (1g/day), 
observed plasma concentrations of DHA measured before treatment (Cmin) were similar to that of 
an effective dose of Omacor at 2 g/day (60 to 95mg/mL and 60 to 90mg/mL, respectively) 
(phase I study of F373280 and Salm and coll study) [16]. With regard to the rythm of 
administration, mean peak/trough fluctuation (baseline corrected) was around 0.3. This value 
supports a once-daily administration allowing a 24-hour plasma exposure in DHA.Therefore, a 
dose of 1 g daily of F373280 is considered to be appropriate to be tested in this POC study. 
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4.2.4. 
Choice of the Sample Size 
See chapter 13. 
5. STUDY POPULATION 
Each patient fulfilling all the inclusion criteria and none of the non inclusion criteria will be 
eligible. 
5.1. 
INCLUSION CRITERIA 
Demographic Characteristics and Other Baseline Characteristics: 
1. Men or women aged more than 18 years (inclusive), 
2. Patient with persistent AF between 7 days and 6 months duration for whom 
electrical cardioversion is warranted. 
3. History of first documented persistent AF less than 1 year 
4. History of ischemic or non ischemic heart failure 
5.  NYHA class I or II chronic heart failure at selection and at inclusion 
6. Reduced left ventricular ejection fraction between 30% and 45% inclusive (using the two-
dimensional echocardiography biplane Simpson’s rule) at selection and at inclusion 
7. On appropriate, stable medical treatments for heart failure, including a diuretic and/or 
angiotensin-converting 
enzyme, 
and/or 
angiotensin-receptor 
blocker 
and/or 
mineralocorticoid receptor (MR) antagonists, and/or betablockers 
8. Left atrial area ≤ 40 cm² at selection and at inclusion 
9. Patient treated or having to be treated by anti-vitamin K 
10. For female patient of child-bearing potential:  
- 
use of an effective method of contraception (hormonal contraception or intra-uterine 
device) assessed by the investigator, for at least 2 months before the selection in the 
study and agreement to go on using it during the whole duration of the study and up to 
1 month after the last dose of the study treatment or 
- 
documented as surgically sterilized 
11. For female patient of child-bearing potential: negative urine pregnancy test at inclusion 
 
Ethical /legal considerations: 
12. Having signed his/her written informed consent, 
13. Affiliated to a social security system, or is a beneficiary (if applicable in the national 
regulation), 
5.2. 
NON INCLUSION CRITERIA 
Criteria related to pathologies: 
1. History of first documented episode of persistent AF more than 1 year, 
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2. More than two successful cardioversions (electrical or pharmacological) in the last 6 months, 
3. Secondary Atrial Fibrillation due to alcohol or severe valvular heart disease (grade III to IV), 
4. NYHA class III or IV heart failure at selection or at inclusion 
5. Thyroid disease uncontrolled by treatment: TSH ± T4L ± T3L to be check in case of treatment 
for thyroid disease  
6. Myocardial infarction or unstable angina or presence of unstable ischemic coronaropathy 
assessed by coronarography or cardiac stress test (Echo stress, exercice stress test, nuclear or 
MR perfusion evaluation methods) within 6 months before selection 
7. Severe chronic kidney disease (creatinine ≥ 25 mg/L or estimated glomerular filtration rate  
< 30 mL/min) at selection 
8. Bradycardia (HR ≤ 50 bpm) 
9. Hyperkalemia or hypokalemia (K > 5.5 mEq/L or K < 3.5 mEq/L) at selection 
10. Cardiac surgery within 3 months before selection or planned during the study duration 
Criteria related to treatments: 
11. Previously ineffective pharmacological or electrical cardioversion 
12. Concomitant treatment with any anti-arrhythmic drug (within 7 days prior to selection), except 
stable dose of digoxin, beta-blockers, calcium-blockers. 
13. Previous treatment with oral amiodarone within 12 months prior to inclusion 
14. Previous treatment with intravenous amiodarone within 6 months prior to inclusion 
15. Patient requiring a cardiac resynchronization therapy (CRT) or having undergone CRT 
implantation within the last 6 months 
16. Treatment with any Polyunsaturated Fatted Acid within the last 3 months 
Dietary supplement with ω3 or ω6 according to investigator’s judgment 
18. Having undergone any form of ablation therapy for AF 
19. Patient treated with other anticoagulant treatment than antivitamin K: thrombin inhibitor such 
as Dabigatran or treated with antiaggregant P2Y12 inhibitors such as Clopidogrel or Prasugrel 
Others criteria:  
20. Patient liable not to comply with protocol instructions and/or with treatment, in the 
investigator’s opinion, 
21. Patient having taken part in a clinical trial in the preceding 2 months or taking part in a trial at 
the time of selection, 
22. Patient linguistically or mentally unable to understand the nature, objectives and possible 
consequences of the trial, or refusing to patient himself / herself to its constraints, 
23. Patient family member or work associate (secretary, nurse, technician…) of the Investigator, 
24. Patient having forfeited his / her freedom by administrative or legal award or being under 
guardianship, 
25. Breastfeeding female patient. 
5.3. 
NUMBER OF  PATIENTS 
76 x 2 patients (taking into account 15 % of non evaluable patients). 
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5.4. 
RECRUITMENT MODALITIES 
Patients will be recruited within the medical consultation of each centre involved in the study. If 
necessary and when authorized by local and national regulation, some specific supports or tools 
will be used to improve the recruitment (announcement, mailing to general practitioners, leaflet, 
website including ClinicalTrials.gov, CRO,…). 
Before implementation, the documents will be submitted to and approved by the Ethics 
Committee. 
5.5. 
 PATIENTS IDENTIFICATION 
The patient's code will contain 7 digits: the 2 first digits corresponding to the country number, the 
following 2 digits corresponding to the centre number and the last 3 digits corresponding to the 
patient's chronological order once having signed the written informed consent. 
5.6. 
WITHDRAWAL CRITERIA 
The reasons for a patient's premature withdrawal from the study may be the following: 
• The patient's decision. A patient who wishes to withdraw from the study for any reason may 
do so at any time but must inform the investigator. In all cases, the Investigator should attempt to 
contact the patient as soon as possible for a final assessment in order to: 
− have the patient's decision written on the consent form 
− obtain the reason(s) for withdrawal and report it/them in the case report form 
− evaluate the patient's clinical condition 
− if necessary, take appropriate therapeutic measures: management of an adverse effect or 
concomitant disease, prescription of another treatment. 
• The Investigator's decision in the patient's interest. Particularly, if a serious adverse event 
occurs and is considered by the Investigator liable to threaten the health of the patient. The 
monitor will be informed by phone or fax and a letter or report explaining the withdrawal will be 
forwarded to the monitor as soon as possible. 
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• An erroneous inclusion according to the study protocol. Any inclusion not respecting 
inclusion / non inclusion criteria will immediately be withdrawn and an appropriate treatment will 
be instored by the investigator under his/her responsibility. Erroneous inclusions will not be paid 
to the investigator. 
• Patients who could not be treated with anti-vitamin K for at least 3 weeks before ECV, 
• Patients who will not stabilize INR between 2 and 3 on at least 3 consecutive weekly tests 
• Patients with only 2 consecutives INR tests between 2 and 3 in the last 3 week for whom  a 
trans-oesophagoal echocardiography can not be performed before ECV or for whom a trans-
oesophagoal echocardiography shows a thrombus in the atria.  
• Patients who will not revert to sinus rhythm or with early relapse within the observation 
period after ECV (i.e. unsuccessful ECV) will be considered to have finished follow-up. 
• An occurrence of AF recurrence that would require, at the investigator’s judgement, a 
cardioversion or an introduction of an anti-arrhythmic because of intolerable and uncomfortable 
clinical symptoms. 
5.7. 
REPLACEMENT OF PATIENTS 
Withdrawn patients will not be replaced. 
5.8. 
POST-STUDY EXCLUSION PERIOD  
Patients will not be allowed to participate to another clinical trial during 3 months following the 
study termination. 
5.9. 
STUDY CARD 
The patient will receive from the Investigating Centre at Visit 1 - Selection Visit, a personal card 
to be kept all along the study duration and providing the following information: patient's name, 
sponsor's name, study code, EUDRACT number, start date and expected end date of the study, 
complete address of the Investigating Centre with the name and phone number of the Investigator 
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and a sponsor 24H/24 phone contact number in case of emergency (French and English 
languages): 33 (0)5 63 35 25 83. 
6. STUDY TREATMENT 
The Clinical Pharmacy Department of the Institut de Recherche Pierre Fabre (IRPF) will supply 
the investigational centres with the treatment necessary for the conduct of the trial.  
6.1. 
SOURCE, PRESENTATION AND COMPOSITION OF 
 
INVESTIGATIONAL PRODUCT 
F373280 and placebo will be prepared in Soft Capsules similar presentation.  
• F373280 
Formulation of F373280, 1g, Soft Capsules: oral administration, oblong size 20, off-white, Soft 
Capsules containing: Panthenyl ester of DHA, gelatine, glycerol, titanium, dioxide, purified water. 
• Placebo 
Formulation of placebo matching tested product, Soft Capsules: oral administration, oblong size 
20, off-white, Soft Capsules containing: paraffin liquid, fish flavour, gelatine, glycerol, titanium, 
dioxide, purified water. 
 
Placebo and F373280 capsules will be packaged in opaque blisters. 
6.2. 
PACKAGING AND LABELLING 
The treatment units will be packed and labelled by the Clinical Pharmacy Department of the IRPF 
according to European Directive and local requirements. 
6.2.1. 
Packaging 
Each treatment unit will be composed of 3 cases for a 12-week treatment period. 
The Investigator will provide the patient with the treatment according to the following schedule: 
At Inclusion Visit (V2): a 12-week treatment unit will contain 3 cases, each case containing: 
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− 10 blister packs of four 1g F373280 soft capsules or placebo soft capsules each. 
At Visit 6 (V6): a 12-week treatment unit will contain 3 cases, each case containing: 
− 10 blister packs of four 1g F373280 soft capsules or placebo soft capsules each. 
6.2.2. 
Labelling 
Investigational Products will be labelled according to the following rules: 
Labelling should comply with the local requirements for Investigational Medicinal Products. 
On the treatment units and cases, the labels will bear the following indications:  
a) name and address of the sponsor 
b) protocol number, 
c) packaging batch number, 
d) the treatment number 
e) storage conditions 
f) expiry date 
g) pharmaceutical dose form 
h) route of administration 
i) quantity of dosage units 
j) direction for use 
k) legal statements:  
− “for clinical trial only”, “keep out of the reach and the sight of children”, “please return 
to your doctor any unused product”, respect the prescribed dose”. 
On the treatment unit, another label will be affixed with the mention of the investigator name and 
patient number (completed by the investigator). 
In addition, on each case, will be mentioned the case number and a detachable label will bear the 
following indications: 
− Protocol number 
− Packaging batch number 
− Expiry date 
− Case number 
− Treatment number 
On the blister pack, the label will mention the protocol number, the packaging batch number, the 
case number and the treatment number. 
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6.3. 
DISTRIBUTION TO CENTRE AND STORAGE 
The Clinical Pharmacy Department of the IRPF will supply the Investigational Centre with the 
treatment units along the study according to the need, upon request triggered by the patient’s 
selection.  
As soon as the Pharmacist or the Investigator receives the trial medication, he/she will check the 
contents and immediately acknowledges the receipt in the IVRS/IWRS. The copy of the 
acknowledgement will be kept in the Investigator’s file. The same procedure will be applied to all 
further supplies during the course of the trial. 
At the time of the delivery to the Centre, the following information will be provided: 
• Details of storage conditions that should be respected 
• And, upon request and for the 1st delivery only, a letter of release for the Investigational 
Medicinal Product from the Sponsor's Qualified Person. 
The CRA will ensure during the monitoring visits that trial medications have been received in 
good conditions and the acknowledgment of receipt has been performed adequately. 
Treatment units should remain intact until dispensation to the patients. They should be kept at 
temperature below 30°C in an appropriate lockable room only accessible to the person authorised 
to dispense them, under the responsibility of the Pharmacist or the Investigator. 
In the case of undue delay in study execution, the Pharmacist or the Investigator should ensure 
that the expiry date has not been exceeded.  
6.4. 
ALLOCATION OF TREATMENTS AND DISPENSATION TO PATIENT 
A randomisation list will be established by the Clinical Pharmacy Department of the IRPF. This 
list will be computer-generated with internal software. The randomisation methodology is 
validated by the Biometry Department before generation. 
Treatments F373280 or placebo will be balanced in a 1:1 ratio. 
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As the treatment units are prepared for 12-week treatment periods, the Investigator will have to 
allocate a treatment number at inclusion Visit and another one at Visit 6.  
For each patient, the treatment number given at Visit 6 will not be the same that the one given at 
inclusion visit (V2). 
The treatment numbers will be given through the IVRS/IWRS. 
Practically, once the patient’s eligibility is confirmed, at selection visit:  
• The Investigator: 
− Calls the vocal server  
− Answers the questions relating to the patient  
− In return, the treatment number to be allocated for the first 12-week period to the patient 
is given by the vocal server.  
• The IVRS/IWRS company: 
− Confirms this information by fax/email to the Investigator 
− Fills the “Request for Delivery of Investigational Product” form and sends it by email 
and/or fax to the Clinical Pharmacy Department of the IRPF.  
• The Clinical Pharmacy Department of the IRPF sends the corresponding treatment unit to the 
Investigator within 5 days from reception of the email request form. 
The Investigator will dispense to the patient the case which label indicates the treatment number 
and the administration period. 
At visit 5, the Investigator will contact again the IVRS/IWRS to obtain for visit 6 the treatment 
number for the last 12-week period of treatment according to the same process as described 
above. 
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6.5. 
DRUG ADMINISTRATION 
6.5.1. 
Duration of Treatment 
For a patient completing the study, the theoretical study treatment exposure will be 24 weeks, 
with F373280 or placebo. 
If the ECV is postponed by 1 week to allow INR stabilization, the treatment duration will be 25 
weeks. 
6.5.2. 
Dose Schedule 
One soft capsule of 1g of F373280 or placebo to be taken each day during 24 weeks. 
6.5.3. 
Route and Conditions of Administration 
The soft capsules are to be taken orally. One soft capsule is to be taken each evening with the 
dinner during 24 weeks.  
6.6. 
ACCOUNTABILITY ON SITE AND RETURN/DESTRUCTION OF 
 
INVESTIGATIONAL PRODUCT 
The Investigator should maintain accurate written records of drug received, dispensed, returned 
and any remaining treatment units, on the drug accountability form. These records should be made 
available for Clinical Research Associate (CRA) monitoring. The packaging of the medication 
should remain intact until just before the dispensation. 
At each visit, the Investigator will record the number of soft capsules returned by each patient 
using the appropriate page of the e-CRF. 
At the end of the study, all used and unused treatments including packaging should be noted, and 
return is organised by the CRA to the Clinical Pharmacy Department of the IRPF for destruction. 
A copy of the drug accountability form should be provided by the Investigator to the CRA. 
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6.7. 
RECALL OF INVESTIGATIONAL PRODUCTS  
In case of recall of investigational products (decided by the Competent Authorities or the 
Sponsor), the Investigator will immediately be informed by the Sponsor. 
The Investigator, in collaboration with the Sponsor representatives (Study Manager, CRA) must 
urgently: 
• Stop the delivery of the concerned investigational products to the patients. 
• Inform the concerned patients that they must immediately stop taking these investigational 
products and bring them back. 
The Study Manager/CRA organises the return of the recalled products to the Clinical Pharmacy 
Department of the IRPF, according to the Sponsor’s procedures. 
7. CONCOMITANT TREATMENTS 
Any existing concomitant treatment (Selection Visit), any new concomitant treatment or change 
in the dosage of an existing concomitant treatment during the course of the study must be noted 
on e-CRF. All treatments should be evaluated by the investigator at selection and their 
prolongation during the study or their stop should be considered. 
For all concomitant treatments taken during the study, the following information must be noted in 
the relevant section(s) of the e-CRF: 
• The name of the treatment and its form 
• The reason for prescription 
• The route of administration 
• The daily dose 
• The duration of treatment. 
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7.1. 
ANTI-VITAMIN K TREATMENT 
Anti-vitamin K should be given for at least 3 weeks before ECV and continued for the whole 
study duration. The anti-vitamin K used will be left to the decision of the each investigator 
according to his/her local practice. 
7.2. 
PROHIBITED TREATMENTS 
- 
Class I and class III antiarrhythmic treatments: 
− Class I  
- 
Class IA: Disopyramide, Procainamide, Quinidine 
- 
Class IB: Lidocaine, Mexiletine 
- 
Class IC: Flecainide, Propafenone 
 
− Class III: Dofetilide, Ibutilide, Sotalol, Amiodarone, Dronedarone.  
- 
Any Polyunsaturated Fatty Acid (PUFA) 
- 
Any anticoagulant treatment other than antivitamin K: thrombin inhibitor such as Dabigatran 
or antiaggregant P2Y12 inhibitors such as Clopidogrel or Prasugrel 
- 
Dietary supplement with Omega 3 or Omega 6 
Prohibited treatments at selection must not be prescribed for the duration of the study except in 
case of occurrence of an adverse event or AF episode that requires a corrective treatment in the 
interest of the patient’s health. 
7.3. 
AUTHORISED TREATMENTS 
Other treatments will be authorised during the study duration. 
However, if medication other than study drugs is administered at any time from the start of the 
study, details must be recorded in the case report form. During the study, patients must be asked 
whether they have been on a course of prescribed drug treatment or have taken any OTC or herbal 
drugs since the visit. 
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8. EVALUATION CRITERIA 
8.1. 
PRIMARY EFFICACY CRITERION:  
8.1.1. 
Time to the first Atrial Fibrillation Recurrence 
8.1.1.1. 
Definition 
Time to first Atrial Fibrillation recurrence is defined by the first episode of Atrial Fibrillation 
(symptomatic or not) lasting for at least 10 minutes. 
8.1.1.2. 
Schedule 
The heart rhythm follow up will be performed from the end of electrical cardioversion visit  
(visit 3) to the final study visit (visit 9).  
For randomised patients with spontaneous cardioversion before ECV, the recurrence of AF will be 
assessed after visit 3 (week 5). 
8.1.1.3. 
Evaluation Methods 
• 7-day holter monitor: 
The heart rhythm monitoring will be carried out  from visit 3 to visit 4 using a 7-day continuous 
ECG (5-leads/2 or 3 channels) ambulatory recording (holter ECG) fixed after ECV visit. 
Following holter monitoring the heart rhythm will be documented using Trans Telephonic ECG 
Monitoring (TTEM) 
• Trans Telephonic ECG Monitoring (TTEM): 
Thus, the follow up will be documented using the TTEM: daily transmission from visit 4 to visit 
6. Then, every two days from visit 6 to visit 9. 
Moreover, during this TTEM period, if patient experiences AF symptoms, it should be 
documented using the TTEM. 
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In case of AF recurrence, and provided that the patient does not required a cardioversion or an 
introduction of an anti-arrhythmic at the investigator’s judgement, he/she could be maintained in 
the study with the treatment, in order to assess a spontaneous cardioversion. For that purpose the 
patient will continue to transmit a TTEM once a week. 
The TTEM will be centralized by the Central Reading Laboratory. The patient will be requested 
to contact the Central Reading Laboratory for transmission of each stored TTEM. The TTEM will 
be validated by a trained technician, then analysed by a cardiologist. The cardiologist 
interpretation will be faxed to the site. The investigator will be asked to review and sign this 
document. 
The TTEM process will be fully described in a separate document. 
8.1.2. 
Secondary Efficacy Criteria 
8.1.2.1. 
Numbers of Atrial Fibrillation episodes in the first week following visit 3 
 
 
(ECV visit) 
8.1.2.1.1. 
Definition 
Number of Atrial Fibrillation episodes will consist in the assessment of episodes of AF with 
duration at least 10 minutes (NSup10) and of less than 10 minutes (NInf10), respectively. 
8.1.2.1.2. 
Schedule 
The heart rhythm follow up will be performed from the end of successful electrical cardioversion 
visit (visit 3) to the study visit 4.  
8.1.2.1.3. 
Evaluation Methods 
• 7-day holter monitor: 
The heart rhythm monitoring will start using a 7-day continuous ECG (5-leads/2 or 3 channels) 
ambulatory recording (holter ECG) after ECV visit from visit 3 to visit 4. 
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8.1.2.2. 
Duration of Atrial Fibrillation episodes in the first week following visit 3 
 
 
(ECV visit) 
8.1.2.2.1. 
Definition 
Duration of AF episodes will consist in the sum of duration of each AF episodes. 
8.1.2.2.2. 
Schedule 
The heart rhythm follow up will be performed from the end of successful electrical cardioversion 
visit (visit 3) to the follow up study visit (visit 4).  
8.1.2.2.3. 
Evaluation Methods 
Duration of AF episodes will be assessed using the 7-day continuous ECG (5-leads/2 or 3 
channels) ambulatory recording. 
8.1.2.3. 
Clinical parameters evaluation 
8.1.2.3.1. 
EHRA score assessment 
8.1.2.3.1.1. Definition: 
AF related symptoms will be evaluated by the EHRA (European Heart Rhythm Association) score 
[20]. The following items “during presumed arrhythmia episodes" are checked to determine the 
score: palpitation, fatigue, dizziness, dyspnea, chest pain and anxiety. 
Classification of AF-related symptoms (EHRA score) are as follows: 
• EHRA I          - ‘No symptoms’ 
• EHRA II         - ‘Mild symptoms’; normal daily activity not affected 
• EHRA III       - ‘Severe symptoms’; normal daily activity affected 
• EHRA IV       - ‘Disabling symptoms’; normal daily activity discontinued  
This classification relates exclusively to the patient-reported symptoms. 
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In addition to this score, the frequency will be classified in three groups, namely occasionally 
(less than once per month); intermediate (1/month to almost daily); and frequent at least daily. 
8.1.2.3.1.2. Schedule 
This evaluation will be performed in case of symptoms evocative of arrhythmia. 
8.1.2.3.1.3. Evaluation Methods 
This evaluation will be collected by Central Reading Laboratory during all the study period. 
8.1.2.3.2. 
Number of recurrence of symptomatic AF  
It consists of number of AF recurrence associated with a symptom (Palpitation, fatigue, dizziness, 
dyspnea, chest pain and anxiety) and confirmed by an ECG in atrial fibrillation. 
8.1.2.3.3. 
Number and duration of hospitalization 
• Number and duration of hospitalization for cardiovascular events 
− Hospitalization for AF treatment 
− Hospitalization for worsening of heart failure 
− Hospitalization for myocardial infarction 
− All cause of hospitalization 
• Number and duration of hospitalization for thromboembolic stroke  
8.1.2.4. 
Cardioversion assessment 
• Assessment of spontaneous cardioversion before visit 3 
• Assessment of successful cardioversion at visit 3 (i.e. return to sinus rhythm) 
• Shock distribution (1, 2 or 3 shocks) 
• Number of patients needing another cardioversion after initial ECV 
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8.1.2.5. 
Evolution of echocardiographic parameters 
8.1.2.5.1. 
Definition 
The following echocardiographic parameters will be assessed: Left atrial diameter (mm), Left 
atrial area (cm2), Left atrial volume (mL), Left atrial volume/BSA (mL/m2), Left ventricular 
ejection fraction (%),Left ventricular volume (mL), Left ventricular volume/BSA(mL/m2, Left 
ventricular end diastolic diameter (mm) Left ventricular end diastolic volume (mL), Left 
ventricular end systolic diameter (mm) and Left ventricular end systolic volume (mL), 
8.1.2.5.2. 
. Schedule 
The measurements will be performed at visit 1 and visit 2 to check the eligibility of the patient.  
The measurements performed at visit 4, visit 6 and visit 9 are done to follow the 
echocardiographic evolution of the patients in sinus rhythm. 
8.1.2.5.3. 
Evaluation method 
The echography evaluations will be carried out according to the recommendations for chamber 
quantification drawn up by the American Society of Echocardiography and the European 
Association of Echocardiography [23]. So, for volume measurements, the recommended method 
is to use the biplane method of discs (modified Simpson’s rule) from 2-D measurement. 
8.2. 
BIOMARKER ASSESSMENT: RED BLOOD CELL  
 
CONCENTRATIONS OF DHA 
8.2.1. 
Definition 
Because of the limited accessibility of human tissues for biopsy, red blood cell DHA contents is a 
marker for tissue DHA concentration [13], [14]. 
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8.2.2. 
Blood samples 
8.2.2.1. 
Collection schedule 
Blood samples will be collected for determination of red blood cells (RBC) concentrations of 
DHA.  
Blood samples will be performed as follows: 
• Visit 2 before treatment, visit 3, visit 6 and visit 9. 
Actual sampling times will be individually reported in the electronic Case Report Forms  
(e-CRFs). 
8.2.2.2. 
Technical handling 
Two blood samples will be collected containing EDTA. They will be gently shaken and 
centrifuged at 3000g for 15 min at room temperature, within 30 minutes after collection. Plasma 
and white blood cells will be discarded. Red blood cells will be stored at +4°C (no freezing will 
be allowed) and sent to Analytical Centre in refrigerated conditions (between +2°C and +8°C) 
within 3 weeks following collection. Analysis will be performed within 2 weeks following 
reception at the Analytical centre. 
8.2.3. 
DHA concentration measurement 
Analytical determination of RBC concentrations of DHA will be carried out by the Analytical 
Centre. 
Lipids will be extracted from red blood cells samples with a mixture of hexane/isopropanol, after 
acidification [17]. Total lipid extracts will be saponified and methylated. The fatty acid methyl 
esters (FAME) will be extracted and analyzed by Gas Chromatography. 
Identification of FAME will be based on retention times obtained for FAME prepared from fatty 
acid standards. The area under peaks will be determined using ChemStation Software (Agilent) 
and results will be expressed as % of total fatty acids. DHA concentration will be calculated using 
the internal standard and expressed as µg/g for red blood cells samples. Thus, omega-3 index will 
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be assessed. The omega-3 index represents the content of EPA plus DHA in red blood cells 
(expressed as a percent of total fatty acids). It is a biomarker considered as a new marker of risk 
for death from coronary disease [18]. 
Results of this analytical determination will be kept confidential by the dosing centre until the end 
of the study, and will be provided only at the end of the study (after database lock), in a separate 
file. 
8.3. 
SAFETY ASSESSMENT 
8.3.1. 
Adverse Events 
At selection, any concomitant disease will be reported on the e-CRF. At each further visit, the 
occurrence of adverse events (AEs) since the last visit will be based on the patient's spontaneous 
reporting, the investigator's non-leading questioning and his/her clinical evaluation. All AEs will 
be reported on the e-CRF (see section 10). 
8.3.2. 
Laboratory Investigations 
8.3.2.1. 
Schedule 
Laboratory investigations will be performed at visit 1 (before treatment) and visit 9 (end of 
treatment) or End of Treatment visit. 
At visit 3 and 6, only an haematology examination will be performed.  
Furthermore the kaliemia will be checked before electrical cardioversion at visit 3. 
The volume of blood samples complete haematology, biochemistry should not exceed 30 mL. 
8.3.2.2. 
Technical Procedures and Parameters 
The following tests will be performed: 
 
Haematology: 
Hematocrit, haemoglobin, Red blood cells (RBC) count, white blood cells 
(WBC) count, WBC differential counts (% and absolute), reticulocytes, 
platelets.  
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Chemistry: 
sodium, potassium, bicarbonate, chloride, alkaline phosphatase, gamma GT, 
albumin, total bilirubin, conjugated bilirubin, creatinin, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), fasting glucose, 
total cholesterol, cholesterol (HDL, LDL), triglycerides, creatine 
phosphokinase (CPK), fibrinogen. 
Blood samples will be taken in the morning, in fasting conditions.  
The estimation of GFR at selection relies on the measurement of serum creatinine and the 
Cockcroft- Gault formula 
Cockcroft-Gault formula 
- with serum creatinine expressed as mg/L:  
in men: 
GFR (mL/min) = [(140-age)] x weight / 7.2 x serum creatinine in mg/L], 
 
in women: 
GFR (mL/min) = [(140-age)] x weight / 7.2 x serum creatinine in mg/L] x 0.85 
 
- with serum creatinine expressed as μmol/l: 
GFR (mL/min) = [(140-age) x weight / serum creatinine in μmol/l] x k,where k = 1.23 for men, 
1.04 for women. 
 
(weight in kg, age in years) 
Additional tests may be done at the Investigator’s discretion, in the patients’ interest. In case of 
any abnormal or clinically significant results, the Investigator will order laboratory control tests. 
8.3.3. 
Global Physical Examination 
A global physical examination including the measurement of body weight will be carried out on 
each body system at visit 1, visit 2, visit 3, visit 5, visit 6, visit 7, visit 8 and visit 9. 
The physical examination will be globally evaluated as “normal/abnormal”. Further target 
inspection will be undertaken for any abnormal finding. 
8.3.4. 
Vital Signs 
Vital signs will consist in blood pressure and heart rate at rest.  
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8.3.4.1. 
Schedule 
Vital signs will be measured at each visit. 
8.3.4.2. 
Technical Procedure and Parameters 
Systolic (SBP) and diastolic (DBP), expressed in mmHg, will be measured after at least 5 minutes 
in supine position and after 2 minutes in standing position.  
The heart rate (HR), expressed in beats per minute (bpm), will be measured by auscultation, after 
at least 5 minutes in supine position and after 2 minutes in standing position by counting the beats 
for at least 30 seconds. 
Bodyweight will be measured in  patient in underwear and with the same balance at each visit.  
8.3.5. 
Electrocardiogram (ECG)  
8.3.5.1. 
Schedule 
An electrocardiogram will be recorded at visit 1, visit 2, visit 3, visit 5, visit 6, visit 7, visit 8 and 
visit 9 using an usual standardised 12-lead cardiograph. 
8.3.5.2. 
Technical Procedure and Parameters 
• Electrocardiogram (ECG): 
The global interpretation from manual reading (normality, clinical relevance) and heart rate 
(bpm), PR (ms), QRS (ms), QT (ms), repolarisation patterns will be reported in the e-CRF. Each 
print-out will include the patient’s code, date, time, technician's initials and investigator's 
signature. 
In case of thermic paper ECG print out, a photocopy will be made by the centre to ensure safe 
filing. 
• 24 hour-Holter - ECG 
An ambulatory continuous 24-hour ECG (5-leads/2 or 3 channels) will be recorded at selection 
visit using a holter ECG, in order to confirm persistent atrial fibrillation.  
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8.3.6. 
Coagulation parameters 
The assessment of coagulation will be evaluated by the following parameters: 
− Prothrombin Time/INR (PT/INR) 
− Activated Partial Thromboplastin Time (aPTT) 
− Thrombin Clotting Time (TCT) 
During the pre-cardioversion period, if the anticoagulation by AVK should be initiated, then the 
INR monitoring will be as follow:  
− INR 2-3 times a week for the first week of treatment 
− INR weekly up to ECV, 
− INR every 4 weeks after ECV 
For patients already treated with AVK, INR monitoring will be as follow: 
− INR weekly up to ECV, 
− INR every 4 weeks after ECV 
aPTT and TCT will be performed at visit 1, visit 2, visit 3, visit 5, visit 6, visit 7, visit 8 and  
visit 9. 
Anti-coagulation by anti-vitamin K should be given at least 3 weeks before ECV and continued 
for the whole study duration. 
The quantity of blood samples collected at each time for coagulation parameters will be 2 mL. 
8.3.7. 
Concomitant Treatments 
Concomitant treatments will be evaluated at each study visit. 
Requirements relating to patient's concomitant treatments started before screening visit and 
continued throughout the trial, or started during the trial can be found in section 7.  
8.4. 
COMPLIANCE 
The patient will be reminded at each visit to bring back any remaining soft capsules, blister, case 
(used or unused) at the following visit. 
At each visit, the Investigator will record the number of supplied and remaining Soft Capsules in 
the e-CRF. 
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9. STUDY PROCEDURES 
Visit 1 - Selection Visit (Week -4 to Week -1) 
The patient considered eligible for selection by the Investigator will be informed of the 
characteristics and the consequences of the trial both verbally and by reviewing the patient's 
information sheet and consent form (see section 14.3). If he/she accepts to participate in the study, 
he/she will sign the informed consent and will keep a copy. 
The patient will be assessed for the following: 
• Demographic characteristics (gender, age, height, body surface area) 
• Personal and medico-surgical history 
• Habits (Tobacco, alcohol consumption, dietary habits including fish consumption…) 
• Cardiovascular diseases, mainly detailed history of Heart Failure and Atrial Fibrillation 
characteristics  
• Echocardiography using a two-dimensional echocardiography.  
• 12-lead ECG 
• Concomitant diseases, adverse signs or symptoms (able to be used for treatment emergent AE 
determination) 
• Concomitant treatments (authorised, disallowed) 
• Global physical examination/bodyweight 
• Vital signs 
• Biology: haematology, biochemistry, assessment of coagulation parameters: Prothrombin 
Time/INR (PT/INR), Activated Partial Thromboplastin Time (aPTT), Thrombin Clotting Time 
(TCT) 
• Biology assessment of renal function: creatinine or estimated glomerular filtration rate 
If the results of the above assessments are compatible with the selection criteria 
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• A 24-hour continuous ECG ambulatory recording (Holter ECG) device will be installed on the 
patient to monitor the patient heart rhythm. The patient will be requested to bring back the device 
after the termination of 24 hours recording. The recording will be transmitted from the 
Investigational site to the Central Reading Laboratory (CRL). The CRL will send his/her 
assessment regarding the confirmation of persistent atrial fibrillation within 2 working days to the 
Investigator. 
• The patient will enter the selection period in which anticoagulant (anti-vitamin K) will be 
adjusted to achieve an International Normalized Ratio (INR) of 2 to 3 before electrical 
cardioversion.  
At the end of the visit, the Investigator will contact the IVRS/IWRS system to confirm the patient 
selection and order the treatment delivery and organise the appointment for the next visit.  
The patient will receive from the investigational centre the study card to be kept for the duration 
of the study. 
Visit 2 - Inclusion Visit (Day 1)  
If the patient's behaviour during the selection period and/or the result of complementary 
examinations particularly the confirmation of the presence of persistent atrial fibrillation by the 
CRL during this period, the INR and laboratory tests, are compatible with the inclusion criteria, 
the patient will be assessed for the following: 
• Adverse events 
• Concomitant treatments (authorised, disallowed) 
• Laboratory examination: red blood cell concentrations of DHA and coagulation parameters 
Prothrombin Time/INR (PT/INR), Activated Partial Thromboplastin Time (aPTT), Thrombin 
Clotting Time (TCT) 
• Global Physical examination/bodyweight 
• Vital signs 
• Echocardiography using a two-dimensional echocardiography. 
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• 12-lead ECG 
• Urine pregnancy test for women of child bearing potential. 
If the results of the above assessments are compatible with the inclusion criteria, the patient will 
be included and allocated a treatment number using the IVRS/IWRS system.  
Between this Inclusion visit and the next visit (V3), the INR will be closely monitored (refer to 
paragraph 8.3.6), in order to ensure that the INR is stable, between 2 to 3 before electrical 
cardioversion. 
At the end of the visit, the Investigator will organise the appointment for the next visit and give 
the treatment to be taken during the next 4-week period. 
Visit 3 (Week 4: D28 -2/+7 days) cardioversion 
Patient will be assessed for the following criteria: 
• Adverse events 
• Concomitant treatments (authorised, disallowed) 
• Laboratory examination: Haematology, Red Blood Cell concentrations of DHA, Prothrombin 
Time/INR (PT/INR), Activated Partial Thromboplastin Time (aPTT), Thrombin Clotting Time 
(TCT) 
• Global Physical examination /bodyweight 
• Vital signs  
• 12-lead ECG 
• Electrocardioversion (ECV): ECV has to be scheduled 4 weeks after randomization and after 
target international normalized ratio levels will be stabilized (between 2 and 3) on at least 3 
consecutive weekly tests in patients with AF. Patients not stabilized for INR (i.e. values between 2 
and 3) on at least 3 consecutive weekly tests performed before ECV will be excluded from the 
study, unless the presence of atrial thrombosis may be excluded with ECHO –TE (trans-
esophageal echocardiograph) performed  in the same day (before ECV). ECV will be performed 
in the morning, with the patient in the fasting state and without dyskalemia. Anesthesia will be 
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induced and patients will be cardioverted with administration of a synchronized, biphasic current. 
The initial shock will be set at 100 J if the body weight is less than 70 kg and at 150 J for higher 
body weights. Successful cardioversion will be defined as recovery of sinus rhythm lasting at least 
1 minute after the shock. If unsuccessful, a second 200-J shock, and eventually a third 200-J 
shock, will be administered. Failure of ECV is defined as the persistence of AF after the third 
attempt at cardioversion. After the procedure, patients will be monitored on telemetry for at least 
6 hours before discharge. Patients who will not revert to sinus rhythm or with early relapse within 
the observation period after ECV will be withdrawn from the study and will be considered to have 
finished their follow-up. 
At the end of the visit, a 7-day continuous ECG (5-leads/2 or 3 channels) ambulatory recording 
(holter ECG) will be installed on the patient in order to monitor the patient heart rhythm after 
ECV.  
At the end of the visit, the Investigator will organise the appointment for the next visit and give 
the treatment to be taken during the next 4-week period. 
Visit 4 (Week 5: D35 ± 2 days) 
After removal of the continuous ECG ambulatory device, the patient will be assessed for the 
following criteria: 
• Assessment of Adverse Events 
• Concomitant treatments (authorised, disallowed) 
• Vitals Signs 
• Echocardiography using a two-dimensional echocardiography 
At the end of the visit, the patient will be given the TTEM device (Trans Telephonic ECG 
Monitoring) for cardiac monitoring. The patient will be clearly instructed on the frequency and 
modalities of transmission. The patient will be requested to performed daily transmission from 
week 6 to week 8, then every 2 days from week 9 to week 24. Moreover, in case of AF symptoms 
additional transmission may be performed. 
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Visit 5 (Week 8: D56 ± 7 days) – Visit 6 (Week 12: D84 ± 7 days) - Visit 7 (Week 16: D112 ± 
7 days) - Visit 8 (Week 20: D140 ± 7 days) 
Patient will be assessed for the following criteria: 
• Adverse events 
• Concomitant treatments (authorised, disallowed) 
• Laboratory examination: Prothrombin Time/INR (PT/INR), Activated Partial Thromboplastin 
Time (aPTT), Thrombin Clotting Time (TCT). However, in case of discontinuation of 
anticoagulation after ECV, the monitoring of INR, aPTT and TCT should be stopped. 
• Global Physical examination/bodyweight  
• Vital signs  
• 12-lead ECG 
• The cardiac monitoring will be continued using a TTEM device (Trans Telephonic ECG 
Monitoring). The device will be given to the patient who will be requested to performed daily 
transmission from week 6 to week 8, then every 2 days from week 9 to week 24. Moreover, in 
case of AF symptoms additional transmission may be performed. 
The Investigator will collect all the cases, blisters and any unused soft capsules and count the 
unused capsules for each 4-week treatment period. 
At the end of the visit, the Investigator will organise the appointment for the next visit and give 
the treatment to be taken during the next 4-week treatment period. 
In addition: 
- at visit 5, the investigator will contact the IVRS/IWRS to obtain another treatment unit to be 
dispensed at visit 6 for the last 12-week period. 
- at visit 6, an echocardiography will be performed, an haematology examination will be done and 
the red blood cell concentration of DHA will be measured.  
End-of-Study Visit - Visit 9 (Week 24: D168 ± 7 days) 
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 Patient will be assessed for the following: 
• Adverse events 
• Concomitant treatments (authorised, disallowed) 
• Global Physical examination/bodyweight 
• Vital signs 
• 12-lead ECG 
• Laboratory examination: haematology, biochemistry, assessment of coagulation parameters: 
Prothrombin Time/INR (PT/INR), Activated Partial Thromboplastin Time (aPTT), Thrombin 
Clotting Time (TCT). Red blood cell concentration of DHA. 
• Urine pregnancy test for women of childbearing potential 
• Echocardiography using a two-dimensional echocardiography 
The Investigator will collect all the cases, blisters and any unused soft capsules and count the 
unused soft capsules. 
10. ADVERSE EVENTS: DEFINITION AND REPORTING 
10.1. 
ADVERSE EVENTS 
10.1.1. Definition of Adverse Events 
An adverse event is any adverse change from the patient's baseline condition, i.e. any subjective 
signs and symptoms or change in a concomitant disease present at the Selection Visit considered 
or not related to the treatment. 
This includes intercurrent signs, symptoms, illnesses and significant deviations from baseline for 
vital signs and laboratory values, which may occur during the course of the clinical study. 
All laboratory tests for which abnormal results are collected after study treatment initiation should 
be repeated until the values return to normal or to a stable status. Abnormal results are defined as 
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those falling out of the laboratory normal ranges and that are clinically significant. The frequency 
of such checks should be defined by the Investigator according to the degree of abnormality. 
In all cases, the aetiology should, as much as possible, be identified and Pierre Fabre Médicament 
notified. 
10.1.2. Grading of Adverse Events 
Adverse or intercurrent events are graded as follows: 
• Mild: awareness of signs or symptoms, but easily tolerated 
• Moderate: uncomfortable enough to cause interference with usual activity 
• Severe: incapacity with inability to work or do usual activity. 
10.1.3. Reporting of Adverse Events 
The records of adverse events in the electronic Case Report Form (e-CRF) describe the nature 
(diagnosis, signs and symptoms), severity, onset date, stop date, outcome and actions taken, and 
relationship to study treatment (in the Investigator's opinion). It must be specified whether the 
event is serious or not. 
10.2. 
SERIOUS ADVERSE EVENTS (SAE) 
10.2.1. Definition 
A serious adverse event (SAE) includes, but is not necessarily restricted to any event which: 
• Results in death (whatever may be the cause) 
• Is life-threatening 
• Results in persistent or significant disability/incapacity 
• Requires the patient's hospitalisation or prolongation of current hospitalisation * 
• Is a congenital anomaly or birth defect. 
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Other events such as cancer, and any additional adverse experience or abnormal laboratory values 
occurring during the study period, defined by the protocol as serious or which the Investigator 
considers significant enough, or that suggest a significant hazard, contra-indications, side effect or 
precaution, must be handled as serious adverse events. 
Any overdosage meeting a seriousness criteria should be reported as a SAE (see section 10.3). 
Any pregnancy occurring during/after exposure to the study drug(s) should be reported on the 
SAE notification form (see section 10.4). 
* any hospitalisation, or prolongation of hospitalisation due to the circumstances listed below: 
− planned (as per protocol) medical/surgical procedure, 
− preparation for routine health assessment/procedure (e.g. routine colonoscopy), 
− planned medical/surgical admission (planned prior to entry into study trial, appropriate 
documentation required), 
− administrative or social reasons (e.g. lack of housing, economic inadequacy, care-giver 
respite, family circumstances) 
will not be reported as a SAE. 
10.2.2. Reporting of SAE 
All serious adverse events, according to the above-mentioned definitions and regardless of 
treatment or relationship to study drug, must be recorded by the Investigator as soon as he/she is 
informed of the event. 
The Investigator must notify the Sponsor of this event by sending, within 24 hours, the 
"Notification of serious adverse event" form ("first notification") (see appendix 17.2) with all the 
available information about the event, to the Sponsor's representative: 
Marlène GUIRAUD, Pharm D 
INSTITUT DE RECHERCHE PIERRE FABRE,  
Centre de R&D Pierre Fabre – BP 13562 
3 Avenue Hubert Curien 
31035 TOULOUSE Cedex 1 
Phone: +33 5 35 50 63 48 
Fax: + 33 5 34 50 65 92 
Email: marlene.guiraud@pierre-fabre.com 
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In case of non-inclusion the reporting period ends when the non-inclusion is documented. 
10.2.3. Follow-up of SAE 
The Investigator must draw-up a specific clinical report and use the "Notification of serious 
adverse event" form ("follow-up") (see appendix 17.2) and collect the results of the carried out 
examinations and the reports of hospitalisation. 
The serious adverse events must be followed up until resolution or stabilisation. 
10.2.4. SAE Occurring After the Study 
Any SAE occurring during 30 days following the end of the study for the patient should be 
notified to the Sponsor. 
Must also be notified to the Sponsor any event occurring at any time after the end of the study for 
the patient which may be related to the study treatment in the Investigator's opinion. 
10.3. 
REPORTING OF OVERDOSAGE TO THE SPONSOR 
For the purpose of this trial an overdosage will be defined as any dose exceeding the planned 
prescribed dose of the study drug or the administration of any dose of an associated product that is 
considered both excessive and medically important. 
In the absence of seriousness criteria, the overdosage, and associated adverse event if any, are 
reported only on the Adverse Event page of the CRF. If the definition of seriousness criteria is 
met, the SAE notification form must be also transmitted to the sponsor. 
10.4. 
REPORTING OF PREGNANCY TO THE SPONSOR 
Pregnancies discovered in the period in between the informed consent form signed but before any 
study drug exposure are not to be reported to the sponsor unless associated to a seriousness 
criteria (e.g. serious adverse event study-protocol related procedure). If pregnancy is confirmed, 
the women must not be administered the study drug and be withdrawn immediately from the 
study.  
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If pregnancy is suspected while the patient is receiving study treatment, the study drug(s) should 
be discontinued immediately until the result of the pregnancy testing is known. If pregnancy is 
confirmed, then the study treatment is permanently discontinued in an appropriate manner and the 
patient is discontinued from the study.  
The investigators must report to the sponsor any pregnancy which occurs during or after the 
patient has been exposed to the study drug and until 30 days after the last study drug 
administration. The investigator must immediately notify the sponsor using the SAE notification 
form and also report the pregnancy on the AE page of the e-CRF. 
Women who become pregnant after exposure to the study drug must be followed by the 
investigator until the completion/termination of the pregnancy. If the pregnancy goes to term, the 
outcome will have to be reported to the sponsor (baby's healthy status). 
10.5. 
SPONSOR'S RESPONSIBILITIES FOR SAFETY REPORTING 
 
PURPOSES 
Sponsor will submit expedited and periodic reports to both Competent Authorities and Ethics 
Committees per corporate standard operating procedures as regards to the EU directive 
2001/20/EC taking into account local specific requirements. 
11. DATA COLLECTION AND STUDY MONITORING 
11.1. 
DATA COLLECTION 
11.1.1. Case Report Form 
An electronic Case Report Forms (e-CRF) will be used to record all patient data required by the 
protocol except the central ECG (Holter ECG, TTEM) and DHA data which will be transferred 
from vendors to the subcontractor as electronic data files and which will be loaded into the study 
database.  
The e-CRF should be fully validated, compliant with ICH-GCP requirements and European 
regulations and include a traceability system for data corrections and deletions (audit trail). 
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Prior to the start of the study, the Investigator will complete a "Delegation of significant study-
related duties" form. The signature and initials of all personal in charge of e-CRF completion 
should be recorded on this form. Each person involved in e-CRF completion, review, correction 
and / or validation will be trained and will have an individual login and access code to the e-CRF. 
Training sessions will be held by the subcontractor for all participants who will use this tool. An 
e-CRF user manual will be available for investigators and CRAs.  
All the information included into the e-CRF will be recorded from source documents onto the e-
CRF by an authorised person. 
The Investigator is responsible for the management and accuracy of the information on the  
e-CRF. At each monitoring visit, the e-CRF(s) should be at the CRA's disposition for review and 
validation. 
At the end of the study, a CD-ROM containing the pdf version of all e-CRF (including audit-trail) 
will be sent by the subcontractor to the Sponsor and to the investigational sites for archiving. The 
subcontractor must store all study data for at least 15 years after the end of the study and ensure 
their legibility and accessibility during all the storage period. 
11.1.2. Source Documents 
A source document is an original record or certified copy of an original record of clinical findings, 
observations or any other medical or paramedical activities performed during the clinical trial, 
necessary for the transcription and the verification of the collected data. 
Source documents along with all other trial-related documents (copies of all "informed consent" 
forms, e-CRFs CD-ROM, drug inventories and any correspondence related to the study) must be 
kept in the investigator's file throughout the study, and then, must be stored in the study centre's 
archives for a period of at least 15 years or as per local legal requirements, whatever is the 
longest.  
For further details see section 15.2. 
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11.2. 
STUDY MONITORING 
11.2.1. Monitoring visits 
On-site visits will be carried out by a representative of the Sponsor's staff (Study Manager or 
CRA) prior to study initiation and at regular intervals (every 4 to 6 weeks) throughout the study. 
Additional visits and communication by telephone fax or meeting may be performed if necessary. 
Any site visit performed by the Sponsor's representatives will be recorded in the Investigator's 
study file. 
11.2.1.1. 
Site Preselection Visit 
Before selecting a centre for the study, a visit will be carried out by the CRA and/or the Study 
Manager to ensure that the Investigator has the necessary capacities (availability, patient's 
recruitment, environment), technical means and staff to carry out the study. 
11.2.1.2. 
Initiation Visit 
Before the start of the study at all investigation sites, an initiation visit will be carried out by the 
CRA to check at the latest that: 
• The Investigator: 
− has received the technical protocol, administrative and financial agreement signed by all 
parties 
− has received the written statement of the Ethics Committee approval and the list of its 
members and their functions 
• The original dated and signed curriculum vitae of the investigator(s) has been collected 
• Laboratory normal ranges have been collected  
• All study materials are available on the study site 
• All participants agree with the monitoring procedures and know the study procedures 
• All participants are aware of a possible audit or inspection 
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The CRA has also to provide training on the study protocol requirements and study specific 
procedures. 
11.2.1.3. 
Follow-up Visits 
Throughout the study, regular follow-up visits will be carried out by the CRA to check 
compliance with GCP, patient’s informed consents, strict application of the protocol, conformity 
of the data entered on the e-CRF with the source documents and ensure its correct completion, 
adverse events reporting, proper retention, storage and management of the study medication, as 
well as the source and other trial-related documents. 
11.2.1.4. 
Closing Visit 
At the end of the study, a final visit will be carried out by the CRA to: 
• Verify that the e-CRFs CD-ROM with pdf files are correctly stored 
• Control the accountability of intact and used treatment units and return them to the Clinical 
Pharmacy Department of the IRPF for destruction 
• Obtain the last data clarifications and/or solutions if any 
• Collect the patient's consent forms in sealed envelopes,  
• Make an on-site review of all study documentation and complete it if necessary 
• And finally, remind the Investigator of his regulatory obligations, study document archiving 
process and duration. 
11.2.2. Direct Access to Source Documents 
In accordance to the requirements of the GCP, all Sponsor representatives (Study Manager, CRA 
and Auditors) have to be given a direct access to all source and study data to perform quality 
monitoring/audit, thus ensuring accuracy and completeness of data).  
Investigators are reminded that all Sponsor representatives keep professional confidentiality with 
regards to the patient data. 
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11.3. 
INDEPENDENT DATA MONITORING COMMITTEE 
An Independent Data Monitoring Committee (IDMC) will be established to assess at intervals the 
progress of the clinical trial, the compliance with the inclusion criteria, the quality of follow up, 
the quality of measures of primary end point, the safety data and to recommend to the Sponsor 
whether to continue, modify, or to stop the study.  
The IDMC operating procedures will be described in an independent document.  
12. DATA MANAGEMENT  
All clinical data related to the study will be collected and saved in a computerised database by the 
Data Management Department of the subcontractor and under the supervision of the Data 
Manager of Pierre Fabre Biometry (PFB) according to the following procedures.  
12.1. DATA ENTRY 
All required data will be collected by the Investigator or authorised designee (duly identified into 
the delegation task list) on a e-CRF.  
The e-CRF used for this study will be developed and maintained by the Data Management 
Department of the subcontractor and approved by the Sponsor.  
Electronic data (Holter ECG, TTEM and DHA) will be transferred by the 3rd party vendor 
according to the specifications given by the Data Manager of the subcontractor. These data will be 
captured and handled in accordance with the European GCP ICH E6 guideline. 
12.2. 
DATA CLEANING 
The subcontractor will define in the Data Validation Plan for reviewing and querying data, 
descriptions of both manual and electronic edit checks. Upon Sponsor approval, the subcontractor 
will program the checks.  
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The subcontractor will review the data over the course of the study, working with the Sponsor to 
identify data inconsistencies. The Investigator will be asked to resolve queries by making changes 
directly into the e-CRF.  
12.3. 
DATA CODING 
Adverse events, concomitant diseases, medical/surgical histories will be coded by the 
subcontractor using the MedDRA dictionary (latest version in use). 
Concomitant medication will be coded by the subcontractor using the WHO-DRUG dictionary 
(latest version in use).  
The Sponsor Clinical Development Physician will validate coding. 
12.4. 
DATA STORAGE 
The computer data files, as well as their modifications, will be archived by the subcontractor and 
kept available upon request of the Sponsor. 
12.5. 
DATABASE LOCK 
The validated database will be locked by the subcontractor upon request of the Data Manager of 
PFB following the completion of all steps required, i.e.: data entry and check of all data, 
resolution of all queries, validation of the coding, Clinical and Products Safety databases 
reconciliation and validation committee.  
Then, the subcontractor will transfer the locked database in SAS format to the Data Manager of 
PFB who assume storage on the PFB secured server. 
13. STATISTICAL ANALYSIS 
After the database lock and the randomisation code release, the statistical analysis will be 
performed by Pierre Fabre Biométrie (PFB) or under the supervision of the statistician of PFB 
using SAS® software, according to the Statistical Analysis Plan (SAP) approved by the Validation 
Committee. 
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13.1. 
GENERAL CONSIDERATIONS 
The main objective of the study is to assess the efficacy of F373280 versus placebo on the 
maintenance of sinus rhythm after direct electrical cardioversion in patients with persistent atrial 
fibrillation and chronic heart failure. 
Only the primary analysis of the primary efficacy criterion, on which is based the sample size 
justification, may lead to a causal interpretation. All other statistical results are to be regarded 
within a descriptive perspective. 
The statistical significance level of the various two sided tests of all analyses will be 5 %. 
13.2. 
SAMPLE SIZE 
Assuming an AF recurrence rate of 85% under placebo and 65% under active group, i.e. a 
clinically relevant difference ∆ of 20%, a sample size of 64 evaluable patients per group is 
required, using a log-rang test of survival curves with a 80 % power and a 5 % two-sided 
significance level. 
According to the previous assumptions and assuming a rate of not assessable patients of 15%, a 
minimum of 76  patients will have to be randomised per group. 
13.3. PROTOCOL DEVIATIONS 
Prior to the database lock and the randomisation code release, the Validation Committee members 
will review the protocol deviations and will classify them as either minor or major. A protocol 
deviation will be considered major when it is likely to bias significantly the treatment effect 
estimate based on the primary efficacy criterion. 
Patients with major deviation(s) will be excluded from the Per Protocol data set (see section 13.4). 
A listing of all protocol deviations will be provided for all randomised patients, including the type 
(major/minor) of protocol deviations according to the decisions made by the members of the 
Validation Committee. 
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The number and percentage of patients with major protocol deviations will be tabulated by 
treatment group and type of major protocol deviations on the Full Analysis Set defined in section 
13.4. 
13.4. DATA SETS ANALYSED 
The following 2 data sets will be analysed (as defined by the Validation Committee):  
 
• The Safety Set composed of all randomised patients having received at least one dose of the 
study treatment. This data set will be used to perform analyses of Safety 
• The Full Analysis Set (FAS) composed of all randomised patients having received at least one 
dose of the study treatment and with a successful cardioversion observed at visit 3. This data set 
will be used to perform analyses of Efficacy.  
• The Per Protocol Set (PP) which is the subset of the Full Analysis Set composed of all patients 
with a primary efficacy criteria available and without any major protocol deviation or other source 
of bias for primary criteria analyses. 
13.5. 
HANDLING OF DROPOUTS AND MISSING DATA 
13.5.1. Dropouts 
The number of patients who withdraw from the study after their randomisation will be provided 
by treatment group for all treated patients (Safety Set). All withdrawn patients will be further 
described regarding their time to dropout and reasons for withdrawal. 
13.5.2. Repositioning of Visits 
No repositioning of visits will be done. 
13.5.3. Missing Data 
Missing values will not be substituted by estimated values, but considered as missing in statistical 
analysis. 
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13.6. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Before the first trial drug intake, patient’s background, medical and surgical history, demographic 
data and disease characteristics will be described by treatment group on the Safety Set. 
- Quantitative parameters will be described by treatment group and overall using the 
following: number of patients, number of missing data, mean, standard deviation, 
minimum, median and maximum values. 
- Qualitative parameters will be described by treatment group and overall using 
frequencies. 
Concomitant diseases, as well as medical and surgical histories will be tabulated descriptively by  
treatment group and overall using the MedDRA codes of System Organ Classes and preferred 
terms. 
If more than 10% of patients are excluded from the FAS and PP set, the description of patients by 
treatment group at selection and inclusion will be repeated on the FAS and PP set for all 
parameters. 
No statistical test of comparability of treatment groups at baseline will be performed.  
13.7. 
EFFICACY ANALYSIS  
13.7.1. Primary Criterion  
13.7.1.1. 
Primary Analysis 
The primary criteria, time to first recurrence, will be analysed using the Kaplan Meier method and 
compared with the Log rank test. Hazard ratios and 95% confidence intervals will be estimated 
with the Cox regression model. 
The primary analysis will be performed on the FAS. 
13.7.1.2. 
Supportive Analysis 
The primary analysis will be repeated on the PP set. 
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13.7.2. Secondary Criteria 
All secondary analyses will be performed on the FAS. If more than 10% of patients are excluded 
from the PP set, the secondary analyses will be repeated on the PP set.  
13.7.2.1. Numbers of Atrial Fibrillation Episodes 
Both the numbers of AF episodes (symptomatic or not) lasting for at least 10 minutes and with 
duration less than 10 minutes (NSup10 and NInf10) will be described by treatment group and 
compared by the chi-square test (or CMH test adjusted for centre) or Fisher’s exact Test. 
13.7.2.2. Duration of Atrial Fibrillation Episodes 
The duration of all AF Episodes will be described by treatment group and compared using the 
Student t (or using an ANOVA with treatment and centres effects) or Wilcoxon test. 
13.7.2.3. Time to first AF recurrence less than 10 minutes or symtomatic 
The time to the first AF recurrence less than 10 minutes and the time to the first symptomatic AF 
recurrence will be analysed as the primary analysis.  
13.7.2.4. Clinical parameters evaluation 
The EHRA score will be described by treatment group and analysed using a chi-squared test (or 
CMH test adjusted for centre) or Fisher’s exact Test.  
The frequency of presumed arrhythmia will be described by treatment group. 
The number of recurrence of symptomatic AF, of hospitalizations (for cardiovascular events, for 
thromboembolic stroke and for all causes), of spontaneous cardioversion, of successful 
cardioversion (including number of shocks distribution) and the number of patients needing 
cardioversion after initial ECV will be described by treatment group and compared using a chi-
square test or a Fisher Test (if the numbers are relevant).  
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The duration of hospitalizations for cardiovascular events, for thromboembolic stroke and for any 
cause will be described by treatment group and compared using the Student t (or using an 
ANOVA with treatment and centre effects) or Wilcoxon test. 
The echocardiographic parameters values will be described at each time (V1, V2, V4, V6 and V9) 
and changes described from V4 to V9 and from V2 to V9. 
13.7.2.5. Biomarker analysis: red blood cell concentrations of DHA 
Values and changes from baseline for red blood cell concentration of DHA will be performed by 
treatment group and assessment time. 
13.8. 
SAFETY ANALYSIS 
The Safety Set will be used to perform all analyses of the safety criteria. 
13.8.1. Adverse Events 
Any adverse event having been reported during the study for a given patients will be classified by 
preferred term and corresponding system organ class using the MedDRA terminology. 
Adverse events will be classified as: 
• Treatment emergent adverse events, i.e., any adverse event which occurs or worsens on study 
treatment during the randomised period. 
• Or non treatment emergent adverse events, i.e., any adverse event which occurs during the 
run-in period (before V2) or is reported as concomitant disease with the same intensity. 
For each study period, any patient with at least one reported adverse event will be classified as a 
patient: 
• With at least one adverse event 
• With at least one treatment emergent adverse event 
• With one TEAE 
• With two TEAE 
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• With at least three TEAE 
• With at least one related TEAE 
• With an adverse event leading to the study treatment discontinuation (definitive or 
temporary) 
• With an adverse event leading to withdrawal 
• With at least one serious adverse event. 
• 
Numbers and percentages of patient with at least one reported treatment emergent adverse 
event will be tabulated by treatment group: 
• By system organ class 
• By system organ class and preferred term 
• By system organ class and preferred term, taking into consideration its most severe 
intensity 
• And by system organ class and preferred term, taking into consideration the most severe 
relationship to the study treatment. 
Recurring adverse events (i.e., adverse events classified with the same preferred term) for a given 
patient will only be counted once and only their most severe intensity or most severe relationship 
to the study treatment will be tabulated. 
"The number and percentage of patient with at least one most common (reported in 1% patients in 
any group) drug related TE AE ("not excluded or unassessable") will be tabulated by Preferred 
Term and Treatment group in decreasing order for the treatment group (for all patient). 
The number and percentage of patients with at least one reported most common treatment 
emergent adverse event will also be plotted by treatment group. This graphical representation will 
highlight the frequencies of the most severe intensities reported by system organ class and 
preferred term. 
Serious adverse events will also be described on an individual basis: treatment group, patient's 
code, sex and age, Investigator's reported term, preferred term, time of onset according to the time 
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of the first study treatment administration, duration, action taken regarding the study treatment 
administration, use of a corrective treatment, outcome and relationship to the study treatment in 
the Investigator’s opinion. 
13.8.2. Clinical Laboratory Evaluation  
For each laboratory parameter, data will be tabulated by treatment group and assessment time. 
The absolute changes post-trial drug administration - baseline (the baseline value being the value 
measured on the last blood sample collected before the first trial drug administration) will be 
calculated and tabulated by parameter, treatment group and post-trial drug administration 
assessment time. Results of retests performed post-trial drug administration will not be analysed 
and tabulated. They will only be displayed in individual data listings. 
For all biochemistry parameters, scatter plots highlighting individual results will display the 
baseline and week 24 of the laboratory measurements for each patient by locating the point 
defined by the baseline value on the abscissa and respectively week 24 value in the ordinate.  
For all haematology parameters, scatter plots highlighting individual results will display the 
baseline and week 4, week 12 and week 24 of the laboratory measurements for each patient by 
locating the point defined by the baseline value on the abscissa and respectively week 4, week 12 
and week 24 value in the ordinate.  
Each treatment group will be identified differently. The first bisecting line (45° line), the lines of 
lower and upper normal range, the lines of PSC range and CNALV range added on the plots (see 
Appendix 17.3). 
For all blood laboratory parameters, shift tables will be provided to depict the numbers of  patients 
with post-trial drug administration variations at each assessment time as compared to the baseline 
values (measured on the last blood sample collected before the first trial drug administration) by 
treatment group. A 3-point scale (low, normal, high) will be used as defined by the normal ranges 
in use in the laboratory in charge of the assays. 
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Clinically noteworthy abnormal laboratory values (CNALV) (see in Appendix 17.3) will be 
identified and described on an individual basis. If relevant, five separate individual data listings by 
treatment group will be provided: 
• CNALV for haemoglobin (including corresponding individual results of erythrocytes and 
haematocrit) 
• CNALV for neutrophils or leucocytes (including corresponding individual results of 
basophils, eosinophils, lymphocytes and monocytes) 
• CNALV for platelets (including corresponding individual results of erythrocytes and 
leucocytes) 
• CNALV for liver function parameters (including corresponding individual results of 
gamma-GT) 
• CNALV for serum creatinine  
13.8.3. Global Physical Examination 
Recorded data of the global physical examination performed will not be tabulated as any 
abnormal findings post-randomisation should be reported as AEs (if clinically significant). 
Physical examination assessments will be provided in the listings of individual data. 
13.8.4. Vital Signs, Physical Findings and Other Observations Related to Safety 
13.8.4.1. 
Vital Sign Measurements Over Time 
For each parameter (systolic blood pressure, diastolic blood pressure and heart rate in supine and 
standing positions), descriptive statistics over time of values and changes from baseline will be 
tabulated by treatment group and assessment time. 
13.8.4.2. 
Body weight 
Descriptive statistics over time of values and changes from baseline will be tabulated by treatment 
group and assessment time. 
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13.8.4.3. 
Individual Patient Changes 
The number and percentage of patient with at least one Predefined Potentially Clinically 
Significant Change (PSC) and with at least one PSC Leading to Clinically Significant Value 
(PSCV) will be tabulated by treatment group (see Table 1 in Appendix 17.3).  
According to the pharmacological drug profile mentioned previously in this Protocol, the changes 
from baseline to the maximum and/or minimum post-baseline value could be categorized and 
tabulated by treatment group with frequencies and decreasing cumulative percentages. 
If there is a signal of a drug effect toward one direction rather than the other, additionally shift 
tables of variations from baseline to the maximum or minimum post-baseline value could be also 
provided (see Table 2 to 4 in Appendix 17.3). 
An individual data listing of patients with symptomatic or asymptomatic orthostatic hypotension 
will be provided by treatment group (see Table 5 in Appendix 17.3). 
13.8.5. ECG 
Frequencies on the clinical interpretation (normal, abnormal CS or NCS) will be presented by 
treatment group and assessment time. Individual tabulated data for ECG abnormalities will be also 
displayed. 
13.8.6. Coagulation parameters 
Scatter plots highlighting individual results for coagulation parameters (prothrombin time/INR, 
activated partial thromboplastin time and thrombin clotting time) before and after study treatment 
administration will be produced. 
13.9. CONCOMITANT TREATMENTS 
Concomitant treatments will be tabulated by treatment group within a descriptive perspective. 
They will be classified by therapeutic area according to the WHO-DRUG dictionary using the 
"anatomical therapeutic chemical" (ATC) classification on the safety set. 
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13.10. 
COMPLIANCE 
 
The percentage of compliance will be described by treatment group using the quantity 
 
100
_
_
_
(%)
×
=
n
consumptio
l
Theoretica
n
consumptio
actual
Estimated
Compliance
 
 
 
with: Estimated actual consumption = number of tablets provided at the start of study (Visit 2) – 
number of tablets returned at the end of study (Visit 9) 
Theoretical consumption = number of days of treatment intake planned between the start and the 
end of study (168 days ± 7days). 
 
13.11. 
INTERIM ANALYSIS AND DATA MONITORING 
No interim analysis is planned. 
14. GENERAL ETHICAL CONSIDERATIONS  
14.1. 
ETHICAL CONDITIONS 
This study is performed in accordance with the principles stated in the Declaration of Helsinki 
(1964) and subsequent amendments and in accordance with the Good Clinical Practice Guideline 
(CPMP/ICH/135/95). 
14.2. 
ETHICS COMMITTEE AND LEGAL REQUIREMENTS 
All the documents required by National Regulations and any other informative documents that 
may be requested are submitted for review to an Ethics Committee whose procedures and 
operations meet the GCP and National Legal Requirements. 
Depending on National Regulations, the application is submitted to the Ethics Committee by the 
Sponsor (or representative) or by the Investigator. 
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A copy of the formal written approval from the Ethics Committee is provided to the Sponsor 
(directly by the Ethics Committee or via the Investigator) with a list of names and qualifications 
of its members. 
The request for authorisation by the Competent Authority or its notification if required (depending 
on National Regulations) is carried out by the Sponsor. 
The screening of patients does not start before the approval of the Ethics Committee has been 
obtained and the study authorised by the Competent Authority or notified to the Competent 
Authority (depending on National Regulations). 
14.3. 
PATIENT'S INFORMATION LEAFLET AND INFORMED CONSENT 
 
FORM 
An information must be given to the patients before their decision to participate or abstain from 
participation. 
This information is based on the elements set out in the Declaration of Helsinki and the ICH GCP 
Guidelines. It must also describe the measures taken to safeguard patient’s privacy and protection 
of personal data, according to European Directive 95/46 EC or other local regulation. 
Restraints and risks must be explained, as well as the right to discontinue participation in the 
study at any stage, without affecting their further relationship with the Investigator and/or their 
future care. 
The written information and consent form must be submitted to the patient with an oral 
explanation. It must be agreed and signed by the patient before any study-related procedure starts. 
This information and consent procedure is under the Investigator’s responsibility. 
The information and consent document are made in triplicate: the original copy is kept by the 
Investigator, one copy is given to the patient and the last copy is kept by the Clinical Quality 
Assurance Unit of the Sponsor in a sealed envelope at the end of study. 
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Specific areas of the Sponsor’s copy are not triplicated to avoid the reading of the patient’s 
surname (except the first 3 letters), first name, address and signature.  
If any information becomes available during the trial that may be relevant to the patient’s 
willingness to keep on participating in the trial, an updated written informed consent must be 
submitted to the patient to confirm  agreement to continue participating. 
14.4. 
PERSONAL DATA PROTECTION 
All information from this study (excluding data from the informed consent) is entered into a 
computer under the Sponsor’s responsibility in accordance with the French law, "Loi 
Informatique et Libertés" (January 6, 1978, and subsequent amendments) and with the European 
Directive 95/46/CE. 
14.5. 
INSURANCE POLICY 
In accordance with the provisions of the law and the GCP, the Sponsor Pierre Fabre Médicament, 
has an insurance policy intended to guarantee against possible damage resulting from the research. 
The studies and/or experiments performed on behalf of the Sponsor Pierre Fabre Médicament, are 
specifically and expressly guaranteed. 
It is advisable to underline that non compliance with the Research Legal Conditions is a cause for 
guarantee exclusion. 
15. ADMINISTRATIVE PROCEDURES 
15.1. 
PROTOCOL AMENDMENT 
Neither the Investigator nor the Sponsor may alter the protocol without the authorisation of the 
other party.  
All changes to the protocol are subject to an amendment which must be dated and signed by both 
parties and must appear as an amendment to the protocol. 
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Substantial amendments are submitted for approval / authorisation to the Ethics Committees and 
Competent Authorities 
Urgent amendments are submitted for approval / authorisation to the Ethics Committees and 
Competent Authorities, but could be implemented immediately under specific conditions defined 
with the Sponsor. 
15.2. 
SOURCE DOCUMENTS, INVESTIGATOR'S FILE STORAGE 
The Investigator: 
• Keeps all trial-related documents in appropriate file folders. Records of patient, original 
informed consent forms, source documents, a CD Rom containing a pdf copy of e-CRF, drug 
inventory, Ethics Committees and Sponsor correspondence pertaining to the study must be kept 
on file. 
• Retains all documents relating to the screening (consent and investigation results) of all 
patients included in the trial or not 
• Retains a list of the patient’s names, addresses (and/or number of medical file), code numbers 
to allow checking of data reported on e-CRFs with those from source documents 
• Authorises direct access to source documents for monitoring, audits and inspections 
• The trial-related documents must be retained as strictly confidential at the Investigator’s site 
for at least 15 years or according to local requirements, whatever is the longest after the 
completion or discontinuation of the trial (European Directive 2003/63/EC). 
15.3. 
END OF THE STUDY 
15.3.1. Definition of the End of Study 
The end of study is the last visit of the last patient undergoing the trial. 
Any change to this definition during the study, for whatever reason, must be notified as a 
substantial amendment. 
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15.3.2. Early Study Termination 
15.3.2.1. 
Early Study Termination Decided by the Sponsor 
The Sponsor may discontinue the study at any time for any of the following reasons: 
• Lack of recruitment 
• Deviations from good clinical practice and/or regulations 
• Poor product safety 
• New information that could jeopardise the patient’s safety 
• Stopping of the development … 
15.3.2.2. 
Early Study Termination Decided by the Competent Authorities 
The Competent Authorities may suspend or prohibit a study if it considers that the conditions of 
authorisation are not being met or has doubt about the safety or scientific validity of the study. 
15.4. 
AUDIT 
The 
Sponsor 
is 
responsible 
for 
making 
sure 
that 
both 
his 
representatives 
(Study Manager, CRA, ...) and the Investigator fulfil the requirements as specified by the GCP 
Guideline.  
An audit can be organised internally at Pierre Fabre Médicament and at the investigational site 
where the e-CRFs are matched against source documents. 
All study documentation must be directly accessible to auditors. 
The practical conditions for the audit are discussed between the Investigator and the Clinical 
Quality Assurance Department. 
Oral information about the audit results are given to the Investigator. 
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15.5. INSPECTION 
The Health Authorities may inspect any investigation site or the Sponsor in the course of the study 
or after its completion, to verify the conduct of the study and quality of the data. The Investigator 
must provide to the inspectors direct access to study documents. 
15.6. CONFIDENTIALITY 
The present materials (protocol and related documentation, e-CRF, Investigator's Brochure) 
contain confidential information.  
Except if agreed to in writing with the Study Manager, the investigators must hold such 
information confidential, and must not disclose it to others (except where required by Applicable 
Law). 
15.7. CLINICAL STUDY REPORT 
Data analysis, and clinical study report writing are under the Sponsor’s responsibility.  
Upon completion of the data analysis, a final report, including a review of the objectives and 
methods, a presentation and discussion of the results are drawn up according to ICH Guidelines 
(Structure and Content of Clinical Study Reports, ICH-E3, CPMP/ICH/137/95). 
The report is a clinical and statistical integrated report. It must be signed by the Sponsor's 
representative(s) and the Coordinating Investigator. 
15.8. STUDY RESULTS COMMUNICATION 
Upon completion of the study, the global results of the Research are communicated to the 
investigator. According to the Local Regulation, the patient can ask the Investigator for the 
results. 
15.9. STUDY RESULTS PUBLICATION 
The information and data collected during the conduct of this clinical study are considered 
confidential and are used by the Sponsor in connection with the development of the study drug. 
This information may be disclosed if deemed necessary by the Sponsor. 
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To allow use of the information derived from this clinical study and to insure compliance with 
Current Regulations, the Investigator must provide the Sponsor with complete test results and all 
data collected during the study.  
Only the Sponsor may make study information available to physicians and to Regulatory 
Agencies, except as required by Current Regulations. 
All the results of this study including data, reports, discoveries and inventions resulting from the 
study, are the property of the Sponsor. 
In the event the Sponsor chooses to publish study data, the manuscript must be provided to the 
author(s) at least 30 days prior to the expected date of submission to the intended publisher. 
The investigator(s) can reserve the right to publish or present study data; if so, the manuscript or 
abstract must be provided to the Sponsor for review at least 30 days prior to the expected date of 
submission to the intended publisher or of planned presentation. 
In addition, if necessary, (the) investigator(s) shall withhold publication for an additional 60 days, 
to allow the filing of a patent application, or to allow the Sponsor to take any measures he deems 
appropriate to establish and preserve his proprietary rights. 
It is agreed that publication of study results by each site shall be made only as part of a 
publication of the study results obtained by all sites performing the protocol, once the study is 
completed and finalised.  
The authors list is agreed by all investigators prior to publication. The names of the authors are 
provided according to their participation in the design of the protocol as well as their recruitment 
of eligible and analysable patients. 
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16. REFERENCES 
 
[1] 
F373280 INVESTIGATOR'S BROCHURE, version January 2013 
 
[2] 
NODARI S., TRIGGIONAI M., CAMPIA U., MANERBA A., MILESI G., CESANA 
M.B., GHEORGHIADE M., DEI CAS L. 
n-3 Polyunsaturated Fatty Acids in the prevention of atrial Fibrillation Recurrences after 
electrical cardioversion. A prospective, Randomised study 
Circulation, 2011; 124:1100-1106 
 
[3] 
NODARI S., TRIGGIANI M., CAMPIA U., MANERBA A., MILESI G., CESANA 
M B., GHEORGHIADE M., DEI CAS L. 
Effects of n-3 polyunsaturated fatty acids on left ventricular function and functional 
capacity in patients with dilated cardiomyopathy 
J. Am. Coll. Cardiol. 2011;57;870-879 
 
[4] 
MOERTL D., HAMMER A., STEINER S., HUTULEAC R., VONBANK K., 
BERGER R. 
Dose-dependant effects of omega-3-polyunsaturated fatty acids on systolic left ventricular 
function, endothelial function, and markers of inflammation in chronic heart failure of non 
ischemic origin: A double-blind, placebo-controlled, 3-arm study  
American Heart Journal 2011; 161:915.e1-915.e9 - volume 161, number 5 
 
[5] 
GISSI-HF INVESTIGATORS 
Effects of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GSSI-
HF Trial): a randomised, double-blind, placebo-controlled trial 
The lancet on line - August 2008 
 
[6] 
CAMM A.J., KIRCHHOF P., LIP G.Y., SCHOTTEN U., SAVELIEVA I., ERNST S., 
VAN GELDER I.C., AL-ATTAR N., HINDRICKS G., PRENDERGAST B., 
HEIDBUCHEL H., ALFIERI O., ANGELINI A., ATAR D., COLONNA P., DE 
CATERINA R., DE SUTTER J., GOETTE A., GORENEK B., HELDAL M., 
HOHLOSER S.H., KOLH P., LE HEUZEY J.Y., PONIKOWSKI P., RUTTEN F.H. 
Guidelines for the management of atrial fibrillation: the Task Force for the Management of 
Atrial Fibrillation of the European Society of Cardiology (ESC). 
European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery,  
Eur Heart J. 2010 Oct;31(19):2369-429 
 
 
[7] 
KOWEY PR, REIFFEL JA, ELLENBOGEN KA, NACCARELLI GV, PRATT CM. 
Efficacy and safety of prescription omega-3 fatty acids for the prevention of recurrent 
symptomatic atrial fibrillation: a randomised controlled trial. 
JAMA. 2010;304:2363–2372. 
 
 
 
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[8] 
BIANCONI L., CALO L., MENNUNI M., SANTINI L., MOROSETTI P., 
AZZOLINI P., BARBATO G., BISCIONE F., ROMANO P., SANTINI M.  
N-3 polyunsaturated fatty acids for the prevention of arrhythmia recurrence after electrical 
cardioversion of chronic persistent atrial fibrillation: a randomised, double-blind, 
multicentre study  
Europace (2011) 13, 174-181 
 
[9] 
OMACOR® SUMMARY PRODUCT CARACTERISTICS (SPC) dated 17/02/2012 
 
[10] 
BEPANTHENE ® SUMMARY PRODUCT CARACTERISTICS (SPC) 
 
[11] 
TOUBOUL P, BRUGADA J, CAPUCCI A, CRIJNS HJ, EDVARDSSON N, 
 
HOHNLOSER SH.  
Dronedarone for prevention of atrial fibrillation: a dose-ranging study.  
Eur Heart J 2003;24(16):1481-7. 
 
[12] LE HEUZEY JY AND ALL.  
A Short-Term, Randomised, Double-Blind, Parallel-Group Study to Evaluate the Efficacy 
and Safety of Dronedarone versus Amiodarone in Patients with Persistent Atrial 
Fibrillation: The DIONYSOS Study. 
J Cardiovasc Electrophysiol. 
 
[13] METCALF G.R., JAMES J.M., GIBSON A.R., EDWARDS J., STUBBERFIELD J., 
STUKLIS R., YOUNG D.G., ROBERTS-THOMSON K. & CLELAND G.L.M.L. & 
OKEN H. 
Effects of fish-oil supplementation on myocardial fatty acids in humans.  
Am J Clin Nutr (2007); 85 : 1225. 
 
[14] ARTERBURN M.L. & OKEN H. 
Distribution, interconversion and dose response of n-3 fatty acids in humans.  
Am J Clin Nutr (2006);83 : 1469-1473S. 
 
[15] TIELEMAN RG, VAN GELDER IC, CRIJNS HJ, DE KAM PJ, VAN DEN BERG 
MP, HAAKSMA J, VAN DER WOUDE HJ, AND ALLESSIE MA. 
Early recurrences of atrial fibrillation after electrical cardioversion: a result of 
fibrillation-induced electrical remodelling of the atria? 
J. Am. Coll. Cardiol. 1998;31;167-173 
 
[16] 
SALM P, TAYLOR PJ, KOSTNER K 
Simultaneous quantification of total eicosapentaenoic acid, docosahexaenoic acid and 
arachidonic acid in plasma by high-performance liquid chromatography-tandem mass 
spectrometry.  
Biomed Chromatogr 2011 Jun;25(6):652-9. 
 
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[17] LEGRAND P., SCHMITT B., MOUROT J., CATHELINE D., CHESNEAU G., 
MIREAUX M., KERHOAS N., WEILL P. 
The consumption of food products from linseed-fed animals maintains erythrocyte omega-3 
fatty acids in obese human 
Lipids, 2010, 45, 11-19. 
 
[18] HARRIS WS, VON SCHACKY C. 
The Omega-3 Index: a new risk factor for death from coronary heart disease? 
Prev Med. 2004 Jul; 39(1):212-20 
 
[19] ABSTRACT: P5161 . 
NODARI S, MANERBA A., MADURERI A., BERLINGHIERI N., PULCINI E., 
FRATTINI S., METRA M, DEI CAS L. 
Effects of Polyunsaturated Fatty Acids n-3 (PUFA n-3) in the prophylaxis of atrial 
fibrillation relapses after external electric cardioversion 
World Congress of Cardiology 2006, 2-6 September, Barcelona – Spain 
 
[20] 
KIRCHHOF P., AURICCHIO A., BAX J., CRIJNS H., CAMM J., DIENER HC., 
 
GOETTE A., HINDRICKS G., HOHNLOSER S., KAPPENBERGER L., KUCK 
 
KH., LIP HYG., OLSSON B., MEINERTZ T., PRIORI S., RAVENS U., 
 
STEINBECK G., SVERHAGE E., TIJSSEN J., VINCENT A., BREITHARDT G. 
 
Outcome parameters from a consensus conference organized by the German Atrial 
 
Fibrillation Competence NETwork and the European Heart Rhythm Association. 
 
Europace 2007, 9, 1006-1023 
 
[21] 
EUROPEAN MEDICINES AGENCY 
 
Addendum to the guideline on antiarrhythmics on atrial fibrillation and atrial flutter. 
 
EMA/CHMA/EWP/213056/2010 
 
[22] 
OWEN AJ, PETER-PRZYBOROWSKA BA, HOY AJ, MCLENNAN PL. 
Dietary fish oil dose- and time-response effects on cardiac phospholipid fatty acid 
composition. 
Lipids. 2004;39:955–961 
 
[23] 
ROBERTO M. LANG, MICHELLE BIERIG, RICHARD B. DEVEREUX, FRANK 
A. FLACHSKAMPF*, ELYSE FOSTER, PATRICIA A. PELLIKKA, MICHAEL H. 
PICARD, MARY J. ROMAN, JAMES SEWARD, JACK SHANEWISE, SCOTT 
SOLOMON, KIRK T. SPENCER, MARTIN ST. JOHN SUTTON, WILLIAM 
STEWART. 
 
Recommendations for chamber quantification 
 
Eur J Echocardiography (2006) 7, 79-108 
 
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17. APPENDICES 
 
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17.1. DECLARATION OF HELSINKI 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
ETHICAL PRINCIPLES FOR MEDICAL RESEARCH INVOLVING 
HUMAN SUBJECTS 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 29th WMA 
General Assembly, Tokyo, Japan, October 1975 35th WMA General Assembly, Venice, Italy, October 1983 41st 
WMA General Assembly, Hong Kong, September 1989 48th WMA General Assembly, Somerset West, Republic of 
South Africa, October 1996 52nd WMA General Assembly, Edinburgh, Scotland, October 2000 53th WMA General 
Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 55th WMA General Assembly, Tokyo 
2004 (Note of Clarification on Paragraph 30 added) 59th WMA General Assembly, Seoul, October 2008 
 
A. INTRODUCTION  
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of 
ethical principles for medical research involving human subjects, including research on identifiable 
human material and data. The Declaration is intended to be read as a whole and each of its constituent 
paragraphs should not be applied without consideration of all other relevant paragraphs.  
2. Although the Declaration is addressed primarily to physicians, the WMA encourages other participants 
in medical research involving human subjects to adopt these principles.  
3. It is the duty of the physician to promote and safeguard the health of patients, including those who are 
involved in medical research. The physician's knowledge and conscience are dedicated to the fulfilment 
of this duty.   
4. The Declaration of Geneva of the WMA binds the physician with the words, “The health of my patient 
will be my first consideration,” and the International Code of Medical Ethics declares that, “A physician 
shall act in the patient's best interest when providing medical care.”  
5. Medical progress is based on research that ultimately must include studies involving human subjects. 
Populations that are underrepresented in medical research should be provided appropriate access to 
participation in research.  
6. In medical research involving human subjects, the well-being of the individual research subject must 
take precedence over all other interests.  
7. The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic interventions 
(methods, procedures and treatments). Even the best current interventions must be evaluated continually 
through research for their safety, effectiveness, efficiency, accessibility and quality.  
8. In medical practice and in medical research, most interventions involve risks and burdens.  
9. Medical research is subject to ethical standards that promote respect for all human subjects and protect 
their health and rights. Some research populations are particularly vulnerable and need special 
protection. These include those who cannot give or refuse consent for themselves and those who may be 
vulnerable to coercion or undue influence.  
10. Physicians should consider the ethical, legal and regulatory norms and standards for research involving 
human subjects in their own countries as well as applicable international norms and standards. No 
national or international ethical, legal or regulatory requirement should reduce or eliminate any of the 
protections for research subjects set forth in this Declaration.  
 
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B. PRINCIPLES FOR ALL MEDICAL RESEARCH  
11. It is the duty of physicians who participate in medical research to protect the life, health, dignity, 
integrity, right to self-determination, privacy, and confidentiality of personal information of research 
subjects.  
12. Medical research involving human subjects must conform to generally accepted scientific principles, be 
based on a thorough knowledge of the scientific literature, other relevant sources of information, and 
adequate laboratory and, as appropriate, animal experimentation. The welfare of animals used for 
research must be respected.   
13. Appropriate caution must be exercised in the conduct of medical research that may harm the 
environment.  
14. The design and performance of each research study involving human subjects must be clearly described 
in a research protocol. The protocol should contain a statement of the ethical considerations involved 
and should indicate how the principles in this Declaration have been addressed. The protocol should 
include information regarding funding, sponsors, institutional affiliations, other potential conflicts of 
interest, incentives for subjects and provisions for treating and/or compensating subjects who are 
harmed as a consequence of participation in the research study. The protocol should describe 
arrangements for post-study access by study subjects to interventions identified as beneficial in the 
study or access to other appropriate care or benefits.   
15. The research protocol must be submitted for consideration, comment, guidance and approval to a 
research ethics committee before the study begins. This committee must be independent of the 
researcher, the sponsor and any other undue influence. It must take into consideration the laws and 
regulations of the country or countries in which the research is to be performed as well as applicable 
international norms and standards but these must not be allowed to reduce or eliminate any of the 
protections for research subjects set forth in this Declaration. The committee must have the right to 
monitor ongoing studies. The researcher must provide monitoring information to the committee, 
especially information about any serious adverse events. No change to the protocol may be made 
without consideration and approval by the committee.  
16. Medical research involving human subjects must be conducted only by individuals with the appropriate 
scientific training and qualifications. Research on patients or healthy volunteers requires the 
supervision of a competent and appropriately qualified physician or other health care professional. The 
responsibility for the protection of research subjects must always rest with the physician or other health 
care professional and never the research subjects, even though they have given consent.  
17. Medical research involving a disadvantaged or vulnerable population or community is only justified if 
the research is responsive to the health needs and priorities of this population or community and if 
there is a reasonable likelihood that this population or community stands to benefit from the results of 
the research.   
18. Every medical research study involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and communities involved in the research in 
comparison with foreseeable benefits to them and to other individuals or communities affected by the 
condition under investigation.  
19. Every clinical trial must be registered in a publicly accessible database before recruitment of the first 
subject.  
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20. Physicians may not participate in a research study involving human subjects unless they are confident 
that the risks involved have been adequately assessed and can be satisfactorily managed. Physicians 
must immediately stop a study when the risks are found to outweigh the potential benefits or when 
there is conclusive proof of positive and beneficial results.  
21. Medical research involving human subjects may only be conducted if the importance of the objective 
outweighs the inherent risks and burdens to the research subjects.  
22. Participation by competent individuals as subjects in medical research must be voluntary. Although it 
may be appropriate to consult family members or community leaders, no competent individual may be 
enrolled in a research study unless he or she freely agrees.  
23. Every precaution must be taken to protect the privacy of research subjects and the confidentiality of 
their personal information and to minimize the impact of the study on their physical, mental and social 
integrity.   
24. In medical research involving competent human subjects, each potential subject must be adequately 
informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional 
affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort 
it may entail, and any other relevant aspects of the study. The potential subject must be informed of the 
right to refuse to participate in the study or to withdraw consent to participate at any time without 
reprisal. Special attention should be given to the specific information needs of individual potential 
subjects as well as to the methods used to deliver the information. After ensuring that the potential 
subject has understood the information, the physician or another appropriately qualified individual 
must then seek the potential subject’s freely-given informed consent, preferably in writing. If the 
consent cannot be expressed in writing, the non-written consent must be formally documented and 
witnessed.  
25. For medical research using identifiable human material or data, physicians must normally seek consent 
for the collection, analysis, storage and/or reuse. There may be situations where consent would be 
impossible or impractical to obtain for such research or would pose a threat to the validity of the 
research. In such situations the research may be done only after consideration and approval of a 
research ethics committee.   
26. When seeking informed consent for participation in a research study the physician should be 
particularly cautious if the potential subject is in a dependent relationship with the physician or may 
consent under duress. In such situations the informed consent should be sought by an appropriately 
qualified individual who is completely independent of this relationship.  
27. For a potential research subject who is incompetent, the physician must seek informed consent from the 
legally authorized representative. These individuals must not be included in a research study that has 
no likelihood of benefit for them unless it is intended to promote the health of the population 
represented by the potential subject, the research cannot instead be performed with competent persons, 
and the research entails only minimal risk and minimal burden.   
28. When a potential research subject who is deemed incompetent is able to give assent to decisions about 
participation in research, the physician must seek that assent in addition to the consent of the legally 
authorized representative. The potential subject’s dissent should be respected.  
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29. Research involving subjects who are physically or mentally incapable of giving consent, for example, 
unconscious patients, may be done only if the physical or mental condition that prevents giving 
informed consent is a necessary characteristic of the research population. In such circumstances the 
physician should seek informed consent from the legally authorized representative. If no such 
representative is available and if the research cannot be delayed, the study may proceed without 
informed consent provided that the specific reasons for involving subjects with a condition that renders 
them unable to give informed consent have been stated in the research protocol and the study has been 
approved by a research ethics committee. Consent to remain in the research should be obtained as soon 
as possible from the subject or a legally authorized representative.  
30. Authors, editors and publishers all have ethical obligations with regard to the publication of the results 
of research. Authors have a duty to make publicly available the results of their research on human 
subjects and are accountable for the completeness and accuracy of their reports. They should adhere to 
accepted guidelines for ethical reporting. Negative and inconclusive as well as positive results should 
be published or otherwise made publicly available. Sources of funding, institutional affiliations and 
conflicts of interest should be declared in the publication. Reports of research not in accordance with 
the principles of this Declaration should not be accepted for publication.  
 
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE  
31. The physician may combine medical research with medical care only to the extent that the research is 
justified by its potential preventive, diagnostic or therapeutic value and if the physician has good 
reason to believe that participation in the research study will not adversely affect the health of the 
patients who serve as research subjects.   
32. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the 
best current proven intervention, except in the following circumstances:  
• 
The use of placebo, or no treatment, is acceptable in studies where no current proven intervention 
exists; or  
• 
Where for compelling and scientifically sound methodological reasons the use of placebo is 
necessary to determine the efficacy or safety of an intervention and the patients who receive 
placebo or no treatment will not be subject to any risk of serious or irreversible harm.  Extreme 
care must be taken to avoid abuse of this option.  
33. At the conclusion of the study, patients entered into the study are entitled to be informed about the 
outcome of the study and to share any benefits that result from it, for example, access to interventions 
identified as beneficial in the study or to other appropriate care or benefits.  
34. The physician must fully inform the patient which aspects of the care are related to the research. The 
refusal of a patient to participate in a study or the patient’s decision to withdraw from the study must 
never interfere with the patient-physician relationship.  
35. In the treatment of a patient, where proven interventions do not exist or have been ineffective, the 
physician, after seeking expert advice, with informed consent from the patient or a legally authorized 
representative, may use an unproven intervention if in the physician's judgement it offers hope of 
saving life, re-establishing health or alleviating suffering. Where possible, this intervention should be 
made the object of research, designed to evaluate its safety and efficacy. In all cases, new information 
should be recorded and, where appropriate, made publicly available.  
 
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17.2. SAE REPORT FORM 
 
 
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N O T I F I C A T I O N  O F  S E R I O U S  A D V E R S E  E V E N T  ( S A E )  O R  P R E G N A N C Y    
TO PIERRE FABRE PRODUCT SAFETY DEPARTMENT 
 
TO BE TRANSMITTED TO THE MONITOR BY FAX WITHIN 24H : M. GUIRAUD  .............. Fax n° +33 5 34 50 65 92 
Transmission date  
 
 
  
 
  
 
 
 
(ddmmyyyy) 
Country :  
........................................
 
 
 
   SAE N° 
 
 
 
                      FIRST NOTIFICATION           FOLLOW-UP   
 
 SUBJECT CHARACTERISTICS  
 
     Surname    
 
 
 
          First name 
 
 
Birth date  
 
 
 
 
 
 
 
 
  
 
 
Gender 
 
1=M,    2=F 
   Height 
 
 
 
cm 
 Weight 
 
 
 
 
 
kg 
 
 
 DESCRIPTION OF THE EVENT 
The serious adverse event resulted in : 
 Death (whatever may be the cause) 
 Hospitalisation (*) or extension thereof 
 Life threatening 
 Invalidity or disability 
 
 Congenital abnormality or abnormal pregnancy outcome 
 Cancer 
 Other  (any other serious clinical or laboratory event 
     according to the investigator or the protocol, overdosage 
      meeting seriousness criteria, suicide attempts) 
Other fact to be notified : 
 Pregnancy exposure 
Nature of the event (if clinical nature, indicate the diagnosis or the major symptom) : 
........................................................................................................................................................................................................... 
........................................................................................................................................................................................................... 
........................................................................................................................................................................................................... 
AE onset date  |__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
 
Seriousness onset date  |__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
 
Summary description (if clinical cause, significant history, progression of event, available laboratory results, etc...) : 
 
 
 
 
 
 
(*) Except hospitalisations with durations and goals planned in the protocol 
 
 THE SAE IN RELATION TO THE TRIAL 
                                                      TREATMENT NUMBER         |___|___|___|___|___|___| 
• Time of occurrence of SAE 
 
 During the selection or run-in period 
 
 During the administration phase of the study treatment 
 
 After the administration phase of the study treatment 
• Date of first study treatment administration 
• Date of last study treatment administration 
   before the occurence of SAE 
|__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
 
|__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
• Was the blind broken ?       Yes         No          Not applicable 
   If yes, or if this is an open study, drug(s) administered : 
 
 
 
 
 
  Conditions of administration (cycles(s), daily dose(s), route(s) of administration, etc..) :  
 
 
 
 
 
 
 
 
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Transmission date 
 
 
  
 
  
 
 
 
  (ddmmyyyy) 
Country : ............................................ 
 
 
 
  SAE N° 
 
 
 
                     FIRST NOTIFICATION           FOLLOW-UP   
 
 CONCOMITANT MEDICATION SINCE TRIAL INITIATION and UP UNTIL THE OCCURRENCE OF THE SAE 
     (EXCEPT THE TREATMENTS GIVEN FOR THE SAE)  
 
INN or trade name 
 
 
Daily dose 
 
Start date 
(ddmmyy) 
Ongoing at 
occurence of the 
event 
 
Stop date 
(ddmmyy) 
Route of 
admin. 
 
Indication 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 MEASURES TAKEN FOLLOWING THE SAE 
• Study treatment 
 
 No change 
 
 Dosage modification, specify :……………………………..….      Modification Date : 
 
 Temporarily discontinued                                                       Readministration date : 
 
 Withdrawn                                                                                                  End date : 
 
 Not applicable 
 
 
 
 
 ____/____/_____ 
 ____/____/_____ 
 ____/____/_____ 
• The event led to : 
 
 Prescription of corrective or symptomatic treatments (specify names and dosages) : 
 
 
 
 Discontinuation of concomitant treatments (specify names) : 
 
 
 
 Others, specify : 
 
 
 OUTCOME 
         Not recovered/Not resolved                  Recovering/Resolving               Recovered/Resolved 
         Recovered/Resolved with sequelae     Fatal                                          Unknown 
 
                In case of death, has an autopsy been conducted ?       Yes         No 
 
 INVESTIGATOR CAUSALITY ASSESSMENT (investigator’s assessment to be done as soon as possible) 
 Not Suspected                          Suspected                    Insufficient data 
comments : ............................................................................................................................................................. 
 
Enclose in the notification the results of carried out examinations, reports of hospitalisation, etc... 
 
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17.3. PREDEFINED LIMITS OF LABORATORY AND VITAL SIGN 
POTENTIALLY CLINICALLY SIGNIFICANT CHANGES AND VALUES  
 
List of Predefined Potentially Clinically Significant Change For Laboratory Values(¤) 
 
 
PARAMETERS 
UNIT 
PSC 
 
 
 
Decrease 
Increase 
MUSCLE 
Creatine  Phosphokinase 
U / l 
- 
236 
KIDNEY 
Creatinine 
Urea 
Uric acid 
Phosphate 
Calcium 
µmol/l 
mmol/l 
µmol/l 
mmol/l 
mmol/l 
- 
- 
- 
0.39 
0.30 
35 
3.2 
119 
0.39 
0.30 
ELECTROLYTES 
Sodium 
Potassium 
Chloride 
Bicarbonate 
mmol/l 
mmol/l 
mmol/l 
mmol/l 
8 
1.1 
8 
7 
8 
1.1 
7 
8 
METABOLISM/ 
NUTRITIONAL 
Glucose (random) 
Albumin 
Protein 
Cholesterol 
HDL cholesterol 
LDL cholesterol 
Triglycerides 
mmol/l 
g/l 
g/l 
mmol/l 
mmol/l 
mmol/l 
mmol/l 
3 
6 
11 
- 
0.91 
2.17 
- 
3.7 
6 
10 
1.97 
0.85 
2.04 
2.91 
ERYTHROCYTES 
Erythrocyte count 
Haemoglobin 
Haematocrit 
MCV  
MCH (Fe) 
MCHC (Fe) 
T/l 
g/l 
1 
fl 
fmol 
mmol/l 
0.7 
20 
0.06 
7 
0.19 
2 
0.7 
- 
0.06 
7 
0.19 
2 
LEUKOCYTES 
Leukocyte count 
G/l 
4.2 
3.8 
DIFFERENTIAL 
COUNT 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
G/l 
G/l 
G/l 
G/l 
G/l 
3.47 
1.76 
- 
- 
- 
3.19 
1.63 
0.49 
0.41 
0.14 
URINE 
Specific gravity 
pH 
- 
- 
0.017 
2 
0.015 
2 
LIVER 
Total bilirubin 
ASAT (SGOT) 
ALAT (SGPT) 
Gamma GT 
Alkaline phosphatase 
µmol/l 
U/l 
U/l 
U/l 
U/l 
- 
- 
- 
- 
-- 
10 
N x (23/36) 
N x (28/45) 
N x (25/38) 
N x (30/95) 
 
N = upper limit of normal range 
 
(¤) Delta-limits from « Routine Laboratory Tests in Clinical Trials » W. Leigh Thompson, Rocco 
L. Brunelle, Gregory G. Enas, Patrick J. Simpson and Randy L. Walker Lilly Research 
Laboratories, Lilly Corporate Centre, Indianapolis, Indiana in « Clinical Trials and Tribulations » 
1988. 
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Definition of Clinically Noteworthy Abnormal Laboratory Values (CNALV) 
 
 
PARAMETERS 
CNALV 
HAEMOGLOBIN 
 
• Decrease of at least 2g/dl and value < 10 g/dl whatever the baseline 
value 
• If missing baseline : value <10g/dl 
NEUTROPHILS 
• < 1 500/mm3 whatever the baseline value 
WBC 
(if missing value for neutrophils) 
• < 3 000/mm3 whatever the baseline value 
PLATELETS 
• < 100 000/mm3 whatever the baseline value 
SERUM CREATININE 
• Increase of at least 30 % as compared to baseline value and 
value > 150 µmol/l whatever the baseline value 
• If missing baseline : value > 150 µmol/l 
LIVER FUNCTION TESTS 
 
 
ALAT 
 
 If normal baseline :  
 
 
•ALAT > 2 N 
 If abnormal baseline : 
→if baseline value ≤ 2.5 N : 
  
• increase of at least 100 % as compared to baseline value 
→ if baseline value > 2.5 N :  
 
 
• value > 5 N 
and/or 
ASAT 
 
  If normal baseline :  
 
 
• ASAT > 2 N 
  If abnormal baseline : 
→ if baseline value ≤ 2.5 N : 
  
• increase of at least 100 % as compared to baseline value 
→ if baseline value > 2.5 N :  
 
 
• value > 5 N 
and/or 
Alkaline phosphatase (AP) 
 
  If normal baseline :  
 
 
• AP > 1.25 N 
  If abnormal baseline :  
 
 
• AP > 2 N 
and/or 
Total bilirubin (TB) 
  If normal baseline :  
 
 
• TB > 1.5 N 
  If abnormal baseline :  
 
 
• TB > 2 N 
N=upper limit of normal range 
International consensus Meeting. International Journal of Clinical Pharmacology, Therapy and Toxicology, 1990;28:317-322 
Standardisation of definitions and criteria of causality assessment of adverse drug reactions: drugs-induced liver disorders: report 
of an Standardisation of definitions and criteria of causality assessment of adverse drug reactions: drugs-induced cytopenia. 
International Journal of Clinical Pharmacology, Therapy and Toxicology, 1991;29:75-81 
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Cardiovascular Safety 
 
Table 1: Predefined Limits for Potentially Clinically Significant Changes (PSC) and PSC 
Leading to Clinically Significant Values (PSCV) 
 
Parameter 
PSC 
PSCV 
SBP 
Increase ≥ 20 mmHg 
Decrease ≥ 20 mmHg 
SBP ≥ 160 mmHg and increase ≥ 20 mmHg 
SBP ≤ 90 mmHg and decrease ≥ 20 mmHg 
DBP 
Increase ≥ 10 mmHg 
Decrease ≥ 10 mmHg 
DBP ≥ 100 mmHg and increase ≥ 10 mmHg 
DBP ≤ 50 mmHg and decrease ≥ 10 mmHg 
HR 
Increase ≥ 10 bpm 
Decrease ≥ 10 bpm 
HR ≥ 110 bpm and increase ≥ 10 bpm 
HR ≤ 50 bpm and decrease ≥ 10 bpm 
 
Table 2: Predefined Classes for changes from Baseline to the Maximum (and/ or Minimum) 
Post-baseline Value 
Classes of Change from Baseline to the Maximum 
Post-baseline Value 
Classes of Change from Baseline to the 
Minimum Post-baseline Value 
SBP  mmHg 
DBP  mmHg 
HR bpm 
SBP  mmHg 
DBP  mmHg 
HR bpm 
All 
All 
All 
All 
All 
All 
≥  0 
≥  0 
≥  0 
≤  0 
≤  0 
≤  0 
>  0 
>  0 
>  0 
<  0 
<  0 
<  0 
≥ 10 
≥  5 
≥ 10 
≤ -10 
≤ - 5 
≤ -10 
≥ 20 
≥ 10 
≥ 20 
≤ -20 
≤ -10 
≤ -20 
≥ 30 
≥ 15 
≥ 30 
≤ -30 
≤ -15 
≤ -30 
≥ 40 
≥ 20 
 
≤ -40 
≤ -20 
 
 
≥ 25 
 
 
≤ -25 
 
 
≥ 30 
 
 
≤ -30 
 
 
Table 3: Classes for Vital Signs Maximum or Minimum Values 
Classes  for  the Maximum Post-baseline Value 
for each parameter 
Classes  for  the Minimum Post-baseline Value 
for each parameter 
SBP  mmHg 
DBP  mmHg 
HR bpm 
SBP  mmHg 
DBP  mmHg 
HR bpm 
< 120 
< 80 
≤ 50 
≤ 90 
≤ 50 
≤ 50 
[120 ;140[ 
[80;90[ 
]50 ;75[ 
[90 ;120[ 
[50;80[ 
]50 ;75[ 
[140;160[ 
 [90;100[ 
[75;100[ 
[120;140[ 
 [80;90[ 
[75;100[ 
≥ 160 
≥ 100 
≥ 100 
≥ 140 
≥ 90 
≥ 100 
 
Table 4: Classes for Maximum or Minimum of BP in its entirety 
Classification of Maximum Values for Blood 
Pressure (mmHg) 
Classification of Minimum Values Blood 
Pressure (mmHg) 
SBP < 140 and DBP < 90 
SBP > 90 and DBP > 50 
SBP [140;160[ and DBP < 100 
or DBP [90;100[ and SBP < 160 
SBP ≤  90 or DBP ≤  50 
SBP ≥ 160 or DBP ≥ 100 
 
 
Table 5: Definition of orthostatic hypotension 
Orthostatic Hypotension * 
SBP Decrease ≥ 20 mmHg or DBP Decrease ≥ 10 mmHg between supine and standing positions 
* Consensus Committee of the American Autonomic Society and the American Academy of Neurolog :Consensus statement on the definition of 
orthostatic hypotension, pure autonomic failure and multiple system atrophy. Neurology 1996;46:1470-3. 
 
 
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16.1.1.3. Protocol amendment n° PA01 
Local (Italy) and substantial dated on 01 March 2013 linked to 
Protocol and appendices (version3: 01 March 2013) 
 
 
 
 
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CLINICAL STUDY PROTOCOL AMENDMENT n° PA01 – Version 1 
Local (Italy) - Substantial 
 
 
Final version
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Pierre Fabre Médicament 
Represented by : Institut de Recherche Pierre Fabre 
45, Place Abel Gance 
F-92100 Boulogne 
 
 
 
 
CLINICAL STUDY PROTOCOL AMENDMENT n° PA01 – Version 1 
 
Local (Italy) - Substantial 
 
 
 
 
Efficacy and safety study of F373280 for maintenance of sinus rhythm after electrical 
cardioversion in patients with persistent Atrial Fibrillation and Chronic Heart Failure. 
 
International, multicentric, randomised, double-blind, placebo controlled study 
 
 
 
 
Pierre Fabre Study Code: 
F373280 CA 2 01 
EudraCT Number: 
2012-003487-48 
Sponsor’s Representative: 
Marlène GUIRAUD 
Coordinating Investigator: 
Pr Savina NODARI 
Date of amendment PA01: 
1st March 2013 
 
 
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Clinical Study Protocol Amendment n° PA 01 – Version 1 
Local (Italy) - Substantial 
COUNTRY COORDINATING INVESTIGATOR SIGNATURE FORM 
 
 
Country Coordinating Investigator: 
Date:  
Signature: 
 
Pr Savina NODARI 
 
 
 
 
 
 
 
 
 
 
 
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Clinical Study Protocol Amendment n° PA 01 – Version 1 
Local (Italy) - Substantial 
INVESTIGATOR SIGNATURE FORM 
 
 
By my signature below, I, Dr _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _, hereby confirm that I have read, taken 
note of (and will apply) the modifications brought by the protocol amendment n° PA 01, dated _ _/_ _/_ 
_and I will conduct the trial according to these new modalities. 
 
 
Date: 
Signature: 
 
 
 
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HISTORY OF PROTOCOL VERSIONS 
 
 
 
PROTOCOL VERSIONS 
 
MODIFICATIONS 
COMMENTS 
Version 1 
09/11/2012 
Initial version  
Version 1 submitted in 
Italy (to Central Ethics 
Committee) 
Version 2 
15/01/2013 
Following French CA request 
(ANSM) : 
- Add of a non inclusion criteria : 
“Breast-feeding female patient” 
- Add of haematology 
examination at visit 3 and 6 
Version 2 not submitted 
to CEC in Italy –  
The version 3 will be 
directly submitted  
 
 
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1. AMENDMENT RATIONALE 
 
This substantial local amendment follows the submission of the study protocol and Informed 
Consent Form (ICF) to the Central Ethics Committee (CEC) and Competent Authority (CA) in 
Italy. 
According to the CEC and CA requirements and, in order to harmonise the protocol and the ICF , 
the following changes have been done to the study protocol :  
- adjustment of the selection criteria n°10 related to the contraception method  
- addition of a letter that is given by the patient to his/her general practitioner (GP) 
- precision that the sponsor can not collect a copy of the Informed Consent Form  
- precision that the patient card is in Italian language only (without any English mention)     
 
 
In addition, the modification performed in the protocol version 2, on French Medicinal Agency  
have been included :  
- Addition of a non-inclusion criteria related to breast-feeding female patient 
- Addition of haematology dosage at visit 3 and 6 
 
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2. CHANGES DESCRIPTION 
 
PREVIOUS 
VERSION 
MODIFIED VERSION 
Final version
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STUDY 
SYNOPSIS 
AND 5.1 
INCLUSION 
CRITERIA 
Demographic 
Characteristics 
and 
Other 
Baseline 
Characteristics: 
10. 
For 
female 
patient 
of 
child-
bearing potential:  
use 
of 
an 
effective 
method 
of 
contraception 
(hormonal 
contraception 
or 
intra-
uterine 
device) 
assessed 
by 
the 
investigator, 
for at least 2 
months 
before 
the 
selection 
in 
the study and 
agreement to 
go on using it 
during 
the 
whole 
duration 
of 
the study and 
up to 1 month 
after the last 
dose of the 
study 
treatment or 
- 
documented 
as 
STUDY SYNOPSIS AND 5.1 INCLUSION CRITERIA 
Demographic Characteristics and Other Baseline Characteristics: 
10. For female patient of child-bearing potential:  
-  
absolute abstention from sexual intercourse during the whole duration of the 
study and for a month after the end of the study or 
-  
use of double barrier contraception method (use of effective medical 
contraception method)  from at least 2 months before the start of the study to the 
entire duration of the study and for a month after the end of the study or 
 - 
documented as surgically sterilized 
11. For female patient of child-bearing potential: negative urine pregnancy test at 
inclusion 
 
12. For male with a childbearing potential partner:  
- 
absolute abstention from sexual intercourse during the whole duration of the 
study and for a month after the end of the study or 
- 
use of double barrier contraception method (use of condom for male and 
effective contraception method for the partner) from the entire duration of the 
study to a month after the end of the study. 
 
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surgical
ly 
sterilize
d 
 
 
11. 
For 
female 
patient 
of 
child-
bearing 
potential: 
negative 
urine 
pregnancy test at 
inclusion 
 
 
 
 
 
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PREVIOUS VERSION 
MODIFIED VERSION 
STUDY SYNOPSIS AND 5.2 NON 
INCLUSION CRITERIA 
Others criteria:  
20. Patient liable not to comply with protocol 
instructions and/or with treatment, in the 
investigator’s opinion, 
21. Patient having taken part in a clinical trial 
in the preceding 2 months or taking part in a 
trial at the time of selection, 
22. Patient linguistically or mentally unable 
to understand the nature, objectives and 
possible consequences of the trial, or refusing 
to patient himself / herself to its constraints, 
23. Patient family member or work associate 
(secretary, 
nurse, 
technician…) 
of 
the 
Investigator, 
24. Patient having forfeited his / her freedom 
by administrative or legal award or being 
under guardianship, 
 
 
 
STUDY SYNOPSIS AND 5.2 NON 
INCLUSION CRITERIA 
Others criteria:  
20. Patient liable not to comply with protocol 
instructions and/or with treatment, in the 
investigator’s opinion, 
21. Patient having taken part in a clinical trial 
in the preceding 2 months or taking part in a 
trial at the time of selection, 
22. Patient linguistically or mentally unable 
to understand the nature, objectives and 
possible consequences of the trial, or refusing 
to patient himself / herself to its constraints, 
23. Patient family member or work associate 
(secretary, 
nurse, 
technician…) 
of 
the 
Investigator, 
24. Patient having forfeited his / her freedom 
by administrative or legal award or being 
under guardianship, 
25. Breastfeeding female patient. 
 
 
 
 
 
 
 
 
 
 
 
 
 
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PREVIOUS VERSION 
MODIFIED VERSION 
5.9 STUDY CARD 
The patient will receive from the Investigating 
Centre at Visit 1 - Selection Visit, a personal card to 
be kept all along the study duration and providing 
the following information: patient's name, sponsor's 
name, study code, EUDRACT number, start date 
and expected end date of the study, complete 
address of the Investigating Centre with the name 
and phone number of the Investigator and a sponsor 
24H/24 phone contact number in case of emergency 
(French and English languages): 33 (0)5 63 35 25 
83. 
 
 
 
5.9 STUDY CARD AND LETTER FOR 
GENERAL PRACTITIONERS (GP) 
The patient will receive from the Investigating 
Centre at Visit 1 - Selection Visit :  
- a personal card to be kept all along the study 
duration and providing the following information: 
patient's name, sponsor's name, study code, 
EUDRACT number, start date and expected end 
date of the study, complete address of the 
Investigating Centre with the name and phone 
number of the Investigator and a sponsor 24H/24 
phone contact number in case of emergency (French 
and English languages): 33 (0)5 63 35 25 83. This 
card will be in Italian without any English 
mention. 
- a letter to be given to his/her general 
practitioner. This letter intends to inform the GP 
(and any other doctors who take care of the 
patient) that the patient participate to this 
clinical study. It describes the study treatment 
and includes some information on the forbidden 
treatment during the study.   
 
 
 
 
 
 
 
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PREVIOUS VERSION 
MODIFIED VERSION 
8.3 SAFETY ASSESSMENT 
8.3.2 Laboratory Investigations 
8.3.2.1 Schedule 
Laboratory investigations will be performed at 
visit 1 (before treatment) and visit 9 (end of 
treatment) or End of Treatment visit. 
Furthermore the kaliemia will be checked 
before electrical cardioversion at visit 3. 
 
 
 
8.3.2.2. Technical Procedures and 
Parameters 
The following tests will be performed: 
 
Haematology: 
 
Hematocrit, haemoglobin, Red blood cells 
(RBC) count, white blood cells (WBC) count, 
WBC differential counts (% and absolute), 
platelets.  
 
 
8.3 SAFETY ASSESSMENT 
8.3.2 Laboratory Investigations 
8.3.2.1 Schedule 
Laboratory investigations will be performed at 
visit 1 (before treatment) and visit 9 (end of 
treatment) or End of Treatment visit. 
At visit 3 and 6, only an haematology 
examination will be performed.  
Furthermore the kaliemia will be checked 
before electrical cardioversion at visit 3. 
 
8.3.2.2. Technical Procedures and 
Parameters 
The following tests will be performed: 
 
Haematology: 
 
Hematocrit, haemoglobin, Red blood cells 
(RBC) count, white blood cells (WBC) count, 
WBC differential counts (% and absolute), 
reticulocytes, platelets.  
 
 
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PREVIOUS VERSION 
MODIFIED VERSION 
9. STUDY PROCEDURES 
Visit 
3 
(Week 
4: 
D28 
-2/+7 
days) 
cardioversion 
Patient will be assessed for the following 
criteria: 
… 
• Laboratory examination: Red Blood Cell 
concentrations of DHA, Prothrombin Time/INR 
(PT/INR), Activated Partial Thromboplastin 
Time (aPTT), Thrombin Clotting Time (TCT) 
…. 
 
Visit 5 (Week 8: D56 ± 7 days) – Visit 6 
(Week 12: D84 ± 7 days) - Visit 7 (Week 16: 
D112 ± 7 days) - Visit 8 (Week 20: D140 ± 7 
days) 
Patient will be assessed for the following 
criteria: 
- … 
- at visit 6, an echocardiography will be 
performed and the red blood cell concentration 
of DHA will be measured.  
… 
 
9. STUDY PROCEDURES 
Visit 
3 
(Week 
4: 
D28 
-2/+7 
days) 
cardioversion 
Patient will be assessed for the following 
criteria: 
… 
• Laboratory 
examination: 
Haematology, 
Red Blood Cell concentrations of DHA, 
Prothrombin Time/INR (PT/INR), Activated 
Partial Thromboplastin Time (aPTT), Thrombin 
Clotting Time (TCT) 
…. 
Visit 5 (Week 8: D56 ± 7 days) – Visit 6 
(Week 12: D84 ± 7 days) - Visit 7 (Week 16: 
D112 ± 7 days) - Visit 8 (Week 20: D140 ± 7 
days) 
Patient will be assessed for the following 
criteria: 
- … 
- at visit 6, an echocardiography will be 
performed, an haematology examination will 
be done and the red blood cell concentration of 
DHA will be measured.  
…. 
 
 
 
 
 
 
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PREVIOUS VERSION 
MODIFIED VERSION 
11.2. STUDY MONITORING 
11.2.1.4. Closing Visit 
At the end of the study, a final visit will be carried 
out by the CRA to: 
• 
Verify that the e-CRFs CD-ROM with pdf files 
are correctly stored 
• 
Control the accountability of intact and used 
treatment units and return them to the Clinical 
Pharmacy Department of the IRPF for destruction 
• 
Obtain the last data clarifications and/or 
solutions if any 
• 
Collect the patient's consent forms in sealed 
envelopes,  
• 
Make 
an 
on-site 
review 
of 
all 
study 
documentation and complete it if necessary 
• 
And finally, remind the Investigator of his 
regulatory obligations, study document archiving 
process and duration. 
 
 
11.2. STUDY MONITORING 
11.2.1.4. Closing Visit 
At the end of the study, a final visit will be carried 
out by the CRA to: 
• 
Verify that the e-CRFs CD-ROM with pdf files 
are correctly stored 
• 
Control the accountability of intact and used 
treatment units and return them to the Clinical 
Pharmacy Department of the IRPF for destruction 
• 
Obtain the last data clarifications and/or 
solutions if any 
• 
Collect the patient's consent forms in sealed 
envelopes (except in case of specific country 
requirement),  
• 
Make 
an 
on-site 
review 
of 
all 
study 
documentation and complete it if necessary 
• 
And finally, remind the Investigator of his 
regulatory obligations, study document archiving 
process and duration. 
 
 
 
 
 
 
 
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PREVIOUS VERSION 
MODIFIED VERSION 
13.8 SAFETY ANALYSIS 
13.8.2 Clinical Laboratory Evaluation  
For all blood laboratory parameters, scatter 
plots highlighting individual results will display 
the baseline and week 24 of the laboratory 
measurements for each patient by locating the 
point defined by the baseline value on the 
abscissa and respectively week 24 value in the 
ordinate.  
Each treatment group will be identified 
differently. The first bisecting line (45° line), 
the lines of lower and upper normal range, the 
lines of PSC range and CNALV range added on 
the plots (see Appendix 17.3). 
 
13.8 SAFETY ANALYSIS 
13.8.2 Clinical Laboratory Evaluation  
For all biochemistry parameters, scatter plots 
highlighting individual results will display the 
baseline and week 24 of the laboratory 
measurements for each patient by locating the 
point defined by the baseline value on the 
abscissa and respectively week 24 value in the 
ordinate.  
For all haematology parameters, scatter 
plots highlighting individual results will 
display the baseline and week 4, week 12 and 
week 24 of the laboratory measurements for 
each patient by locating the point defined by 
the baseline value on the abscissa and 
respectively week 4, week 12 and week 24 
value in the ordinate.  
Each treatment group will be identified 
differently. The first bisecting line (45° line), 
the lines of lower and upper normal range, the 
lines of PSC range and CNALV range added on 
the plots (see Appendix 17.3). 
 
 
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PREVIOUS VERSION 
MODIFIED VERSION 
14.3 PATIENT'S INFORMATION 
LEAFLET AND INFORMED 
CONSENT FORM 
The information and consent document are made in 
triplicate: the original copy is kept by the 
Investigator, one copy is given to the patient and the 
last copy is kept by the Clinical Quality Assurance 
Unit of the Sponsor in a sealed envelope at the end 
of study. 
 
14.3 PATIENT'S INFORMATION 
LEAFLET AND INFORMED 
CONSENT FORM 
The information and consent document are made in 
triplicate: the original copy is kept by the 
Investigator, one copy is given to the patient and the 
last copy is kept by the Clinical Quality Assurance 
Unit of the Sponsor in a sealed envelope at the end 
of study (except in case of specific country 
requirement). 
 
 
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F 373280 CA 2 01 
 
 
 
 
 
 
 
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Pierre Fabre Médicament 
Represented by: Institut de Recherche Pierre Fabre 
45, Place Abel Gance 
F-92100 Boulogne 
 
CLINICAL STUDY PROTOCOL 
 
Efficacy and safety study of F373280 for maintenance of sinus rhythm after 
electrical cardioversion in patients with persistent Atrial Fibrillation and 
Chronic Heart Failure. 
International, multicentric, randomised, double-blind, placebo controlled study 
F373280 / Soft Capsules / 1g  
 
Pierre Fabre Study Code: 
EudraCT Number: 
 
Sponsor's Representative: 
 
 
 
 
 
 
 
 
 
Study Coordinating Investigator 
F 373280 CA 2 01  
2012 – 003487 - 48 
 
Marlène GUIRAUD, Pharm D  
INSTITUT DE RECHERCHE PIERRE FABRE - 
Centre de R&D Pierre Fabre - BP 13562  
3 avenue Hubert Curien  
31035 TOULOUSE Cédex 1 
Phone: +33 5 34 50 63 48  
Fax:+33 5 34 50 65 92  
E-mail:marlene.guiraud@pierre-fabre.com  
 
Pr Savina NODARI 
Section of Cardiology  
Department of Experimental and Applied Sciences 
University of Brescia 
BRESCIA, ITALY 
Phone: +39 030 3996 587 - Fax: +39 030 3700 359 
E-mail: savinanodari@gmail.com  
 
Version 3– 01 MAR 2013 
 
The information contained in this document is confidential and is the property of the Sponsor, Pierre Fabre 
Medicament. This information is given for the needs of the study and must not be disclosed without prior written 
consent of the Sponsor Pierre Fabre Medicament. Persons to whom this information is given for the needs of the 
study must be informed that it is confidential and must not be disclosed. 
 
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SPONSOR PERSONNEL 
PIERRE FABRE MEDICAMENT 
represented by 
Institut de Recherche Pierre Fabre 
 
Clinical Study Manager (Monitor) 
Marlène GUIRAUD, Pharm D 
Phone: +33 5 34 50 63 48 
Fax: + 33 5 34 50 65 92 
E-mail: marlene.guiraud@pierre-
fabre.com 
Institut de Recherche Pierre Fabre 
Centre de R&D Pierre Fabre 
BP 13 562 
3, Avenue Hubert Curien 
31035 TOULOUSE Cedex 1 
 
Head of Therapeutic Area 
Alain DELARUE, MD 
Phone: + 33 5 34 50 61 88 
Fax: +33 5 34 50 65 92 
E-mail: alain.delarue@pierre-
fabre.com 
Institut de Recherche Pierre Fabre 
Centre de R&D Pierre Fabre 
BP 13 562 
3, Avenue Hubert Curien 
31035 TOULOUSE Cedex 1 
 
Clinical Development Physician 
Richard ROCHE, MD 
Phone: +33 5 34 50 61 94 
Fax: +33 5 34 50 65 92 
E-mail: richard.roche@pierre-
fabre.com 
Institut de Recherche Pierre Fabre 
Centre de R&D Pierre Fabre 
BP 13 562 
3, Avenue Hubert Curien 
31035 TOULOUSE Cedex 1 
 
 
 
 
 
 
 
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CONTRACT RESEARCH ORGANISATIONS 
 
 
 
 
For Feasibility, Monitoring and Regulatory issues: 
Pharmaceutical Service Network (PSN) 
Rufino Gonzalez 
28 037 Madrid - SPAIN 
Phone: +34 91 375 6930 - Fax: +34 91 375 6931 
E-mail: www.psnglobal.org 
 
 
For Centralised Randomisation and Electronic Case Report Form 
S-Clinica 
6, Chaussée de Boondael 
B-1050 Brussels - BELGIUM 
Phone: +32 2 645 0567 - Fax: +32 2 645 0569 
E-mail: irena.seredina@s-clinica.com 
 
 
 
For Centralised Reading of Holder ECG and TTEM and equipment supply: 
Biomedical System 
1945 Chaussée de Wavre 
B-1160 Brussels - BELGIUM 
Phone: +32 2 661 20 70 - Fax: +32 2 661 20 71 
E-mail: sjacobs@biomedsys.com 
 
 
 
For intra erythrocyte DHA dosage 
Agrocampus Ouest 
Laboratoire de Biochimie 
65 rue de Saint Brieuc – CS 84215 
35042 RENNES Cedex - FRANCE 
Phone: +33 2 23 48 55 49 - Fax: +33 2 23 48 55 50 
E-mail: daniel.catheline@agrocampus-ouest.fr 
 
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Protocol F 373280 CA 2 01 
COUNTRY COORDINATING  INVESTIGATOR  
SIGNATURE FORM 
Protocol Version 3 – 01 MAR 2013 
 
 
Country: …………………….. 
 
Country Coordinating Investigator:  
"Name"  
Date:   
 
 
 
 
 
 
Signature:  
 
 
 
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Protocol F 373280 CA 2 01 
INVESTIGATOR SIGNATURE FORM 
Protocol Version 3 – 01 MAR 2013 
 
 
 
By my signature below, I, Dr / Pr "                                         ", hereby confirm that I agree: 
♦ to conduct the trial described in the protocol F 373280 CA 2 01, dated 1st March 2013 in 
compliance with GCP, with applicable regulatory requirements and with the protocol 
agreed upon by the Sponsor Pierre Fabre Médicament and given approval / favourable* 
opinion by the Ethics Committee; 
♦ to document the delegation of significant study-related tasks and to notify the Sponsor of 
changes in site personnel involved in the study; 
♦ to comply with the procedure for data recording and reporting; 
♦ to allow monitoring, auditing and inspection; 
♦ to retain the trial-related essential documents until the Sponsor informs that these documents 
are no longer needed. 
Furthermore, I hereby confirm that I will have and will use the available adequate resources, 
personnel and facilities for conduct this trial. 
 
I have been informed that certain regulatory authorities require the Sponsor Pierre Fabre 
Médicament to obtain and supply details about the investigator’s ownership interest in the 
Sponsor or the study drug, and more generally about his/her financial relationships with the 
Sponsor. The Sponsor will use and disclose the information solely for the purpose of complying 
with regulatory requirements. 
Hence I agree: 
♦ to supply the Sponsor with any information regarding ownership interest and financial 
relationships with the Sponsor (including those of my spouse and dependent children); 
♦ to promptly update this information if any relevant changes occur during the course of the 
study and for 1 year following completion of the study; 
♦ that the Sponsor may disclose this information about such ownership interests and financial 
relationships to regulatory authorities. 
* To be adapted  
 
Date:  
Signature:  
 
 
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TABLE OF CONTENTS OF CLINICAL STUDY PROTOCOL 
 
1. 
INTRODUCTION AND STUDY RATIONALE ................................................................ 22 
1.1. 
TARGET PATHOLOGY AND THERAPY ........................................................................ 22 
1.2. 
INFORMATION ON THE TEST PRODUCT .................................................................... 24 
1.2.1. 
Chemical and pharmaceutical characteristics .................................................................... 25 
1.2.1.1. 
Nomenclature and structure ............................................................................................ 25 
1.2.1.2. 
Physical and chemical general properties ...................................................................... 25 
1.2.2. 
Non-clinical Data .............................................................................................................. 26 
1.2.2.1. 
Pharmacological profile ................................................................................................. 26 
1.2.2.2. 
Safety pharmacology ...................................................................................................... 27 
1.2.2.3. 
Toxicology profile .......................................................................................................... 27 
1.2.2.4. 
Pharmacokinetic data ..................................................................................................... 27 
1.2.3. 
Clinical data ....................................................................................................................... 27 
1.3. 
STUDY RATIONALE ......................................................................................................... 30 
1.4. 
OVERALL RISK AND BENEFIT ASSESSMENT ............................................................ 30 
2. 
STUDY OBJECTIVES ......................................................................................................... 33 
2.1. 
PRIMARY OBJECTIVE ..................................................................................................... 33 
2.2. 
SECONDARY OBJECTIVES ............................................................................................. 33 
3. 
ETHICAL CONSIDERATIONS RELATING TO THE STUDY .................................... 33 
4. 
STUDY DESIGN ................................................................................................................... 35 
4.1. 
OVERALL DESCRIPTION ................................................................................................ 35 
4.2. 
DISCUSSION OF THE STUDY DESIGN .......................................................................... 36 
4.2.1. 
Choice of the Study Population ......................................................................................... 36 
4.2.2. 
Choice of the Study Design ............................................................................................... 37 
4.2.3. 
Choice of the Dose ............................................................................................................ 38 
4.2.4. 
Choice of the Sample Size ................................................................................................. 39 
5. 
STUDY POPULATION ........................................................................................................ 39 
5.1. 
INCLUSION CRITERIA ..................................................................................................... 39 
5.2. 
NON INCLUSION CRITERIA ........................................................................................... 40 
5.3. 
NUMBER OF  PATIENTS .................................................................................................. 41 
5.4. 
RECRUITMENT MODALITIES ........................................................................................ 41 
5.5. 
PATIENTS IDENTIFICATION .......................................................................................... 41 
5.6. 
WITHDRAWAL CRITERIA ............................................................................................... 41 
5.7. 
REPLACEMENT OF PATIENTS ....................................................................................... 42 
5.8. 
POST-STUDY EXCLUSION PERIOD .............................................................................. 43 
5.9. 
STUDY CARD ..................................................................................................................... 43 
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6. 
STUDY TREATMENT ......................................................................................................... 43 
6.1. 
SOURCE, PRESENTATION AND COMPOSITION OF  INVESTIGATIONAL 
PRODUCT ........................................................................................................................... 43 
6.2. 
PACKAGING AND LABELLING ..................................................................................... 44 
6.2.1. 
Packaging .......................................................................................................................... 44 
6.2.2. 
Labelling ............................................................................................................................ 44 
6.3. 
DISTRIBUTION TO CENTRE AND STORAGE .............................................................. 45 
6.4. 
ALLOCATION OF TREATMENTS AND DISPENSATION TO PATIENT ................... 46 
6.5. 
DRUG ADMINISTRATION ............................................................................................... 47 
6.5.1. 
Duration of Treatment ....................................................................................................... 47 
6.5.2. 
Dose Schedule ................................................................................................................... 47 
6.5.3. 
Route and Conditions of Administration ........................................................................... 47 
6.6. 
ACCOUNTABILITY ON SITE AND RETURN/DESTRUCTION OF  
INVESTIGATIONAL PRODUCT ...................................................................................... 47 
6.7. 
RECALL OF INVESTIGATIONAL PRODUCTS ............................................................. 48 
7. 
CONCOMITANT TREATMENTS ..................................................................................... 48 
7.1. 
ANTI-VITAMIN K TREATMENT ..................................................................................... 49 
7.2. 
PROHIBITED TREATMENTS ........................................................................................... 49 
7.3. 
AUTHORISED TREATMENTS ......................................................................................... 49 
8. 
EVALUATION CRITERIA ................................................................................................. 50 
8.1. 
PRIMARY EFFICACY CRITERION: ................................................................................ 50 
8.1.1. 
Time to the first Atrial Fibrillation Recurrence ................................................................. 50 
8.1.1.1. 
Definition ........................................................................................................................ 50 
8.1.1.2. 
Schedule ......................................................................................................................... 50 
8.1.1.3. 
Evaluation Methods ........................................................................................................ 50 
8.1.2. 
Secondary Efficacy Criteria .............................................................................................. 51 
8.1.2.1. 
Numbers of Atrial Fibrillation episodes in the first week following visit 3   (ECV 
visit) ................................................................................................................................ 51 
8.1.2.2. 
Duration of Atrial Fibrillation episodes in the first week following visit 3   (ECV 
visit) ................................................................................................................................ 52 
8.1.2.3. 
Clinical parameters evaluation ....................................................................................... 52 
8.1.2.4. 
Cardioversion assessment ............................................................................................... 53 
8.1.2.5. 
Evolution of echocardiographic parameters ................................................................... 54 
8.2. 
BIOMARKER ASSESSMENT: RED BLOOD CELL   CONCENTRATIONS OF 
DHA ..................................................................................................................................... 54 
8.2.1. 
Definition ........................................................................................................................... 54 
8.2.2. 
Blood samples ................................................................................................................... 55 
8.2.2.1. 
Collection schedule ........................................................................................................ 55 
8.2.2.2. 
Technical handling ......................................................................................................... 55 
8.2.3. 
DHA concentration measurement ..................................................................................... 55 
8.3. 
SAFETY ASSESSMENT .................................................................................................... 56 
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8.3.1. 
Adverse Events .................................................................................................................. 56 
8.3.2. 
Laboratory Investigations .................................................................................................. 56 
8.3.2.1. 
Schedule ......................................................................................................................... 56 
8.3.2.2. 
Technical Procedures and Parameters ............................................................................ 56 
8.3.3. 
Global Physical Examination ............................................................................................ 57 
8.3.4. 
Vital Signs ......................................................................................................................... 57 
8.3.4.1. 
Schedule ......................................................................................................................... 58 
8.3.4.2. 
Technical Procedure and Parameters.............................................................................. 58 
8.3.5. 
Electrocardiogram (ECG) .................................................................................................. 58 
8.3.5.1. 
Schedule ......................................................................................................................... 58 
8.3.5.2. 
Technical Procedure and Parameters.............................................................................. 58 
8.3.6. 
Coagulation parameters ..................................................................................................... 59 
8.3.7. 
Concomitant Treatments ................................................................................................... 59 
8.4. 
COMPLIANCE .................................................................................................................... 59 
9. 
STUDY PROCEDURES ....................................................................................................... 60 
10. ADVERSE EVENTS: DEFINITION AND REPORTING ............................................... 65 
10.1. ADVERSE EVENTS ........................................................................................................... 65 
10.1.1. Definition of Adverse Events ............................................................................................ 65 
10.1.2. Grading of Adverse Events ............................................................................................... 66 
10.1.3. Reporting of Adverse Events ............................................................................................ 66 
10.2. SERIOUS ADVERSE EVENTS (SAE) .............................................................................. 66 
10.2.1. Definition ........................................................................................................................... 66 
10.2.2. Reporting of SAE .............................................................................................................. 67 
10.2.3. Follow-up of SAE ............................................................................................................. 68 
10.2.4. SAE Occurring After the Study ......................................................................................... 68 
10.3. REPORTING OF OVERDOSAGE TO THE SPONSOR ................................................... 68 
10.4. REPORTING OF PREGNANCY TO THE SPONSOR ...................................................... 68 
10.5. SPONSOR'S RESPONSIBILITIES FOR SAFETY REPORTING  PURPOSES ............... 69 
11. DATA COLLECTION AND STUDY MONITORING ..................................................... 69 
11.1. DATA COLLECTION ......................................................................................................... 69 
11.1.1. Case Report Form .............................................................................................................. 69 
11.1.2. Source Documents ............................................................................................................. 70 
11.2. STUDY MONITORING ...................................................................................................... 71 
11.2.1. Monitoring visits ............................................................................................................... 71 
11.2.1.1. Site Preselection Visit .................................................................................................... 71 
11.2.1.2. Initiation Visit ................................................................................................................. 71 
11.2.1.3. Follow-up Visits ............................................................................................................. 72 
11.2.1.4. Closing Visit ................................................................................................................... 72 
11.2.2. Direct Access to Source Documents ................................................................................. 72 
11.3. INDEPENDENT DATA MONITORING COMMITTEE ................................................... 73 
12. DATA MANAGEMENT ...................................................................................................... 73 
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12.1. DATA ENTRY ..................................................................................................................... 73 
12.2. DATA CLEANING ............................................................................................................. 73 
12.3. DATA CODING .................................................................................................................. 74 
12.4. DATA STORAGE ............................................................................................................... 74 
12.5. DATABASE LOCK ............................................................................................................. 74 
13. STATISTICAL ANALYSIS ................................................................................................. 74 
13.1. GENERAL CONSIDERATIONS ........................................................................................ 75 
13.2. SAMPLE SIZE ..................................................................................................................... 75 
13.3. PROTOCOL DEVIATIONS ................................................................................................ 75 
13.4. DATA SETS ANALYSED .................................................................................................. 76 
13.5. HANDLING OF DROPOUTS AND MISSING DATA ..................................................... 76 
13.5.1. Dropouts ............................................................................................................................ 76 
13.5.2. Repositioning of Visits ...................................................................................................... 76 
13.5.3. Missing Data ...................................................................................................................... 76 
13.6. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ............................... 77 
13.7. EFFICACY ANALYSIS ...................................................................................................... 77 
13.7.1. Primary Criterion ............................................................................................................... 77 
13.7.1.1. Primary Analysis ............................................................................................................ 77 
13.7.1.2. Supportive Analysis ....................................................................................................... 77 
13.7.2. Secondary Criteria ............................................................................................................. 78 
13.7.2.1. Numbers of Atrial Fibrillation Episodes ........................................................................ 78 
13.7.2.2. Duration of Atrial Fibrillation Episodes ......................................................................... 78 
13.7.2.3. Time to first AF recurrence less than 10 minutes or symtomatic .................................. 78 
13.7.2.4. Clinical parameters evaluation ....................................................................................... 78 
13.7.2.5. Biomarker analysis: red blood cell concentrations of DHA ........................................... 79 
13.8. SAFETY ANALYSIS .......................................................................................................... 79 
13.8.1. Adverse Events .................................................................................................................. 79 
13.8.2. Clinical Laboratory Evaluation ......................................................................................... 81 
13.8.3. Global Physical Examination ............................................................................................ 82 
13.8.4. Vital Signs, Physical Findings and Other Observations Related to Safety ....................... 82 
13.8.4.1. Vital Sign Measurements Over Time ............................................................................. 82 
13.8.4.2. Body weight ................................................................................................................... 82 
13.8.4.3. Individual Patient Changes ............................................................................................. 83 
13.8.5. ECG ................................................................................................................................... 83 
13.8.6. Coagulation parameters ..................................................................................................... 83 
13.9. CONCOMITANT TREATMENTS ..................................................................................... 83 
13.10. COMPLIANCE .................................................................................................................... 84 
13.11. INTERIM ANALYSIS AND DATA MONITORING ........................................................ 84 
14. GENERAL ETHICAL CONSIDERATIONS .................................................................... 84 
14.1. ETHICAL CONDITIONS ................................................................................................... 84 
14.2. ETHICS COMMITTEE AND LEGAL REQUIREMENTS ................................................ 84 
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14.3. PATIENT'S INFORMATION LEAFLET AND INFORMED CONSENT  FORM ........... 85 
14.4. PERSONAL DATA PROTECTION ................................................................................... 86 
14.5. INSURANCE POLICY ........................................................................................................ 86 
15. ADMINISTRATIVE PROCEDURES ................................................................................ 86 
15.1. PROTOCOL AMENDMENT .............................................................................................. 86 
15.2. SOURCE DOCUMENTS, INVESTIGATOR'S FILE STORAGE ..................................... 87 
15.3. END OF THE STUDY ......................................................................................................... 87 
15.3.1. Definition of the End of Study .......................................................................................... 87 
15.3.2. Early Study Termination ................................................................................................... 88 
15.3.2.1. Early Study Termination Decided by the Sponsor ......................................................... 88 
15.3.2.2. Early Study Termination Decided by the Competent Authorities.................................. 88 
15.4. AUDIT .................................................................................................................................. 88 
15.5. INSPECTION ....................................................................................................................... 89 
15.6. CONFIDENTIALITY .......................................................................................................... 89 
15.7. CLINICAL STUDY REPORT ............................................................................................. 89 
15.8. STUDY RESULTS COMMUNICATION .......................................................................... 89 
15.9. STUDY RESULTS PUBLICATION ................................................................................... 89 
16. REFERENCES ...................................................................................................................... 91 
17. APPENDICES ....................................................................................................................... 94 
17.1. DECLARATION OF HELSINKI ........................................................................................ 95 
17.2. SAE REPORT FORM .......................................................................................................... 99 
17.3. PREDEFINED LIMITS OF LABORATORY AND VITAL SIGN POTENTIALLY 
CLINICALLY SIGNIFICANT CHANGES AND VALUES ............................................ 102 
 
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SYNOPSIS 
 
Name of Sponsor: 
Pierre Fabre Médicament represented by the Institut de Recherche Pierre Fabre (IRPF) 
Name of Finished Product: 
Not applicable 
Name of Active Substance:  
F373280 (Panthenyl-Ester of DHA) 
Title of the Study: 
Efficacy and safety study of F373280 for maintenance of sinus rhythm after electrical 
cardioversion in patients with persistent Atrial Fibrillation and Chronic Heart Failure. 
 
Abbreviated Title: 
Not applicable 
Study Coordinating Investigator: 
Pr Savina NODARI 
 
Study Centres: 
International, multicentric 
Publication / Rationale: 
F373280 is a new therapy based on DHA delivery (pro-drug) developed for the maintenance 
of sinus rhythm after electrical cardioversion in persistent atrial fibrillation (AF) patients with 
chronic heart failure. 
The results of a pharmacological study performed in animals evidenced that DHA reduces the 
duration of Atrial Fibrillation (AF) induced by burst pacing.[1] 
Moreover, the effectiveness of PUFA (PolyUnsaturated Fatty Acid) has been proven in the 
following conditions: 
− 
prevention of Atrial Fibrillation recurrence in patients with persistent Atrial 
Fibrillation, in co-administration with amiodarone (add on therapy) [2]  
− 
Improvement of ventricular functional parameters, morbi-mortality and duration 
of hospitalisation in patients with heart failure [3, 4, 5] 
Taking into account these studies, it seems that DHA might be of therapeutic interest in the 
treatment of patients with both persistent atrial fibrillation and chronic heart failure. 
This phase IIa study is designed to assess the efficacy and the safety of the investigational 
product (F373280) for maintenance of sinus rhythm after electrical cardioversion (ECV) in 
patients with persistent atrial fibrillation and chronic heart failure. 
Planned Study Period: 
January 2013 –  April 2014 
Clinical Phase: IIa 
 
Objectives: 
Primary: 
- Efficacy of F373280 on the maintenance of sinus rhythm after direct electrical 
cardioversion in patients with persistent atrial fibrillation and chronic heart failure 
Secondary: 
- Efficacy of F373280 on the efficiency of direct electrical  cardioversion 
- Effect of F373280 on echocardiographic parameters 
- Safety and tolerability of F373280 
Methodology: 
- International, multicentre, randomised, double-blind, placebo-controlled 
- Selection period 
- Start of treatment 4 weeks before ECV 
• 
Condition to ECV:  
− 
INR 2-3 (anti-vitamin K should be given at least 3 weeks before ECV) 
− 
No spontaneous cardioversion before ECV 
- Follow-up 20 weeks after visit 3  (ECV visit) 
• 
Condition: successful ECV or spontaneous CV 
- Cardiac monitoring: 
• 
7-days continuous ECG ambulatory recording (Holter ECG)  between visit 3 (ECV 
visit) and visit 4  (week 5) in patients with sinusal rhythm 
• 
TTEM: daily transmission from week 6 to week 8; then every two days from week 
9 to week 24, and in case of AF symptoms 
- Treatment duration: 24 weeks 
Study Schedule 
9 visits will be scheduled: 
- V1/ W-4 to W-1: selection visit (7 to 28 days before the inclusion visit)  
- V2/ D1: Inclusion visit (start of treatment) 
- V3/ W4 (D28 -2/+7 days): cardioversion visit (Outpatient or hospitalization according to 
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clinical practice of the centre) (installation of the Holter device) 
- V4/ W5 (D35± 2 days): follow-up visit (removing of the Holter device and installation of 
the TTEM) 
- V5/ W8 (D56± 7 days): follow-up visit 
- V6/ W12 (D84 ± 7 days): follow-up visit 
- V7/ W16 (D112 ± 7 days): follow-up visit 
- V8/ W20 (D140 ± 7 days): follow-up visit 
- V9/ W24 (D168 ± 7 days): final study visit 
 
Number of  Patients: 
76 x 2 patients  
Diagnosis and Criteria for Inclusion: 
Inclusion Criteria: 
Demographic Characteristics and Other Baseline Characteristics: 
1. 
Men or women aged more than 18 years (inclusive), 
2. 
Patients with persistent AF between 7 days and 6 months duration for whom electrical 
cardioversion is warranted. 
3. 
History of first documented persistent AF less than 1 year 
4. 
History of ischemic or non ischemic heart failure  
5. 
NYHA class I or II chronic heart failure at selection and at inclusion 
6. 
Reduced left ventricular ejection fraction between 30% and 45% inclusive (using the 
two-dimensional echocardiography biplane Simpson’s rule) ) at selection and at 
inclusion 
7. 
On appropriate, stable medical treatments for heart failure, including a diuretic and/or 
angiotensin-converting enzyme, and/or angiotensin-receptor blocker and/or 
mineralocorticoid receptor (MR) antagonists, and/or betablockers 
8. 
Left atrial area ≤ 40 cm² ) at selection and at inclusion 
9. 
Patients treated or having to be treated by anti-vitamin K 
10. For female patient of child-bearing potential : 
• 
in all the countries except Italy:  
- 
use of an effective method of contraception (hormonal contraception or intra-
uterine device) assessed by the investigator, for at least 2 months before the 
selection in the study, and agreement to go on using it during the whole duration of 
the study and up to 1 month after the last dose of the study treatment 
- 
documented as surgically sterilized 
 
• 
in Italy only:  
- 
absolute abstention from sexual intercourse during the whole duration of the study 
and for a month after the end of the study or 
- 
use of double barrier contraception method (use of effective medical contraception 
method) from at least 2 months before the start of the study to the entire duration of 
the study and for a month after the end of the study or 
- 
documented as surgically sterilized 
 
11. For female patient of child-bearing potential: negative urine pregnancy test at inclusion 
12. For male with a child-bearing potential partner (In Italy only): 
- 
Absolute abstention from sexual intercourse during the whole duration of the study 
and for a month after the end of the study or 
- 
 use of double barrier contraception method (use of condom for male and effective 
contraception method for the partner) from the entire duration of the study to a 
month after the end of the study. 
  
Ethical /legal considerations: 
13. Having signed his/her written informed consent, 
14. Affiliated to a social security system, or is beneficiary (if applicable in the national 
regulation) 
 
Non-Inclusion Criteria: 
Criteria related to pathologies: 
1. 
History of first documented episode of persistent AF more than 1 year 
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2. 
More than two successful cardioversions (electrical or pharmacological) in the last 6 
months 
3. 
Secondary Atrial Fibrillation due to alcohol or severe valvular heart disease (grade III to 
IV) 
4. 
NYHA class III or IV heart failure at selection or at inclusion 
5. 
Thyroid disease uncontrolled by treatment: TSH ± T4L ± T3L to be checked in case of 
treatment for thyroid disease 
6. 
Myocardial infarction or unstable angina or presence of unstable ischemic 
coronaropathy assessed by coronarography or cardiac stress test (Echo stress, exercice 
stress test, nuclear or MR perfusion evaluation methods) within 6 months before 
selection 
7. 
Severe chronic kidney disease (creatinine ≥ 25 mg/L or estimated glomerular filtration 
rate < 30 mL/min) at selection 
8. 
Bradycardia (HR ≤ 50 bpm) 
9. 
Hyperkalemia or hypokalemia (K>5.5 mEq/L or K < 3.5 mEq/L) at selection  
10. Cardiac surgery within 3 months before selection or planned during the study duration 
 
 
Criteria related to treatments: 
11. Previously ineffective pharmacological or electrical cardioversion 
12. Concomitant treatment with any anti-arrhythmic drug (within 7 days prior to selection), 
except stable dose of digoxin, betablockers, calcium-blockers 
13. Previous treatment with oral amiodarone within 12 months prior to inclusion 
14. Previous treatment with intravenous amiodarone within 6 months prior to inclusion 
15. Patient requiring a cardiac resynchronization therapy (CRT) or having undergone CRT 
implantation within the last 6 months  
16. Treatment with any Polyunsaturated Fatty Acid (PUFA) within the last 3 months 
17. Dietary supplement with ω3 or ω6 according to investigator’s judgement 
18. Having undergone any form of ablation therapy for AF 
19. Patient treated with other anticoagulant treatment than antivitamin K: thrombin inhibitor 
such as Dabigatran or treated with antiaggregant P2Y12 inhibitors such as Clopidogrel 
or Prasugrel 
 
Other criteria: 
20. Patient liable not to comply with protocol instructions and/or with treatment, in the 
investigator’s opinion 
21. Patient having taken part in a clinical trial in the preceding 2 months or taking part in a 
trial at the time of selection 
22. Patient linguistically or mentally unable to understand the nature, objectives and 
possible consequences of the trial, or refusing to patient himself/herself to its constraints 
23. Patient family member or work associate (secretary, nurse, technician,..) of the 
Investigator 
24. Patient having forfeited his / her freedom by administrative or legal award or being 
under guardianship 
25. Breastfeeding female patient 
 
Exclusion criteria before V3: 
Patients not stabilized for INR (i.e. values between 2 and 3) on at least 3 consecutive weekly 
tests performed before ECV will be excluded from the study, unless the presence of atrial 
thrombosis may be excluded with ECHO –TE (trans-esophageal echocardiograph) performed  
in the same day (before ECV) 
ECV will be performed in patients without dyskalemia 
If necessary for obtaining stabilized INR between 2 and 3, the ECV (and following visits) 
could be postponed by 7 days. 
Test Product:  
F373280  
Soft Capsules  
Dose: 
Arm with 1g of F373280 
Mode of Administration: 
Oral, one capsule each evening with dinner. 
Duration of Treatment: 
24 weeks of treatment exposure with F373280 (25 weeks if ECV postponed by 1 week) 
Reference Therapy 
Placebo soft capsules 
Placebo will be administered in the same conditions as the tested product. 
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Mode of Administration: 
Oral, one capsule each evening with dinner 
Evaluation Criteria: 
Efficacy evaluation variables: 
 
Primary evaluation variable: 
- Time to first Atrial Fibrillation recurrence defined by the first episode of Atrial Fibrillation 
lasting for at least 10 minutes (Follow up of 20 weeks after  visit 3 (ECV visit) 
Handling of AF recurrences: 7-day continuous ECG (5-leads/2 or 3 channels) ambulatory 
recording (holter ECG) between visit 3 (ECV visit) and visit 4 (week 5). Then, the follow 
up will be documented using the TTEM: daily transmission from week 6 to week 8. Then, 
every two days from week 9 to week 24. 
For randomised patients with spontaneous cardioversion before ECV, the recurrence of AF 
will be assessed after visit 3 (week 5).  
Moreover, during this TTEM period, if patient experiences any AF symptoms, it should be 
recorded and documented using the TTEM.  
All ECG traces will be evaluated by a Central Reading Laboratory. 
 
Secondary evaluation variables: 
During the 7-day continuous ECG monitoring, 
• 
Numbers of AF episodes 
• 
Duration of AF episodes 
 
Clinical parameters: 
During the whole study: 
• 
Number of recurrence of symptomatic AF episodes 
• 
EHRA score 
• 
Hospitalization for cardiovascular events 
• 
Hospitalization for thromboembolic stroke 
• 
All cause of hospitalization 
 
Cardioversion: 
• 
Assessment of spontaneous cardioversion 
• 
Assessment of successful cardioversion 
• 
Number of patients needing an other cardioversion after the initial ECV 
 
Other: 
• 
Evolution of echocardiographic parameters (from V4 to V6 and V9) (Left atrial 
diameter (mm), Left atrial area (cm²), Left atrial volume (mL), Left atrial 
volume/BSA (mL/m2), Left ventricular ejection fraction (%),Left ventricular 
volume (mL), Left ventricular volume/BSA(mL/m2, Left ventricular end diastolic 
diameter (mm), Left ventricular end diastolic volume (mL) Left ventricular end 
systolic diameter (mm), Left ventricular end systolic volume (mL)) 
• 
Evolution of omega 3 index and intra erythrocyte DHA (For this assessment 
samples will be centralized). 
 
Safety criteria: 
- Adverse events (observed and / or spontaneously reported) 
- Vital signs (Blood pressure (supine and standing), heart rate 
-  Physical examination (body weight),  
- Standard 12-lead ECG: heart rate (bpm), PR (ms), QRS (ms), QT (ms), repolarisation 
patterns (ECG not centralized). 
- Haematology: haematocrit, haemoglobin, RBC, WBC, differential count, platelets 
- Biochemistry: sodium, potassium, bicarbonate, chloride, alkaline phosphatase, gamma 
GT, albumin, total bilirubin, conjugated bilirubin, creatinin, aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), fasting glucose, total cholesterol, cholesterol 
(HDL, LDL), triglycerides, creatin phosphokinase (CPK) fibrinogen (local laboratory) 
- Coagulation parameters: Activated partial thromboplastin time (aPTT), thrombin clotting 
time (TCT), INR (local laboratory), Prothrombine Time (PT) 
Statistical Methods: 
Sample Size: 
Assuming an AF recurrence rate under placebo of 85%, a power of 80%, an alpha risk of 5% 
and a rate of not assessable patients of 15%, 76 randomised patients per group will be 
necessary, using a log-rank test of survival curves, a difference between groups of 20%.  
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Primary Efficacy Analysis 
The primary analysis, performed on the Full Analysis Set (FAS: all randomised patients with 
at least one dose of treatment and with a successful cardioversion observed at visit 3), will be 
a survival analysis using the Kaplan Meier method and Cox regression model. 
Secondary Analyses  
All secondary efficacy criteria will be described and compared using appropriate tests on the 
FAS. 
Safety Analyses 
Descriptive statistics will be performed on the Safety Set (all randomised patients with at 
least one dose of treatment)  
 
 
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STUDY FLOW-CHART 
 
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F373280 CA 201
V1
V2
V3
V4
V5
V6
V7
V8
V9
Weeks
W-4 to W-1
D1
W4
 (28 -2D/+7 D) 
W5
 (35 +/-2 D)
W8 
(56+/-7D)
W12 
(84+/-7D)
W16 
(112+/-7D)
W20 
(140+/-7D) 
W24 
(168+/-7D)
Outpatient or Hospitalization (1)
X
Informed consent
X
Demographic characteristics
X
Medico-surgical history
X
Concomitant disease
X
Concomitant treatment
X
X
X
X
X
X
X
X
X
Habits
X
Global physical examination (body weight)
X
X
X
X
X
X
X
X
Echocardiography
X
X
X
X
X
Eligibility criteria check
X
X
Blood pressure, heart rate 
X
X
X
X
X
X
X
X
X
12-Lead  ECG Recording
X
X
X
X
X
X
X
X
INR 
 
 
 (2)
X
X
X
X
X
aPTT, TCT 
X
X
X
X
X
X
X
X
Biochemistry
X
X
Hematology
X
X
X
X
Urinary pregnancy test
X
X
Red Blood Cell concentrations of DHA 
X
X
X
X
Treatment allocation
X
X
IVRS
X
X
X
X
ECV (3)
X
Drug administration 
 
 
 
 
 
 
 
 
Adverse events recording
X
X
X
X
X
X
X
X
Holter ECG 
 (4)
 
 (5)
TTEM (6)
 
 
 
 
(3) In patients with AF
(1) Outpatient or hospitalization according to clinical practice of the centre (less or more than 24 hours)
(6) TTEM everyday from week 6 to week 8. Then every 2 days from week 9 to week 24. In case of AF symptoms. In case of AF recurrence for at least 10 minutes and the patient does not 
stop  the study treatment then TTEM every 4 weeks
(2) In case of AVK introduction: INR 2 to 3 times a week, then weekly untill the ECV, then every 4 weeks after ECV.
(5) 7-day Holter ECG
(4) 24-hour Holter ECG
 
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LIST OF ABBREVIATIONS 
 
aPTT 
Activated partial thromboplastin time 
AE 
: 
Adverse event 
AERP 
Atrial effective refractory period 
AF 
: 
Atrial fibrillation 
ALA 
Alpha-linoleic acid 
ALT 
: 
Alanine aminotransferase 
AST 
: 
Aspartate aminotransferase 
AUC 
: 
Area under the plasma concentration versus time curve 
AUCinf 
: 
Total area under the curve extrapolated to infinity 
AVK 
Anti vitamin K 
βHCG 
: 
beta human chorionic gonadotrophin 
BLQ 
: 
Below the limit of quantification 
BMI 
: 
Body mass index 
BP 
Blood pressure 
BSA 
: 
Body Surface Area 
CEP 
Protocol evaluation committee 
CHF 
: 
Congestive heart failure 
CHMP 
: 
Committee for medicinal products for human use 
Cmax 
: 
Maximum concentration 
Cmin 
Minimum concentration 
CNALV 
: 
Clinically noteworthy abnormal laboratory value 
CPK 
Creatin phosphokinase 
CPP 
: 
Comité de protection des personnes  
CRA 
: 
Clinical research associate 
CRT 
Cardiac resynchronization therapy 
CSC 
: 
“Clinically Significant Change”, i.e., Predefined potentially clinically significant 
change leading to a potentially clinically significant value (vital signs) 
CV 
: 
Coefficient of variation 
DBP 
: 
Diastolic blood pressure 
DHA 
: 
Docosahexaenoic acid 
EC 
: 
Ethics committee 
ECG 
: 
Electrocardiogram 
ECHO –TE 
Trans-esophageal echocardiograph 
ECV 
: 
Electrical cardioversion 
EHRA 
European heart rhythm association 
EPA 
Eicosapentaenoic acid 
eCRF 
Electronic case report form 
FAS 
: 
Full analysis set 
Fe 
: 
Fraction of the administered drug excreted in urine 
GCP 
: 
Good clinical practice 
GFR 
:  Glomerular Filtration Rate 
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HBs 
: 
Hepatitis B antigen 
HCV 
: 
Hepatitis C virus 
HDL 
High density lipoprotein 
HF 
Heart failure 
HIV 
: 
Human immunodeficiency virus 
HR 
: 
Heart rate 
ICH 
: 
International conference on harmonisation of technical requirements for 
registration of pharmaceuticals for human use 
IDMC 
: 
Independent data monitoring committee 
INR 
International normalized ratio 
IRPF 
: 
Institut de Recherche Pierre Fabre 
IVRS 
Interactive voice response system 
LAA 
Left atrial area 
LC/MS-MS : 
Liquid chromatography with tandem mass spectrometry 
LDL 
Low density lipoprotein 
LOQ 
: 
Limit of quantification 
LVEF 
Left ventricular ejection fraction 
MedDRA 
: 
Medical dictionary for regulatory activities 
MR 
Mineralocorticoid receptor 
MR perfusion 
Magnetic Resonance perfusion 
MTD 
: 
Maximum tolerated dose 
N 
: 
Number of determinations or replicates 
NOAEL 
: 
No observed adverse effect level 
NYHA 
New York heart association 
od 
: 
Once a day 
PC 
: 
“Predefined Change”, i.e., Predefined potentially clinically significant change (lab 
or vital signs) 
PCA 
: 
PC leading to an out-of-range value (lab values) 
PFB 
: 
Pierre Fabre Biométrie 
POC 
Proof of concept 
PUFA 
: 
PolyUnsaturated fatty acid 
PK 
: 
Pharmacokinetics 
p.o. 
: 
Per os 
PP 
: 
Per protocol data set 
RBC 
: 
Red blood cells 
SAE 
: 
Serious adverse event 
SBP 
: 
Systolic blood pressure 
SD 
: 
Standard deviation 
T1/2 
: 
Terminal half-life 
T0 
: 
Time of drug administration 
Tmax 
: 
Time to reach the maximal concentration 
TCT 
Thrombin clotting time 
TEAEs 
Treatment emergent adverse events 
TTEM 
TransTelephonic ECG monitoring 
VTP 
: 
Ventricular tachypacing 
WBC 
White blood cells 
WHO-DRUG : 
World health organization drug reference list 
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1. INTRODUCTION AND STUDY RATIONALE 
1.1. 
TARGET PATHOLOGY AND THERAPY 
Atrial Fibrillation (AF) is a supraventricular arrhythmia characterized by uncoordinated atrial 
electric activity with consequent deterioration of atrial mechanical function. It is the most 
common sustained cardiac rhythm disorder, increasing in prevalence with age. Haemodynamic 
impairment and thromboembolic events related to AF result in significant morbidity and mortality 
[7]. 
In 2009, Decision Resources estimated that there were 7.8 million diagnosed prevalent cases of 
atrial fibrillation (AF) in US, Europe and Japan. This age-related pathology should increase to 9.4 
million cases in 2019.  
Except for the conventional class I and class III anti-arrhythmic agents, the PUFAs 
(Polyunsaturated Fatty Acids) constitute one emerging antiarrhythmic therapy. These compounds 
potently address the AF substrate by directly targeting both the electrical and the structural 
remodelling of the deficient atria. The n-3 PUFAs, essential for human, are ALA, EPA and DHA. 
First, PUFAs specifically modulate ionic channels by fastening their inactivating mode which 
renders these compounds selective for pathological situations (such as AF) without any major 
effect in normal conditions. PUFAs are “open Kv1.5 channel blockers” leading to a lengthening of 
atrial action potential duration and are “persistent Nav1.5 channel blockers” leading to 
hyperpolarization of diastolic resting potential. Second, PUFAs influence structural remodelling 
through their anti-inflammatory effects as they directly compete with arachidonic acid in the 
production of inflammatory eicosanoids. In summary, PUFAs share unique, well-tolerated 
antiarrhythmic potential by interacting with the electrical and structural remodelling during 
sustained AF. In animal studies, it was recently demonstrated that DHA is particularly effective in 
pathologic conditions such as ischemia and/or atrial fibrillation. 
The potential anti-arrythmic effects of a PUFA was previously developed in atrial fibrillation: 
nicotinyl ester of DHA (pro-drug based on DHA delivery) were assessed in a two-week 
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ventricular tachypaced canine model. Dogs were subjected to 4 weeks of medication prior to 
undergoing an electrophysiology study, and received either placebo or nicotinyl ester of DHA. 
Dogs were tachypaced at 240 beats per min for the final two weeks of the treatment plan. The 
results showed that the tested PUFA reduced the duration of atrial fibrillation (AF) induced by 
burst pacing, and the incidence of sustained AF, compared to dogs treated with the placebo [1]. 
In clinical practice, Nodari and coll assessed n-3 Polyunsaturated Fatty Acids in the prevention of 
atrial fibrillation recurrences after electrical cardioversion. All included patients were treated with 
amiodarone and a renin-angiotensin-aldosterone system inhibitor. The 199 patients were assigned 
either to placebo or n-3 PUFAs 2 g/d and then underwent direct electrical cardioversion (ECV) 4 
weeks later. The primary end point was the maintenance of sinus rhythm at 1 year after 
cardioversion. At the 1-year follow up, the maintenance of sinus rhythm was significantly higher 
in the n-3 PUFAs treated patients compared with the placebo group (hazard ratio, 0.62 [95% 
confidence interval, 0.52 to 0.72] and 0.36 [95% confidence interval, 0.26 to 0.46], respectively; p 
= 0.0001). The study concludes that in patients with persistent atrial fibrillation on amiodarone 
and a renin-angiotensin-aldosterone system inhibitor, the addition of n-3 PUFAs 2 g/d improves 
the probability of the maintenance of sinus rhythm after direct current cardioversion [2]. 
Previously, during the World Congress of Cardiology in 2006, an abstract reported the 
effectiveness of PUFA on top of traditional treatment (amiodarone, beta blockers, renin-
angiotensin-aldosterone system inhibitor) in the prevention of AF relapses in patients having 
undergone ECV. In the PUFA group, AF relapses were significantly lower than placebo group at 
one month (3.3% vs 10%; p=0.043), at 3 months (10% vs 25%; p=0.004) and at 6 months (13.3% 
vs 40%; p<0.0001) [19]. 
In contrast, in the general AF population (paroxystic atrial fibrillation and persistent atrial 
fibrillation), PUFAs failed to prove their efficacy [7] because of the absence of cardiac 
remodelling or because of a short pre-treatment duration before ECV (1 week) [8].The effect of 
PUFAs were only observed in patients with persistent AF on add on therapy and after a sufficient 
pre-treatment before ECV. Persistent AF is commonly associated to heart failure. Previous studies 
performed in heart failure population demonstrated the benefit of PUFAs on the improvement of 
functional ventricular parameters and morbi-mortality, and on the reduction of hospitalisation [3, 
4, 5]. 
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Nodari and coll [3] performed a trial in patients with a chronic heart failure (NYHA I to III and 
LVEF< 45%). After a treatment of 133 patients with PUFAs (n=67) or placebo (n=66) at a dosage 
of 5 g/day for 1 month, then 2 g/day for 11 months, the n-3 PUFAs group and the placebo group 
differed significantly (p <0.001) in regard to:  
− LVEF (increased by 10.4% and decreased by 5.0%, respectively) 
− peak VO2 (increased by 6.2% and decreased by 4.5%, respectively) 
− exercise duration (increased by 7.5% and decreased by 4.8%, respectively) 
− mean New York Heart Association functional class (decreased from 1.88+/- 0.33 to 1.61 
+/- 0.49 and increased from 1.83+/- 0.38 to 2.14 +/- 0.65, respectively).  
The hospitalization rates for HF were 6% in the n-3 PUFAs and 30% in the placebo group  
(p <0.0002). 
Moertl and coll [4] performed a dose-ranging study in patients with a more severe chronic heart 
failure (NYHA III and IV and LVEF < 35%). It was a double-blind, randomised, controlled pilot 
trial in 43 patients treated with PUFAs or placebo for 3 months (1 g/d n3-PUFA (n = 14), 4 g/d 
n3-PUFA (n = 13), or placebo (n = 16)). After treatment, left ventricular ejection fraction 
increased in a dose-dependent manner (P = 0.01 for linear trend) in the 4 g/d (baseline vs 3 
months [mean ± SD]: 24% ± 7% vs 29% ± 8%, p = 0.005) and 1 g/d treatment groups (24% ± 8% 
vs 27% ± 8%, P = 0.02). 
No changes in any investigated parameters were noted with placebo. 
Taking into account these studies performed with PUFAs, it seems that the best target for DHA is 
persistent AF in patients with heart failure. The aim of this proof of concept study is to assess in 
stand alone therapy (without association of other anti-arrhythmic treatments), the effect of 
F373280 in patients with persistent atrial fibrillation and heart failure in the maintenance of sinus 
rhythm after electrical cardioversion. 
1.2. 
INFORMATION ON THE TEST PRODUCT 
F373280 or panthenyl ester of DHA (docosahexaenoic acid) is the mono-ester of panthotenic 
alcohol and DHA, selected to be developed for the management of atrial fibrillation.  
F373280 is a prodrug of DHA. 
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A brief summary of F373280 known characteristics is presented in this section. For further details, 
please refer to the F373280 Investigator’s Brochure. [1] 
1.2.1. 
Chemical and pharmaceutical characteristics 
1.2.1.1. 
Nomenclature and structure 
Chemical name (IUPAC):  
(4Z,7Z,10Z,13Z,16Z,19Z)-3-((R)-2,4-dihydroxy-3,3-diméthylbutanamido) 
propyl 
docosa-
4,7,10,13,16,19-hexaenoate 
Structural formula: 
O
O
O
O
NNHH
O
O
OHH
O
OHH
 
Laboratory code: F373280 
Molecular formula: C31H49NO5 
Molecular mass: 515.7 
1.2.1.2. 
Physical and chemical general properties 
Appearance: Clear oily viscous liquid 
Solubilities:  
− Water: Practically insoluble 
− Alcohol: Very soluble  
− Trimethylpentane: Slightly soluble  
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1.2.2. 
Non-clinical Data 
Non-clinical data are exhaustively detailed in the Investigator’s brochure [1]. A brief summary is 
provided below. 
1.2.2.1. 
Pharmacological profile 
F373280 (mono-ester of panthotenic alcohol and DHA) is a novel pro-drug of DHA which exerts 
antiarrhythmic properties by interacting with the electrical and structural remodelling of the atria.  
Experimental investigations were conducted in HEK293 cell line transfected with human Kv1.5 
channel using the whole cell patch clamp technique to evaluate whether F373280 could block the 
sustained component of IKv1.5. F373280 concentration-dependently reduced Kv1.5 channel activity 
with an IC50 value of 13.7 µM. 
The effects of F373280 on atrial effective refractory period (AERP) were investigated in 
anesthetized pig using a conventional pacing protocol through epicardial electrodes placed on the 
left atrium. F373280 administered as a bolus and an infusion (10 mg/kg) significantly increased 
AERP (23.8 ± 2.2 ms versus -7.3 ± 11.5 ms in the presence of vehicle, P<0.05). In addition, 
F373280 was devoid of significant effect on the hemodynamic and the ECG intervals.  
Proof of the pharmacological concept was performed with a different DHA derivative named: 
Nicotinyl ester of DHA (pro-drug based on DHA delivery). Ventricular tachypacing (VTP)-
induced congestive heart failure (CHF) provides a clinically-relevant animal model of AF 
associated with structural remodelling, as is often seen clinically. It has been shown that sustained 
oral PUFA administration suppresses CHF-induced AF-promotion and fibrosis in the VTP canine 
model. Nicotinyl ester of DHA was tested in this model, at 1g/day and 5g/day, during 4 weeks, to 
prevent CHF-related atrial structural remodelling and AF promotion in dogs. Nicotinyl ester of 
DHA dose dependently reduced heart failure-induced increases in atrial fibrillation duration (989 
± 111 sec, n=5 in the presence of placebo versus 637 ± 196 sec, n=5 in the presence of 1g/kg/d 
Nicotinyl ester of DHA and 79 ± 51 sec, n=5, in the presence of 5g/kg/d Nicotinyl ester of DHA 
The protective effect of Nicotinyl ester of DHA was associated with a marked increase of plasma 
level of DHA and important incorporation of DHA in the left atrial tissue. Because F373280 
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similarly to Nicotinyl ester of DHA increases plasma level of DHA, it could be estimated that the 
compound may exert a similar protective effect [1]. 
1.2.2.2. 
Safety pharmacology 
A battery of safety pharmacology studies was performed to evaluate the effects of F373280 on the 
central nervous, cardiovascular and respiratory systems. Data of these studies are exhaustively 
detailed in the Investigator’s brochure [1]. 
No particular alerts were evidenced with F373280. 
1.2.2.3. 
Toxicology profile 
 
Concerning the toxicological data, 4-week and 26-week repeat-dose studies in rat and dog were 
performed. Compared to the high administered doses of F373280 (500 to 2000 gm/kg/day), low 
circulating concentrations of F373280 were measured.  
During these toxicity studies , no toxicity was observed in rat after 4 and 26 weeks of dosing and 
in dog after 4 weeks of dosing. A NOAEL of 2000 mg/kg/day was established in these repeat 
toxicity studies.  
During the 26-week toxicity study in dogs, the NOAEL was set at 1000 mg/kg/day based on 
changes observed on red blood cell parameters. 
Based on toxicological profiles, F373280 is considered to support the proposed clinical trial. 
 
1.2.2.4. 
Pharmacokinetic data  
According to animal studies described in the Investigator’s brochure [1], the non-clinical 
pharmacokinetic profile of F373280 is not associated with particular alerts concerning the 
proposed clinical phase IIa study. 
1.2.3. 
Clinical data 
Part A: single dose 
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6 consecutive single ascending doses were tested (0.5g, 1g, 2g, 4g, 8g and 16g) on 6 independent 
cohorts of 8 subjects (6 verum + 2 placebo). 49 subjects were treated and 48 completed the study. 
No Serious Adverse Events occurred in the course of the study. 
Regarding the reported Treatment Emergent Adverse Events (TEAEs) that were judged by the 
Investigator as having a causal relationship with the study drug administration in the absence of 
an alternative explanation, 4 were observed in the placebo group (palpitation, dizziness in 
standing position , 2 symptomatic orthostatic hypotensions without loss of consciousness) and 4 in 
the group of F373280 at the dosage of 16g (meteorism, liquid stool, symptomatic orthostatic 
hypotension and dizziness in standing position). None of these adverse events were reported in the 
groups of F373280 at the dosages of 0.5g, 1g, 2g, 4g and 8g. 
After a single administration of the different tested doses no difference between the tested product 
and placebo has been reported, regarding vital signs (heart rate, systolic blood pressure and 
diastolic blood pressure), biological parameters (related to coagulation: platelets and fibrinogen) 
and coagulation parameters (bleeding time, prothrombin time/INR, activated partial 
thromboplastin time, thrombin clotting time). Variations of these parameters were within the 
physiological ranges. 
After single oral administration of F373280 from 0.5g to 16 g in 36 young male healthy subjects 
(6 per dose level), the following was observed: 
 
- F373280: Whatever the tested dose there is no circulating F373280 in plasma: only few, 
sparse and non consecutive samples with quantifiable level of F373280 close to LOQ were 
observed. This confirm that F373280 is a prodrug. 
- Panthenol: Cmax and AUC increased with the administered dose between 0.5 and 16g. 
Panthenol concentrations were rapidly cleared from plasma with a mean terminal half-life 
around 2 hours. 
- DHA: after 0.5 and 1g, low increased in DHA plasma concentrations compared to the 
baseline levels led to a high inter-individual variability of the corresponding PK parameters. 
Plasma exposure in DHA increased with the administered dose between 2 and 16g with no 
departure from proportionality (baseline corrected parameters). 
 
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Part B: Multiple dose  
Three consecutive repeated ascending doses (1, 2 and 4g) were tested on 3 independent cohorts of 
12 subjects (9 verum + 3 placebo, double blind). 36 subjects completed the study. Each treatment 
was administered over a period of 28 days. Pharmacokinetic parameters were assessed over a 
period of 14 days.  
Among the TEAE judged by the investigator as suspected to F373280 5/9 TEAE were classified 
according the SOC in vascular system disorder with orthostatic hypotension (2 in the 1 g group, 1 
in the 2 g group and 2 in the 4 g group) and 4/9 were classified in nervous system disorder with 3 
dizziness (2 in the 2 g group and 1 in the 4 g group) and 1 migraine (in the 1 g group). These 
TEAE have already been reported with Poly Unsaturated Fatty Acids and are commonly observed 
in phase I studies. 
After a repeated administration of the different tested doses, no difference between the tested 
products and placebo was reported regarding vital signs (heart rate, systolic blood pressure and 
diastolic blood pressure), biological parameters. The assessment of coagulation parameters and 
platelet function after administration of repeated dose of F373280 did not report any bleeding 
issue. The reported changes in coagulation parameters and platelet function were within 
physiological ranges. 
After a 14-day repeated oral administration of F373280 from 1 g to 4 g, the following was 
observed: 
 Panthenol: Cmax and AUC increased with the administered dose between 1 and 4 g. No 
accumulation of panthenol in plasma was observed. 
 
 DHA: Plasma exposure increased with dose. A 2-fold accumulation in total plasma exposure 
of DHA was observed after 14 days of administration, whatever the administered dose. 
 
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1.3. 
STUDY RATIONALE 
F373280 is a new therapy based on DHA delivery (pro-drug) developed for the maintenance of 
sinus rhythm after electrical cardioversion in persistent atrial fibrillation (AF) patients with 
chronic heart failure. 
The results of a pharmacological study performed in animals evidenced that DHA reduces the 
duration of atrial fibrillation (AF) induced by burst pacing [1]. 
Moreover, the effectiveness of PUFA has been proven in the following conditions: 
- 
Prevention of atrial fibrillation recurrence in patients with persistent atrial fibrillation in 
co-administration with amiodarone (add on therapy) [2], 
- 
Improvement of ventricular functional parameters, morbi-mortality and duration of 
hospitalisation in patients with heart failure [3, 4, 5]  
Taking into account these studies, it seems that DHA might be of therapeutic interest in the 
treatment of patients with both persistent atrial fibrillation and chronic heart failure. 
This phase IIa study is designed to assess the efficacy and the safety of the investigational product 
(F373280) for maintenance of sinus rhythm after electrical cardioversion in patients with 
persistent atrial fibrillation and chronic heart failure. 
1.4. 
OVERALL RISK AND BENEFIT ASSESSMENT 
F373280 is a new pro-drug of DHA.  
DHA is a well-known long chain PUFAs with a long-term clinical experience in cardiovascular 
diseases. DHA is contained in several medicinal products such as Omacor, (1g of Omacor 
contains about 320 mg of DHA acid) marketed by Laboratoires Pierre Fabre for 
hypertriglyceridemia and as an adjuvant treatment for secondary prevention after myocardial 
infarction. According to the summary product characteristics of Omacor, [9]: 
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- The frequencies of adverse reactions are ranked according to the following: common (> 
1/100, < 1/10); uncommon (>1/1000 < 1/100); rare (>1/10000, < 1/1000); very rare ( < 1/10000), 
not known (cannot be estimated from the available data). 
- The reported adverse events are: 
• Infection and infestations 
Uncommon: gastroenteritis 
• Immune system disorders: 
Uncommon: hypersensitivity 
• Metabolism and nutrition disorders: 
Rare: hyperglycaemia 
• Nervous system disorders: 
Uncommon: dizziness, dysgeusia 
Rare: headache 
• Vascular disorders: 
Very rare: hypotension 
• Respiratory thoracic and mediastinal disorders:  
Very rare: nasal dryness 
• Gastrointestinal disorders: 
Common: dyspepsia, nausea 
Uncommon: abdominal pain, gastrointestinal disorders, gastritis, abdominal pain upper 
Rare: gastrointestinal pain 
Very rare: lower gastrointestinal haemorrhage 
• Hepatobiliary disorders:  
Rare: hepatic disorders  
• Skin and subcutaneous tissue disorders:  
Rare: acne, rash pruritic 
Very rare: urticaria 
• General disorders and administration site conditions: 
Rare: malaise sensation 
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• Investigations: 
Very rare: white blood count increased, blood lactate dehydrogenase increased 
Moderate elevation of transaminases has been reported in patients with hypertriglyceridaemia. 
Panthenol is a well-known substance with a long-term experience in medical, nutraceutic and 
cosmetic uses. According to the summary product characteristics of a product such as 
Bépanthene (tablet indicated in alopecia) which contains panthenol (100 mg), adverse event 
observed are rare cases of urticaria and erythema [10]. Panthenol is metabolised in panthotenic 
acid, i.e. B5 vitamin. 
Concerning toxicological studies performed results can support the administration of F373280 in 
the proposed clinical phase II study without particular alert [1]. 
Any safety warning was reported during a phase I study performed with F373280 administered to 
84 healthy volunteers in single dose in a range between 500 mg and 16 g or in repeated dose 
during 28 days in a range between 1g and 4g. Adverse events reported and related to study 
treatment were minor to moderate. The adverse events were palpitations, orthostatic hypotension, 
dizziness, meteorism and liquid stool. Most were reported in both groups (placebo and F373280) 
without a dose relationship. The assessment of coagulation parameters and platelet function after 
administration of repeated dose of F373280 did not report any bleeding concern: the reported 
changes in coagulation parameters and platelet function were within physiological ranges. 
Moreover, DHA has been associated with anticoagulant products in Atrial Fibrillation studies [2, 
8]. The range of PUFAs doses tested was between 2g to 3g (640 mg to 960 mg of DHA) and the 
range of study durations between 6 to 12 months. This association did not report a significant side 
effect of bleeding. 
DHA has already been used in heart failure patients in several studies without safety concern [3, 
4, 5]. The range of PUFAs doses tested was between 1g to 5g (1g of the tested PUFAs contains 
about 320 mg of DHA acid) and the range of study durations was between 3 months to 3.9 years. 
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Thus, inclusion of patients with no specific antiarrhythmic treatment is acceptable. They will 
receive an anticoagulant treatment to prevent the thrombo-embolic complications of AF 
(particularly stroke) and the adequate treatments to control the heart rate and heart failure.   
In conclusion, the overall available data allow in safe conditions the treatment of patients with 
persistent AF and chronic heart failure with F373280 in safe conditions. 
2. STUDY OBJECTIVES 
2.1. 
PRIMARY OBJECTIVE 
The primary objective of the study is to assess the efficacy of F373280 on the maintenance of 
sinus rhythm after direct electrical cardioversion in patients with persistent atrial fibrillation and 
chronic heart failure. 
2.2. 
SECONDARY OBJECTIVES 
The secondary objectives of the study are to assess: 
• the efficacy of F373280 on the efficiency of direct electrical cardioversion 
• the effect of F373280 on echocardiographic parameters 
• the safety and tolerability of F373280 
3. ETHICAL CONSIDERATIONS RELATING TO THE STUDY 
The trial is conducted according to Good Clinical Practices (CPMP/ICH/135/95), the National 
regulations and the Declaration of Helsinki and its subsequent amendments (see Appendix 17.1). 
This protocol and the informed consent form will be submitted for approval to independent local 
or national Institutional Review Boards/Ethics Committees before the study set up, according to 
national regulation. 
All the protocol amendments or critical events liable to increase the risks incurred by the patients 
or to compromise the validity of the study or patients' rights will be submitted to the coordinator 
and to the Ethics Committees. 
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After being informed orally and in writing of all potential risks and constraints of the trial, as well 
as their freedom to withdraw their participation at any time, patients will then sign a consent.  
A time of reflection will be given to the patients, before giving a written consent and starting the 
study procedures. 
The use of a placebo is in accordance with EMA Addendum to the guideline on antiarrhythmics 
on atrial fibrillation and atrial flutter (EMA/CHMP/EWP/213056/2010) [21] and is acceptable 
because the included patients will remain under the standard treatment of atrial fibrillation and 
chronic heart failure. Except antiarrythmics, they will receive anticoagulant (AVK), rate control 
treatment, chronic heart failure treatment. During the study, in case of AF recurrence that would 
require a cardioversion or an introduction of an anti-arrhythmic because of intolerable and/or 
uncomfortable clinical symptoms, patients will be withdrawn and the tested product stopped. 
These patients will be considered as treatment failure. 
In this study, patients will be carefully screened, particularly for their cardiac condition, with 
ECG, 24-hour holter monitor and echocardiographic data, and their biologic and coagulation 
condition. 
The study will be addressed only to patients requiring an ECV due to their persistent AF, in the 
following conditions: 
- 
ECV in patients not presenting a contra-indication,  
- 
Anticoagulation  with anti-vitamin K for at least 3 weeks before ECV,  
- 
ECV in patients with stabilized INR (i.e. values between 2 and 3) on at least 3 
consecutive weekly tests performed. Patients not stabilized for INR (i.e. values 
between 2 and 3) on at least 3 consecutive weekly tests performed before ECV will be 
excluded from the study, unless the presence of atrial thrombosis may be excluded 
with ECHO –TE (trans-esophageal echocardiograph) performed  in the same day 
(before ECV) 
 
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- 
Patients who do not revert to sinus rhythm or present an early relapse within the 
observation period after ECV will be withdrawn and the tested product stopped. 
During the whole study, patients will remain under medical control: visits in cardiology units will 
be scheduled at least every month. This follow up will include clinical signs, ECG, biological and 
coagulation parameters. Moreover, patient’s cardiac rhythm will be monitored between visits 
using daily, then every 2 days Trans Telephonic ECG Monitoring (TTEM) reviewed by a Central 
Reading Laboratory. 
Patients may withdraw from the study at any time without having to give a reason and can expect 
to receive regular conventional therapy. 
4. STUDY DESIGN 
4.1. 
OVERALL DESCRIPTION 
This phase IIa trial will be conducted as an international, multicentric, 24 weeks, double-blind, 
placebo-controlled, randomised, parallel group design, trial in 152 patients suffering from 
persistent atrial fibrillation and chronic heart failure. 
After a 1 to 4-week of run-in period without treatment, patients will be randomised into one of the 
following treatment groups: F373280 1g or placebo for 24 weeks.  
Nine visits are planned for the study: 
- 
Visit 1 (V1): W-4 to W-1: Selection visit (7 to 28 days before the Inclusion Visit) 
- 
Visit 2 (V2): D1: Inclusion visit (start of treatment)  
- 
Visit 3 (V3): W4 (D28 -2/+7D): cardioversion visit (outpatient or hospitalization 
according to clinical practice of the centre) (installation of the Holter ECG device) 
- 
Visit 4 (V4): W5 (D35 ± 2D): follow-up visit (removing of Holter ECG device and 
installation of the TTEM) 
- 
Visit 5 (V5): W8 (D56 ± 7D): follow-up visit 
- 
Visit 6 (V6): W12 (D84 ± 7D): follow-up visit 
- 
Visit 7 (V7): W16 (D112 ± 7D) : follow-up visit 
- 
Visit 8 (V8): W20 (D140 ± 7D): follow-up visit 
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- 
Visit 9 (V9): W24 (D168 ± 7D): final study visit 
4.2. 
DISCUSSION OF THE STUDY DESIGN 
4.2.1. 
Choice of the Study Population 
The target indication of F373280 will be the maintenance of sinus rhythm after cardioversion of 
patients with persistent atrial fibrillation and chronic heart failure. In the present proof of concept 
study, the evaluation will focus on patients within this indication. This target population is 
justified by: 
− The proved efficacy of PUFAs in patients with persistent atrial fibrillation with or 
without heart failure in co-administration with amiodarone (add on therapy) [2] 
− The proved efficacy of PUFAs on the improvement of ventricular functional parameters, 
morbi-mortality and duration of hospitalisation in patients with heart failure  [3, 4, 5] 
The study aim is to investigate the product effect in patients with: 
− early persistent atrial fibrillation history (less than one year) with a duration of a the 
current episode between 7 days to 6 months  
− a moderately abnormal moderately systolic heart failure (Left Ventricular Ejection 
Fraction (LVEF) between 30 to 45% as defined in the report from the American Society 
of Echocardiography’s Guideline). According to a sub-group analysis performed in 
patients with persistent atrial fibrillation associated to heart failure ( Nodari S. personnal 
data), PUFAs would be effective to prevent recurrence of AF after cardioversion in 
patients with moderately abnormal LVEF. 
 
− A Left Atrial Area (LAA) not severely abnormal (less than 40 cm2 as defined in the 
report from the American Society of Echocardiography’s Guideline). According to a 
sub-group analysis performed in patients with persistent atrial fibrillation associated to 
heart failure ( Nodari S. personnal data), PUFAs would not be effective to prevent 
recurrence of AF after cardioversion of patients with severely abnormal LAA. 
For the successful rate of electrical cardioversion, patients should have a stable medical 
treatment of heart failure and should not have myocardial infarction or unstable angina or 
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unstable ischemic coronaropathy (assessed by coronarography or cardiac stress test or effort 
test within 6 months before selection).  
4.2.2. 
Choice of the Study Design 
As the target indication would be the prevention of AF recurrence after ECV, the study design 
meets the requirements of EMA guideline on anti-arrhythmics on atrial fibrillation 
(EMA/CHMP/EWP/213056/2010) [21]. 
As F373280 aims to be developed as a safe treatment for the prevention of AF recurrence, it will 
not be tested as an add-on therapy during the study. To avoid any interaction with the tested 
product, anti-arhythmics class I and III will be forbidden during the study. 
The study design is defined in order to avoid methodological bias. A double blind study is 
appropriate to assess the efficacy and safety of the use of F373280 to prevent recurrence of AF 
episodes. Moreover, this study design is similar to the design of almost all trials that have assessed 
intervention for rhythm control [2, 8, 11, 12].  
According to the target indication, only patients with persistent atrial fibrillation and requiring an 
electrical cardioversion will be included in order to assess the time to first documented recurrence 
of atrial fibrillation since cardioversion. 
To confirm the persistent nature of atrial fibrillation, a 24-hour holter monitoring will be 
performed during the selection visit.  
Eligible participants will enter a selection phase in which anticoagulant treatment (anti-vitamin K) 
will be adjusted to achieve an International Normalized Ratio (INR) of 2.0 to 3.0 before electrical 
cardioversion. According to guidelines for the management of atrial fibrillation [6], anti-vitamin 
K should be given at least 3 weeks before cardioversion because of risk of thrombo-embolism due 
to post-cardioversion.  
Experimental data suggest that the maximal incorporation, of n-3 PUFAs in the myocardial cell 
membrane takes up to 28 days to occur [22]. In addition, as shown in Nodary study [2], the 
duration of pre-treatment with PUFA before cardioversion appears to be a contributing factor in 
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success.Therefore, before starting follow up for the assessment of AF recurrence, treatment with 
F373280 should be started 28 days before ECV.  
Detection of atrial fibrillation recurrence will be performed using systematic (scheduled) ECG 
recording, thus allowing detection of asymptomatic (about 50% of episodes) as well as 
symptomatic AF episodes. According to previous studies, most of atrial fibrillation recurrence 
occurred during the first days after cardioversion [11, 15]. So that, the heart rhythm will be 
closely monitored during the first week after successful cardioversion using an ambulatory 
continuous 7-day holter ECG recording in order to increase sensibility to detect asymptomatic AF 
episodes. Thereafter, to improve patient compliance, this follow up will be continued using  a 
more easy to carry and easy to use device, a TTEM.  
Finally, during the study, patients will be scheduled for a clinical visit every month (with an 
additional visit 7 days after visit 3 (ECV visit)) in order to ensure a close medical monitoring and 
to assess efficacy and safety parameters. 
4.2.3. 
Choice of the Dose  
According to a previous study in patients with atrial fibrillation [2], the tested PUFA product 
(Omacor) at the dose of 2 g (i.e. 640 mg of DHA acid) was effective in the prevention of atrial 
fibrillation after cardioversion. Moreover, PUFAs at dosage of 1g and 2g were also effective on 
the improvement of ventricular functional parameters, morbi-mortality and duration of 
hospitalisation in patients with heart failure [3, 4, 5].  
From the F373280 phase I study, after a 14-day repeated administration of F373280 (1g/day), 
observed plasma concentrations of DHA measured before treatment (Cmin) were similar to that of 
an effective dose of Omacor at 2 g/day (60 to 95mg/mL and 60 to 90mg/mL, respectively) 
(phase I study of F373280 and Salm and coll study) [16]. With regard to the rythm of 
administration, mean peak/trough fluctuation (baseline corrected) was around 0.3. This value 
supports a once-daily administration allowing a 24-hour plasma exposure in DHA.Therefore, a 
dose of 1 g daily of F373280 is considered to be appropriate to be tested in this POC study. 
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4.2.4. 
Choice of the Sample Size 
See chapter 13. 
5. STUDY POPULATION 
Each patient fulfilling all the inclusion criteria and none of the non inclusion criteria will be 
eligible. 
5.1. 
INCLUSION CRITERIA 
Demographic Characteristics and Other Baseline Characteristics: 
1. Men or women aged more than 18 years (inclusive), 
2. Patient with persistent AF between 7 days and 6 months duration for whom 
electrical cardioversion is warranted. 
3. History of first documented persistent AF less than 1 year 
4. History of ischemic or non ischemic heart failure 
5.  NYHA class I or II chronic heart failure at selection and at inclusion 
6. Reduced left ventricular ejection fraction between 30% and 45% inclusive (using the two-
dimensional echocardiography biplane Simpson’s rule) at selection and at inclusion 
7. On appropriate, stable medical treatments for heart failure, including a diuretic and/or 
angiotensin-converting 
enzyme, 
and/or 
angiotensin-receptor 
blocker 
and/or 
mineralocorticoid receptor (MR) antagonists, and/or betablockers 
8. Left atrial area ≤ 40 cm² at selection and at inclusion 
9. Patient treated or having to be treated by anti-vitamin K 
10. For female patient of child-bearing potential:  
• in all the countries except Italy: 
 
- 
use of an effective method of contraception (hormonal contraception or intra-uterine 
device) assessed by the investigator, for at least 2 months before the selection in the 
study and agreement to go on using it during the whole duration of the study and up to 
1 month after the last dose of the study treatment or 
- 
documented as surgically sterilized 
• in Italy only: 
- 
absolute abstention from sexual intercourse during the whole duration of the study and 
for a month after the end of the study or 
- 
use of double barrier contraception method (use of effective medical contraception 
method) from at least 2 months before the start of the study to the entire duration of the 
study and for a month after the end of the study or 
- 
documented as surgically sterilized  
11. For female patient of child-bearing potential: negative urine pregnancy test at inclusion 
12. For male with a child-bearing potential partner (In Italy only): 
- 
absolute abstention from sexual intercourse during the whole duration of the study and 
for a month after the end of the study or 
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- 
use of double barrier contraception method (use of condom for male and effective 
contraception method for the partner) from the entire duration of the study to a month 
after the end of the study. 
 
Ethical /legal considerations: 
13. Having signed his/her written informed consent, 
14. Affiliated to a social security system, or is a beneficiary (if applicable in the national 
regulation), 
5.2. 
NON INCLUSION CRITERIA 
Criteria related to pathologies: 
1. History of first documented episode of persistent AF more than 1 year, 
2. More than two successful cardioversions (electrical or pharmacological) in the last 6 months, 
3. Secondary Atrial Fibrillation due to alcohol or severe valvular heart disease (grade III to IV), 
4. NYHA class III or IV heart failure at selection or at inclusion 
5. Thyroid disease uncontrolled by treatment: TSH ± T4L ± T3L to be check in case of treatment 
for thyroid disease  
6. Myocardial infarction or unstable angina or presence of unstable ischemic coronaropathy 
assessed by coronarography or cardiac stress test (Echo stress, exercice stress test, nuclear or 
MR perfusion evaluation methods) within 6 months before selection 
7. Severe chronic kidney disease (creatinine ≥ 25 mg/L or estimated glomerular filtration rate  
< 30 mL/min) at selection 
8. Bradycardia (HR ≤ 50 bpm) 
9. Hyperkalemia or hypokalemia (K > 5.5 mEq/L or K < 3.5 mEq/L) at selection 
10. Cardiac surgery within 3 months before selection or planned during the study duration 
Criteria related to treatments: 
11. Previously ineffective pharmacological or electrical cardioversion 
12. Concomitant treatment with any anti-arrhythmic drug (within 7 days prior to selection), except 
stable dose of digoxin, beta-blockers, calcium-blockers. 
13. Previous treatment with oral amiodarone within 12 months prior to inclusion 
14. Previous treatment with intravenous amiodarone within 6 months prior to inclusion 
15. Patient requiring a cardiac resynchronization therapy (CRT) or having undergone CRT 
implantation within the last 6 months 
16. Treatment with any Polyunsaturated Fatted Acid within the last 3 months 
Dietary supplement with ω3 or ω6 according to investigator’s judgment 
18. Having undergone any form of ablation therapy for AF 
19. Patient treated with other anticoagulant treatment than antivitamin K: thrombin inhibitor such 
as Dabigatran or treated with antiaggregant P2Y12 inhibitors such as Clopidogrel or Prasugrel 
Others criteria:  
20. Patient liable not to comply with protocol instructions and/or with treatment, in the 
investigator’s opinion, 
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21. Patient having taken part in a clinical trial in the preceding 2 months or taking part in a trial at 
the time of selection, 
22. Patient linguistically or mentally unable to understand the nature, objectives and possible 
consequences of the trial, or refusing to patient himself / herself to its constraints, 
23. Patient family member or work associate (secretary, nurse, technician…) of the Investigator, 
24. Patient having forfeited his / her freedom by administrative or legal award or being under 
guardianship, 
25. Breastfeeding female patient. 
5.3. 
NUMBER OF  PATIENTS 
76 x 2 patients (taking into account 15 % of non evaluable patients). 
5.4. 
RECRUITMENT MODALITIES 
Patients will be recruited within the medical consultation of each centre involved in the study. If 
necessary and when authorized by local and national regulation, some specific supports or tools 
will be used to improve the recruitment (announcement, mailing to general practitioners, leaflet, 
website including ClinicalTrials.gov, CRO,…). 
Before implementation, the documents will be submitted to and approved by the Ethics 
Committee. 
5.5. 
 PATIENTS IDENTIFICATION 
The patient's code will contain 7 digits: the 2 first digits corresponding to the country number, the 
following 2 digits corresponding to the centre number and the last 3 digits corresponding to the 
patient's chronological order once having signed the written informed consent. 
5.6. 
WITHDRAWAL CRITERIA 
The reasons for a patient's premature withdrawal from the study may be the following: 
• The patient's decision. A patient who wishes to withdraw from the study for any reason may 
do so at any time but must inform the investigator. In all cases, the Investigator should attempt to 
contact the patient as soon as possible for a final assessment in order to: 
− have the patient's decision written on the consent form 
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− obtain the reason(s) for withdrawal and report it/them in the case report form 
− evaluate the patient's clinical condition 
− if necessary, take appropriate therapeutic measures: management of an adverse effect or 
concomitant disease, prescription of another treatment. 
• The Investigator's decision in the patient's interest. Particularly, if a serious adverse event 
occurs and is considered by the Investigator liable to threaten the health of the patient. The 
monitor will be informed by phone or fax and a letter or report explaining the withdrawal will be 
forwarded to the monitor as soon as possible. 
• An erroneous inclusion according to the study protocol. Any inclusion not respecting 
inclusion / non inclusion criteria will immediately be withdrawn and an appropriate treatment will 
be instored by the investigator under his/her responsibility. Erroneous inclusions will not be paid 
to the investigator. 
• Patients who could not be treated with anti-vitamin K for at least 3 weeks before ECV, 
• Patients who will not stabilize INR between 2 and 3 on at least 3 consecutive weekly tests 
• Patients with only 2 consecutives INR tests between 2 and 3 in the last 3 week for whom  a 
trans-oesophagoal echocardiography can not be performed before ECV or for whom a trans-
oesophagoal echocardiography shows a thrombus in the atria.  
• Patients who will not revert to sinus rhythm or with early relapse within the observation 
period after ECV (i.e. unsuccessful ECV) will be considered to have finished follow-up. 
• An occurrence of AF recurrence that would require, at the investigator’s judgement, a 
cardioversion or an introduction of an anti-arrhythmic because of intolerable and uncomfortable 
clinical symptoms. 
5.7. 
REPLACEMENT OF PATIENTS 
Withdrawn patients will not be replaced. 
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5.8. 
POST-STUDY EXCLUSION PERIOD  
Patients will not be allowed to participate to another clinical trial during 3 months following the 
study termination. 
5.9. 
STUDY CARD AND LETTER FOR GENERAL PRACTITIONER(S)  
The patient will receive from the Investigating Centre at Visit 1 - Selection Visit : 
- a personal card to be kept all along the study duration and providing the following information: 
patient's name, sponsor's name, study code, EUDRACT number, start date and expected end date 
of the study, complete address of the Investigating Centre with the name and phone number of the 
Investigator and a sponsor 24H/24 phone contact number in case of emergency (French and 
English languages): 33 (0)5 63 35 25 83. For Italy, this card will be in Italian only, without any 
English mention. 
- in Italy, a letter to be given to his/her general practitioner. This letter intends to inform the 
general practitioner(s) (and any other doctors who take care of the patient) that the patient 
participates to the clinical study. It describes the study treatment and includes some information 
on the forbidden treatment during the study.  
6. STUDY TREATMENT 
The Clinical Pharmacy Department of the Institut de Recherche Pierre Fabre (IRPF) will supply 
the investigational centres with the treatment necessary for the conduct of the trial.  
6.1. 
SOURCE, PRESENTATION AND COMPOSITION OF 
 
INVESTIGATIONAL PRODUCT 
F373280 and placebo will be prepared in Soft Capsules similar presentation.  
• F373280 
Formulation of F373280, 1g, Soft Capsules: oral administration, oblong size 20, off-white, Soft 
Capsules containing: Panthenyl ester of DHA, gelatine, glycerol, titanium, dioxide, purified water. 
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• Placebo 
Formulation of placebo matching tested product, Soft Capsules: oral administration, oblong size 
20, off-white, Soft Capsules containing: paraffin liquid, fish flavour, gelatine, glycerol, titanium, 
dioxide, purified water. 
 
Placebo and F373280 capsules will be packaged in opaque blisters. 
6.2. 
PACKAGING AND LABELLING 
The treatment units will be packed and labelled by the Clinical Pharmacy Department of the IRPF 
according to European Directive and local requirements. 
6.2.1. 
Packaging 
Each treatment unit will be composed of 3 cases for a 12-week treatment period. 
The Investigator will provide the patient with the treatment according to the following schedule: 
At Inclusion Visit (V2): a 12-week treatment unit will contain 3 cases, each case containing: 
− 10 blister packs of four 1g F373280 soft capsules or placebo soft capsules each. 
At Visit 6 (V6): a 12-week treatment unit will contain 3 cases, each case containing: 
− 10 blister packs of four 1g F373280 soft capsules or placebo soft capsules each. 
6.2.2. 
Labelling 
Investigational Products will be labelled according to the following rules: 
Labelling should comply with the local requirements for Investigational Medicinal Products. 
On the treatment units and cases, the labels will bear the following indications:  
a) name and address of the sponsor 
b) protocol number, 
c) packaging batch number, 
d) the treatment number 
e) storage conditions 
f) expiry date 
g) pharmaceutical dose form 
h) route of administration 
i) quantity of dosage units 
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j) direction for use 
k) legal statements:  
− “for clinical trial only”, “keep out of the reach and the sight of children”, “please return 
to your doctor any unused product”, respect the prescribed dose”. 
On the treatment unit, another label will be affixed with the mention of the investigator name and 
patient number (completed by the investigator). 
In addition, on each case, will be mentioned the case number and a detachable label will bear the 
following indications: 
− Protocol number 
− Packaging batch number 
− Expiry date 
− Case number 
− Treatment number 
On the blister pack, the label will mention the protocol number, the packaging batch number, the 
case number and the treatment number. 
6.3. 
DISTRIBUTION TO CENTRE AND STORAGE 
The Clinical Pharmacy Department of the IRPF will supply the Investigational Centre with the 
treatment units along the study according to the need, upon request triggered by the patient’s 
selection.  
As soon as the Pharmacist or the Investigator receives the trial medication, he/she will check the 
contents and immediately acknowledges the receipt in the IVRS/IWRS. The copy of the 
acknowledgement will be kept in the Investigator’s file. The same procedure will be applied to all 
further supplies during the course of the trial. 
At the time of the delivery to the Centre, the following information will be provided: 
• Details of storage conditions that should be respected 
• And, upon request and for the 1st delivery only, a letter of release for the Investigational 
Medicinal Product from the Sponsor's Qualified Person. 
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The CRA will ensure during the monitoring visits that trial medications have been received in 
good conditions and the acknowledgment of receipt has been performed adequately. 
Treatment units should remain intact until dispensation to the patients. They should be kept at 
temperature below 30°C in an appropriate lockable room only accessible to the person authorised 
to dispense them, under the responsibility of the Pharmacist or the Investigator. 
In the case of undue delay in study execution, the Pharmacist or the Investigator should ensure 
that the expiry date has not been exceeded.  
6.4. 
ALLOCATION OF TREATMENTS AND DISPENSATION TO PATIENT 
A randomisation list will be established by the Clinical Pharmacy Department of the IRPF. This 
list will be computer-generated with internal software. The randomisation methodology is 
validated by the Biometry Department before generation. 
Treatments F373280 or placebo will be balanced in a 1:1 ratio. 
As the treatment units are prepared for 12-week treatment periods, the Investigator will have to 
allocate a treatment number at inclusion Visit and another one at Visit 6.  
For each patient, the treatment number given at Visit 6 will not be the same that the one given at 
inclusion visit (V2). 
The treatment numbers will be given through the IVRS/IWRS. 
Practically, once the patient’s eligibility is confirmed, at selection visit:  
• The Investigator: 
− Calls the vocal server  
− Answers the questions relating to the patient  
− In return, the treatment number to be allocated for the first 12-week period to the patient 
is given by the vocal server.  
• The IVRS/IWRS company: 
− Confirms this information by fax/email to the Investigator 
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− Fills the “Request for Delivery of Investigational Product” form and sends it by email 
and/or fax to the Clinical Pharmacy Department of the IRPF.  
• The Clinical Pharmacy Department of the IRPF sends the corresponding treatment unit to the 
Investigator within 5 days from reception of the email request form. 
The Investigator will dispense to the patient the case which label indicates the treatment number 
and the administration period. 
At visit 5, the Investigator will contact again the IVRS/IWRS to obtain for visit 6 the treatment 
number for the last 12-week period of treatment according to the same process as described 
above. 
6.5. 
DRUG ADMINISTRATION 
6.5.1. 
Duration of Treatment 
For a patient completing the study, the theoretical study treatment exposure will be 24 weeks, 
with F373280 or placebo. 
If the ECV is postponed by 1 week to allow INR stabilization, the treatment duration will be 25 
weeks. 
6.5.2. 
Dose Schedule 
One soft capsule of 1g of F373280 or placebo to be taken each day during 24 weeks. 
6.5.3. 
Route and Conditions of Administration 
The soft capsules are to be taken orally. One soft capsule is to be taken each evening with the 
dinner during 24 weeks.  
6.6. 
ACCOUNTABILITY ON SITE AND RETURN/DESTRUCTION OF 
 
INVESTIGATIONAL PRODUCT 
The Investigator should maintain accurate written records of drug received, dispensed, returned 
and any remaining treatment units, on the drug accountability form. These records should be made 
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available for Clinical Research Associate (CRA) monitoring. The packaging of the medication 
should remain intact until just before the dispensation. 
At each visit, the Investigator will record the number of soft capsules returned by each patient 
using the appropriate page of the e-CRF. 
At the end of the study, all used and unused treatments including packaging should be noted, and 
return is organised by the CRA to the Clinical Pharmacy Department of the IRPF for destruction. 
A copy of the drug accountability form should be provided by the Investigator to the CRA. 
6.7. 
RECALL OF INVESTIGATIONAL PRODUCTS  
In case of recall of investigational products (decided by the Competent Authorities or the 
Sponsor), the Investigator will immediately be informed by the Sponsor. 
The Investigator, in collaboration with the Sponsor representatives (Study Manager, CRA) must 
urgently: 
• Stop the delivery of the concerned investigational products to the patients. 
• Inform the concerned patients that they must immediately stop taking these investigational 
products and bring them back. 
The Study Manager/CRA organises the return of the recalled products to the Clinical Pharmacy 
Department of the IRPF, according to the Sponsor’s procedures. 
7. CONCOMITANT TREATMENTS 
Any existing concomitant treatment (Selection Visit), any new concomitant treatment or change 
in the dosage of an existing concomitant treatment during the course of the study must be noted 
on e-CRF. All treatments should be evaluated by the investigator at selection and their 
prolongation during the study or their stop should be considered. 
For all concomitant treatments taken during the study, the following information must be noted in 
the relevant section(s) of the e-CRF: 
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• The name of the treatment and its form 
• The reason for prescription 
• The route of administration 
• The daily dose 
• The duration of treatment. 
7.1. 
ANTI-VITAMIN K TREATMENT 
Anti-vitamin K should be given for at least 3 weeks before ECV and continued for the whole 
study duration. The anti-vitamin K used will be left to the decision of the each investigator 
according to his/her local practice. 
7.2. 
PROHIBITED TREATMENTS 
- 
Class I and class III antiarrhythmic treatments: 
− Class I  
- 
Class IA: Disopyramide, Procainamide, Quinidine 
- 
Class IB: Lidocaine, Mexiletine 
- 
Class IC: Flecainide, Propafenone 
 
− Class III: Dofetilide, Ibutilide, Sotalol, Amiodarone, Dronedarone.  
- 
Any Polyunsaturated Fatty Acid (PUFA) 
- 
Any anticoagulant treatment other than antivitamin K: thrombin inhibitor such as Dabigatran 
or antiaggregant P2Y12 inhibitors such as Clopidogrel or Prasugrel 
- 
Dietary supplement with Omega 3 or Omega 6 
Prohibited treatments at selection must not be prescribed for the duration of the study except in 
case of occurrence of an adverse event or AF episode that requires a corrective treatment in the 
interest of the patient’s health. 
7.3. 
AUTHORISED TREATMENTS 
Other treatments will be authorised during the study duration. 
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However, if medication other than study drugs is administered at any time from the start of the 
study, details must be recorded in the case report form. During the study, patients must be asked 
whether they have been on a course of prescribed drug treatment or have taken any OTC or herbal 
drugs since the visit. 
8. EVALUATION CRITERIA 
8.1. 
PRIMARY EFFICACY CRITERION:  
8.1.1. 
Time to the first Atrial Fibrillation Recurrence 
8.1.1.1. 
Definition 
Time to first Atrial Fibrillation recurrence is defined by the first episode of Atrial Fibrillation 
(symptomatic or not) lasting for at least 10 minutes. 
8.1.1.2. 
Schedule 
The heart rhythm follow up will be performed from the end of electrical cardioversion visit  
(visit 3) to the final study visit (visit 9).  
For randomised patients with spontaneous cardioversion before ECV, the recurrence of AF will be 
assessed after visit 3 (week 5). 
8.1.1.3. 
Evaluation Methods 
• 7-day holter monitor: 
The heart rhythm monitoring will be carried out  from visit 3 to visit 4 using a 7-day continuous 
ECG (5-leads/2 or 3 channels) ambulatory recording (holter ECG) fixed after ECV visit. 
Following holter monitoring the heart rhythm will be documented using Trans Telephonic ECG 
Monitoring (TTEM) 
• Trans Telephonic ECG Monitoring (TTEM): 
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Thus, the follow up will be documented using the TTEM: daily transmission from visit 4 to visit 
6. Then, every two days from visit 6 to visit 9. 
Moreover, during this TTEM period, if patient experiences AF symptoms, it should be 
documented using the TTEM. 
In case of AF recurrence, and provided that the patient does not required a cardioversion or an 
introduction of an anti-arrhythmic at the investigator’s judgement, he/she could be maintained in 
the study with the treatment, in order to assess a spontaneous cardioversion. For that purpose the 
patient will continue to transmit a TTEM once a week. 
The TTEM will be centralized by the Central Reading Laboratory. The patient will be requested 
to contact the Central Reading Laboratory for transmission of each stored TTEM. The TTEM will 
be validated by a trained technician, then analysed by a cardiologist. The cardiologist 
interpretation will be faxed to the site. The investigator will be asked to review and sign this 
document. 
The TTEM process will be fully described in a separate document. 
8.1.2. 
Secondary Efficacy Criteria 
8.1.2.1. 
Numbers of Atrial Fibrillation episodes in the first week following visit 3 
 
 
(ECV visit) 
8.1.2.1.1. 
Definition 
Number of Atrial Fibrillation episodes will consist in the assessment of episodes of AF with 
duration at least 10 minutes (NSup10) and of less than 10 minutes (NInf10), respectively. 
8.1.2.1.2. 
Schedule 
The heart rhythm follow up will be performed from the end of successful electrical cardioversion 
visit (visit 3) to the study visit 4.  
8.1.2.1.3. 
Evaluation Methods 
• 7-day holter monitor: 
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The heart rhythm monitoring will start using a 7-day continuous ECG (5-leads/2 or 3 channels) 
ambulatory recording (holter ECG) after ECV visit from visit 3 to visit 4. 
8.1.2.2. 
Duration of Atrial Fibrillation episodes in the first week following visit 3 
 
 
(ECV visit) 
8.1.2.2.1. 
Definition 
Duration of AF episodes will consist in the sum of duration of each AF episodes. 
8.1.2.2.2. 
Schedule 
The heart rhythm follow up will be performed from the end of successful electrical cardioversion 
visit (visit 3) to the follow up study visit (visit 4).  
8.1.2.2.3. 
Evaluation Methods 
Duration of AF episodes will be assessed using the 7-day continuous ECG (5-leads/2 or 3 
channels) ambulatory recording. 
8.1.2.3. 
Clinical parameters evaluation 
8.1.2.3.1. 
EHRA score assessment 
8.1.2.3.1.1. Definition: 
AF related symptoms will be evaluated by the EHRA (European Heart Rhythm Association) score 
[20]. The following items “during presumed arrhythmia episodes" are checked to determine the 
score: palpitation, fatigue, dizziness, dyspnea, chest pain and anxiety. 
Classification of AF-related symptoms (EHRA score) are as follows: 
• EHRA I          - ‘No symptoms’ 
• EHRA II         - ‘Mild symptoms’; normal daily activity not affected 
• EHRA III       - ‘Severe symptoms’; normal daily activity affected 
• EHRA IV       - ‘Disabling symptoms’; normal daily activity discontinued  
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This classification relates exclusively to the patient-reported symptoms. 
In addition to this score, the frequency will be classified in three groups, namely occasionally 
(less than once per month); intermediate (1/month to almost daily); and frequent at least daily. 
8.1.2.3.1.2. Schedule 
This evaluation will be performed in case of symptoms evocative of arrhythmia. 
8.1.2.3.1.3. Evaluation Methods 
This evaluation will be collected by Central Reading Laboratory during all the study period. 
8.1.2.3.2. 
Number of recurrence of symptomatic AF  
It consists of number of AF recurrence associated with a symptom (Palpitation, fatigue, dizziness, 
dyspnea, chest pain and anxiety) and confirmed by an ECG in atrial fibrillation. 
8.1.2.3.3. 
Number and duration of hospitalization 
• Number and duration of hospitalization for cardiovascular events 
− Hospitalization for AF treatment 
− Hospitalization for worsening of heart failure 
− Hospitalization for myocardial infarction 
− All cause of hospitalization 
• Number and duration of hospitalization for thromboembolic stroke  
8.1.2.4. 
Cardioversion assessment 
• Assessment of spontaneous cardioversion before visit 3 
• Assessment of successful cardioversion at visit 3 (i.e. return to sinus rhythm) 
• Shock distribution (1, 2 or 3 shocks) 
• Number of patients needing another cardioversion after initial ECV 
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8.1.2.5. 
Evolution of echocardiographic parameters 
8.1.2.5.1. 
Definition 
The following echocardiographic parameters will be assessed: Left atrial diameter (mm), Left 
atrial area (cm2), Left atrial volume (mL), Left atrial volume/BSA (mL/m2), Left ventricular 
ejection fraction (%),Left ventricular volume (mL), Left ventricular volume/BSA(mL/m2, Left 
ventricular end diastolic diameter (mm) Left ventricular end diastolic volume (mL), Left 
ventricular end systolic diameter (mm) and Left ventricular end systolic volume (mL), 
8.1.2.5.2. 
. Schedule 
The measurements will be performed at visit 1 and visit 2 to check the eligibility of the patient.  
The measurements performed at visit 4, visit 6 and visit 9 are done to follow the 
echocardiographic evolution of the patients in sinus rhythm. 
8.1.2.5.3. 
Evaluation method 
The echography evaluations will be carried out according to the recommendations for chamber 
quantification drawn up by the American Society of Echocardiography and the European 
Association of Echocardiography [23]. So, for volume measurements, the recommended method 
is to use the biplane method of discs (modified Simpson’s rule) from 2-D measurement. 
8.2. 
BIOMARKER ASSESSMENT: RED BLOOD CELL  
 
CONCENTRATIONS OF DHA 
8.2.1. 
Definition 
Because of the limited accessibility of human tissues for biopsy, red blood cell DHA contents is a 
marker for tissue DHA concentration [13], [14]. 
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8.2.2. 
Blood samples 
8.2.2.1. 
Collection schedule 
Blood samples will be collected for determination of red blood cells (RBC) concentrations of 
DHA.  
Blood samples will be performed as follows: 
• Visit 2 before treatment, visit 3, visit 6 and visit 9. 
Actual sampling times will be individually reported in the electronic Case Report Forms  
(e-CRFs). 
8.2.2.2. 
Technical handling 
Two blood samples will be collected containing EDTA. They will be gently shaken and 
centrifuged at 3000g for 15 min at room temperature, within 30 minutes after collection. Plasma 
and white blood cells will be discarded. Red blood cells will be stored at +4°C (no freezing will 
be allowed) and sent to Analytical Centre in refrigerated conditions (between +2°C and +8°C) 
within 3 weeks following collection. Analysis will be performed within 2 weeks following 
reception at the Analytical centre. 
8.2.3. 
DHA concentration measurement 
Analytical determination of RBC concentrations of DHA will be carried out by the Analytical 
Centre. 
Lipids will be extracted from red blood cells samples with a mixture of hexane/isopropanol, after 
acidification [17]. Total lipid extracts will be saponified and methylated. The fatty acid methyl 
esters (FAME) will be extracted and analyzed by Gas Chromatography. 
Identification of FAME will be based on retention times obtained for FAME prepared from fatty 
acid standards. The area under peaks will be determined using ChemStation Software (Agilent) 
and results will be expressed as % of total fatty acids. DHA concentration will be calculated using 
the internal standard and expressed as µg/g for red blood cells samples. Thus, omega-3 index will 
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be assessed. The omega-3 index represents the content of EPA plus DHA in red blood cells 
(expressed as a percent of total fatty acids). It is a biomarker considered as a new marker of risk 
for death from coronary disease [18]. 
Results of this analytical determination will be kept confidential by the dosing centre until the end 
of the study, and will be provided only at the end of the study (after database lock), in a separate 
file. 
8.3. 
SAFETY ASSESSMENT 
8.3.1. 
Adverse Events 
At selection, any concomitant disease will be reported on the e-CRF. At each further visit, the 
occurrence of adverse events (AEs) since the last visit will be based on the patient's spontaneous 
reporting, the investigator's non-leading questioning and his/her clinical evaluation. All AEs will 
be reported on the e-CRF (see section 10). 
8.3.2. 
Laboratory Investigations 
8.3.2.1. 
Schedule 
Laboratory investigations will be performed at visit 1 (before treatment) and visit 9 (end of 
treatment) or End of Treatment visit. 
At visit 3 and 6, only an haematology examination will be performed.  
Furthermore the kaliemia will be checked before electrical cardioversion at visit 3. 
The volume of blood samples complete haematology, biochemistry should not exceed 30 mL. 
8.3.2.2. 
Technical Procedures and Parameters 
The following tests will be performed: 
 
Haematology: 
Hematocrit, haemoglobin, Red blood cells (RBC) count, white blood cells 
(WBC) count, WBC differential counts (% and absolute), reticulocytes,  
platelets.  
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Chemistry: 
sodium, potassium, bicarbonate, chloride, alkaline phosphatase, gamma GT, 
albumin, total bilirubin, conjugated bilirubin, creatinin, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), fasting glucose, 
total cholesterol, cholesterol (HDL, LDL), triglycerides, creatine 
phosphokinase (CPK), fibrinogen. 
Blood samples will be taken in the morning, in fasting conditions.  
The estimation of GFR at selection relies on the measurement of serum creatinine and the 
Cockcroft- Gault formula 
Cockcroft-Gault formula 
- with serum creatinine expressed as mg/L:  
in men: 
GFR (mL/min) = [(140-age)] x weight / 7.2 x serum creatinine in mg/L], 
 
in women: 
GFR (mL/min) = [(140-age)] x weight / 7.2 x serum creatinine in mg/L] x 0.85 
 
- with serum creatinine expressed as μmol/l: 
GFR (mL/min) = [(140-age) x weight / serum creatinine in μmol/l] x k,where k = 1.23 for men, 
1.04 for women. 
 
(weight in kg, age in years) 
Additional tests may be done at the Investigator’s discretion, in the patients’ interest. In case of 
any abnormal or clinically significant results, the Investigator will order laboratory control tests. 
8.3.3. 
Global Physical Examination 
A global physical examination including the measurement of body weight will be carried out on 
each body system at visit 1, visit 2, visit 3, visit 5, visit 6, visit 7, visit 8 and visit 9. 
The physical examination will be globally evaluated as “normal/abnormal”. Further target 
inspection will be undertaken for any abnormal finding. 
8.3.4. 
Vital Signs 
Vital signs will consist in blood pressure and heart rate at rest.  
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8.3.4.1. 
Schedule 
Vital signs will be measured at each visit. 
8.3.4.2. 
Technical Procedure and Parameters 
Systolic (SBP) and diastolic (DBP), expressed in mmHg, will be measured after at least 5 minutes 
in supine position and after 2 minutes in standing position.  
The heart rate (HR), expressed in beats per minute (bpm), will be measured by auscultation, after 
at least 5 minutes in supine position and after 2 minutes in standing position by counting the beats 
for at least 30 seconds. 
Bodyweight will be measured in  patient in underwear and with the same balance at each visit.  
8.3.5. 
Electrocardiogram (ECG)  
8.3.5.1. 
Schedule 
An electrocardiogram will be recorded at visit 1, visit 2, visit 3, visit 5, visit 6, visit 7, visit 8 and 
visit 9 using an usual standardised 12-lead cardiograph. 
8.3.5.2. 
Technical Procedure and Parameters 
• Electrocardiogram (ECG): 
The global interpretation from manual reading (normality, clinical relevance) and heart rate 
(bpm), PR (ms), QRS (ms), QT (ms), repolarisation patterns will be reported in the e-CRF. Each 
print-out will include the patient’s code, date, time, technician's initials and investigator's 
signature. 
In case of thermic paper ECG print out, a photocopy will be made by the centre to ensure safe 
filing. 
• 24 hour-Holter - ECG 
An ambulatory continuous 24-hour ECG (5-leads/2 or 3 channels) will be recorded at selection 
visit using a holter ECG, in order to confirm persistent atrial fibrillation.  
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8.3.6. 
Coagulation parameters 
The assessment of coagulation will be evaluated by the following parameters: 
− Prothrombin Time/INR (PT/INR) 
− Activated Partial Thromboplastin Time (aPTT) 
− Thrombin Clotting Time (TCT) 
During the pre-cardioversion period, if the anticoagulation by AVK should be initiated, then the 
INR monitoring will be as follow:  
− INR 2-3 times a week for the first week of treatment 
− INR weekly up to ECV, 
− INR every 4 weeks after ECV 
For patients already treated with AVK, INR monitoring will be as follow: 
− INR weekly up to ECV, 
− INR every 4 weeks after ECV 
aPTT and TCT will be performed at visit 1, visit 2, visit 3, visit 5, visit 6, visit 7, visit 8 and  
visit 9. 
Anti-coagulation by anti-vitamin K should be given at least 3 weeks before ECV and continued 
for the whole study duration. 
The quantity of blood samples collected at each time for coagulation parameters will be 2 mL. 
8.3.7. 
Concomitant Treatments 
Concomitant treatments will be evaluated at each study visit. 
Requirements relating to patient's concomitant treatments started before screening visit and 
continued throughout the trial, or started during the trial can be found in section 7.  
8.4. 
COMPLIANCE 
The patient will be reminded at each visit to bring back any remaining soft capsules, blister, case 
(used or unused) at the following visit. 
At each visit, the Investigator will record the number of supplied and remaining Soft Capsules in 
the e-CRF. 
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9. STUDY PROCEDURES 
Visit 1 - Selection Visit (Week -4 to Week -1) 
The patient considered eligible for selection by the Investigator will be informed of the 
characteristics and the consequences of the trial both verbally and by reviewing the patient's 
information sheet and consent form (see section 14.3). If he/she accepts to participate in the study, 
he/she will sign the informed consent and will keep a copy. 
The patient will be assessed for the following: 
• Demographic characteristics (gender, age, height, body surface area) 
• Personal and medico-surgical history 
• Habits (Tobacco, alcohol consumption, dietary habits including fish consumption…) 
• Cardiovascular diseases, mainly detailed history of Heart Failure and Atrial Fibrillation 
characteristics  
• Echocardiography using a two-dimensional echocardiography.  
• 12-lead ECG 
• Concomitant diseases, adverse signs or symptoms (able to be used for treatment emergent AE 
determination) 
• Concomitant treatments (authorised, disallowed) 
• Global physical examination/bodyweight 
• Vital signs 
• Biology: haematology, biochemistry, assessment of coagulation parameters: Prothrombin 
Time/INR (PT/INR), Activated Partial Thromboplastin Time (aPTT), Thrombin Clotting Time 
(TCT) 
• Biology assessment of renal function: creatinine or estimated glomerular filtration rate 
If the results of the above assessments are compatible with the selection criteria 
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• A 24-hour continuous ECG ambulatory recording (Holter ECG) device will be installed on the 
patient to monitor the patient heart rhythm. The patient will be requested to bring back the device 
after the termination of 24 hours recording. The recording will be transmitted from the 
Investigational site to the Central Reading Laboratory (CRL). The CRL will send his/her 
assessment regarding the confirmation of persistent atrial fibrillation within 2 working days to the 
Investigator. 
• The patient will enter the selection period in which anticoagulant (anti-vitamin K) will be 
adjusted to achieve an International Normalized Ratio (INR) of 2 to 3 before electrical 
cardioversion.  
At the end of the visit, the Investigator will contact the IVRS/IWRS system to confirm the patient 
selection and order the treatment delivery and organise the appointment for the next visit.  
The patient will receive from the investigational centre the study card to be kept for the duration 
of the study. 
Visit 2 - Inclusion Visit (Day 1)  
If the patient's behaviour during the selection period and/or the result of complementary 
examinations particularly the confirmation of the presence of persistent atrial fibrillation by the 
CRL during this period, the INR and laboratory tests, are compatible with the inclusion criteria, 
the patient will be assessed for the following: 
• Adverse events 
• Concomitant treatments (authorised, disallowed) 
• Laboratory examination: red blood cell concentrations of DHA and coagulation parameters 
Prothrombin Time/INR (PT/INR), Activated Partial Thromboplastin Time (aPTT), Thrombin 
Clotting Time (TCT) 
• Global Physical examination/bodyweight 
• Vital signs 
• Echocardiography using a two-dimensional echocardiography. 
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• 12-lead ECG 
• Urine pregnancy test for women of child bearing potential. 
If the results of the above assessments are compatible with the inclusion criteria, the patient will 
be included and allocated a treatment number using the IVRS/IWRS system.  
Between this Inclusion visit and the next visit (V3), the INR will be closely monitored (refer to 
paragraph 8.3.6), in order to ensure that the INR is stable, between 2 to 3 before electrical 
cardioversion. 
At the end of the visit, the Investigator will organise the appointment for the next visit and give 
the treatment to be taken during the next 4-week period. 
Visit 3 (Week 4: D28 -2/+7 days) cardioversion 
Patient will be assessed for the following criteria: 
• Adverse events 
• Concomitant treatments (authorised, disallowed) 
• Laboratory examination: Haematology, Red Blood Cell concentrations of DHA, Prothrombin 
Time/INR (PT/INR), Activated Partial Thromboplastin Time (aPTT), Thrombin Clotting Time 
(TCT) 
• Global Physical examination /bodyweight 
• Vital signs  
• 12-lead ECG 
• Electrocardioversion (ECV): ECV has to be scheduled 4 weeks after randomization and after 
target international normalized ratio levels will be stabilized (between 2 and 3) on at least 3 
consecutive weekly tests in patients with AF. Patients not stabilized for INR (i.e. values between 2 
and 3) on at least 3 consecutive weekly tests performed before ECV will be excluded from the 
study, unless the presence of atrial thrombosis may be excluded with ECHO –TE (trans-
esophageal echocardiograph) performed  in the same day (before ECV). ECV will be performed 
in the morning, with the patient in the fasting state and without dyskalemia. Anesthesia will be 
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induced and patients will be cardioverted with administration of a synchronized, biphasic current. 
The initial shock will be set at 100 J if the body weight is less than 70 kg and at 150 J for higher 
body weights. Successful cardioversion will be defined as recovery of sinus rhythm lasting at least 
1 minute after the shock. If unsuccessful, a second 200-J shock, and eventually a third 200-J 
shock, will be administered. Failure of ECV is defined as the persistence of AF after the third 
attempt at cardioversion. After the procedure, patients will be monitored on telemetry for at least 
6 hours before discharge. Patients who will not revert to sinus rhythm or with early relapse within 
the observation period after ECV will be withdrawn from the study and will be considered to have 
finished their follow-up. 
At the end of the visit, a 7-day continuous ECG (5-leads/2 or 3 channels) ambulatory recording 
(holter ECG) will be installed on the patient in order to monitor the patient heart rhythm after 
ECV.  
At the end of the visit, the Investigator will organise the appointment for the next visit and give 
the treatment to be taken during the next 4-week period. 
Visit 4 (Week 5: D35 ± 2 days) 
After removal of the continuous ECG ambulatory device, the patient will be assessed for the 
following criteria: 
• Assessment of Adverse Events 
• Concomitant treatments (authorised, disallowed) 
• Vitals Signs 
• Echocardiography using a two-dimensional echocardiography 
At the end of the visit, the patient will be given the TTEM device (Trans Telephonic ECG 
Monitoring) for cardiac monitoring. The patient will be clearly instructed on the frequency and 
modalities of transmission. The patient will be requested to performed daily transmission from 
week 6 to week 8, then every 2 days from week 9 to week 24. Moreover, in case of AF symptoms 
additional transmission may be performed. 
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Visit 5 (Week 8: D56 ± 7 days) – Visit 6 (Week 12: D84 ± 7 days) - Visit 7 (Week 16: D112 ± 
7 days) - Visit 8 (Week 20: D140 ± 7 days) 
Patient will be assessed for the following criteria: 
• Adverse events 
• Concomitant treatments (authorised, disallowed) 
• Laboratory examination: Prothrombin Time/INR (PT/INR), Activated Partial Thromboplastin 
Time (aPTT), Thrombin Clotting Time (TCT). However, in case of discontinuation of 
anticoagulation after ECV, the monitoring of INR, aPTT and TCT should be stopped. 
• Global Physical examination/bodyweight  
• Vital signs  
• 12-lead ECG 
• The cardiac monitoring will be continued using a TTEM device (Trans Telephonic ECG 
Monitoring). The device will be given to the patient who will be requested to performed daily 
transmission from week 6 to week 8, then every 2 days from week 9 to week 24. Moreover, in 
case of AF symptoms additional transmission may be performed. 
The Investigator will collect all the cases, blisters and any unused soft capsules and count the 
unused capsules for each 4-week treatment period. 
At the end of the visit, the Investigator will organise the appointment for the next visit and give 
the treatment to be taken during the next 4-week treatment period. 
In addition: 
- at visit 5, the investigator will contact the IVRS/IWRS to obtain another treatment unit to be 
dispensed at visit 6 for the last 12-week period. 
- at visit 6, an echocardiography will be performed, an haematology examination will be done and 
the red blood cell concentration of DHA will be measured.  
End-of-Study Visit - Visit 9 (Week 24: D168 ± 7 days) 
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 Patient will be assessed for the following: 
• Adverse events 
• Concomitant treatments (authorised, disallowed) 
• Global Physical examination/bodyweight 
• Vital signs 
• 12-lead ECG 
• Laboratory examination: haematology, biochemistry, assessment of coagulation parameters: 
Prothrombin Time/INR (PT/INR), Activated Partial Thromboplastin Time (aPTT), Thrombin 
Clotting Time (TCT). Red blood cell concentration of DHA. 
• Urine pregnancy test for women of childbearing potential 
• Echocardiography using a two-dimensional echocardiography 
The Investigator will collect all the cases, blisters and any unused soft capsules and count the 
unused soft capsules. 
10. ADVERSE EVENTS: DEFINITION AND REPORTING 
10.1. 
ADVERSE EVENTS 
10.1.1. Definition of Adverse Events 
An adverse event is any adverse change from the patient's baseline condition, i.e. any subjective 
signs and symptoms or change in a concomitant disease present at the Selection Visit considered 
or not related to the treatment. 
This includes intercurrent signs, symptoms, illnesses and significant deviations from baseline for 
vital signs and laboratory values, which may occur during the course of the clinical study. 
All laboratory tests for which abnormal results are collected after study treatment initiation should 
be repeated until the values return to normal or to a stable status. Abnormal results are defined as 
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those falling out of the laboratory normal ranges and that are clinically significant. The frequency 
of such checks should be defined by the Investigator according to the degree of abnormality. 
In all cases, the aetiology should, as much as possible, be identified and Pierre Fabre Médicament 
notified. 
10.1.2. Grading of Adverse Events 
Adverse or intercurrent events are graded as follows: 
• Mild: awareness of signs or symptoms, but easily tolerated 
• Moderate: uncomfortable enough to cause interference with usual activity 
• Severe: incapacity with inability to work or do usual activity. 
10.1.3. Reporting of Adverse Events 
The records of adverse events in the electronic Case Report Form (e-CRF) describe the nature 
(diagnosis, signs and symptoms), severity, onset date, stop date, outcome and actions taken, and 
relationship to study treatment (in the Investigator's opinion). It must be specified whether the 
event is serious or not. 
10.2. 
SERIOUS ADVERSE EVENTS (SAE) 
10.2.1. Definition 
A serious adverse event (SAE) includes, but is not necessarily restricted to any event which: 
• Results in death (whatever may be the cause) 
• Is life-threatening 
• Results in persistent or significant disability/incapacity 
• Requires the patient's hospitalisation or prolongation of current hospitalisation * 
• Is a congenital anomaly or birth defect. 
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Other events such as cancer, and any additional adverse experience or abnormal laboratory values 
occurring during the study period, defined by the protocol as serious or which the Investigator 
considers significant enough, or that suggest a significant hazard, contra-indications, side effect or 
precaution, must be handled as serious adverse events. 
Any overdosage meeting a seriousness criteria should be reported as a SAE (see section 10.3). 
Any pregnancy occurring during/after exposure to the study drug(s) should be reported on the 
SAE notification form (see section 10.4). 
* any hospitalisation, or prolongation of hospitalisation due to the circumstances listed below: 
− planned (as per protocol) medical/surgical procedure, 
− preparation for routine health assessment/procedure (e.g. routine colonoscopy), 
− planned medical/surgical admission (planned prior to entry into study trial, appropriate 
documentation required), 
− administrative or social reasons (e.g. lack of housing, economic inadequacy, care-giver 
respite, family circumstances) 
will not be reported as a SAE. 
10.2.2. Reporting of SAE 
All serious adverse events, according to the above-mentioned definitions and regardless of 
treatment or relationship to study drug, must be recorded by the Investigator as soon as he/she is 
informed of the event. 
The Investigator must notify the Sponsor of this event by sending, within 24 hours, the 
"Notification of serious adverse event" form ("first notification") (see appendix 17.2) with all the 
available information about the event, to the Sponsor's representative: 
Marlène GUIRAUD, Pharm D 
INSTITUT DE RECHERCHE PIERRE FABRE,  
Centre de R&D Pierre Fabre – BP 13562 
3 Avenue Hubert Curien 
31035 TOULOUSE Cedex 1 
Phone: +33 5 35 50 63 48 
Fax: + 33 5 34 50 65 92 
Email: marlene.guiraud@pierre-fabre.com 
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In case of non-inclusion the reporting period ends when the non-inclusion is documented. 
10.2.3. Follow-up of SAE 
The Investigator must draw-up a specific clinical report and use the "Notification of serious 
adverse event" form ("follow-up") (see appendix 17.2) and collect the results of the carried out 
examinations and the reports of hospitalisation. 
The serious adverse events must be followed up until resolution or stabilisation. 
10.2.4. SAE Occurring After the Study 
Any SAE occurring during 30 days following the end of the study for the patient should be 
notified to the Sponsor. 
Must also be notified to the Sponsor any event occurring at any time after the end of the study for 
the patient which may be related to the study treatment in the Investigator's opinion. 
10.3. 
REPORTING OF OVERDOSAGE TO THE SPONSOR 
For the purpose of this trial an overdosage will be defined as any dose exceeding the planned 
prescribed dose of the study drug or the administration of any dose of an associated product that is 
considered both excessive and medically important. 
In the absence of seriousness criteria, the overdosage, and associated adverse event if any, are 
reported only on the Adverse Event page of the CRF. If the definition of seriousness criteria is 
met, the SAE notification form must be also transmitted to the sponsor. 
10.4. 
REPORTING OF PREGNANCY TO THE SPONSOR 
Pregnancies discovered in the period in between the informed consent form signed but before any 
study drug exposure are not to be reported to the sponsor unless associated to a seriousness 
criteria (e.g. serious adverse event study-protocol related procedure). If pregnancy is confirmed, 
the women must not be administered the study drug and be withdrawn immediately from the 
study.  
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If pregnancy is suspected while the patient is receiving study treatment, the study drug(s) should 
be discontinued immediately until the result of the pregnancy testing is known. If pregnancy is 
confirmed, then the study treatment is permanently discontinued in an appropriate manner and the 
patient is discontinued from the study.  
The investigators must report to the sponsor any pregnancy which occurs during or after the 
patient has been exposed to the study drug and until 30 days after the last study drug 
administration. The investigator must immediately notify the sponsor using the SAE notification 
form and also report the pregnancy on the AE page of the e-CRF. 
Women who become pregnant after exposure to the study drug must be followed by the 
investigator until the completion/termination of the pregnancy. If the pregnancy goes to term, the 
outcome will have to be reported to the sponsor (baby's healthy status). 
10.5. 
SPONSOR'S RESPONSIBILITIES FOR SAFETY REPORTING 
 
PURPOSES 
Sponsor will submit expedited and periodic reports to both Competent Authorities and Ethics 
Committees per corporate standard operating procedures as regards to the EU directive 
2001/20/EC taking into account local specific requirements. 
11. DATA COLLECTION AND STUDY MONITORING 
11.1. 
DATA COLLECTION 
11.1.1. Case Report Form 
An electronic Case Report Forms (e-CRF) will be used to record all patient data required by the 
protocol except the central ECG (Holter ECG, TTEM) and DHA data which will be transferred 
from vendors to the subcontractor as electronic data files and which will be loaded into the study 
database.  
The e-CRF should be fully validated, compliant with ICH-GCP requirements and European 
regulations and include a traceability system for data corrections and deletions (audit trail). 
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Prior to the start of the study, the Investigator will complete a "Delegation of significant study-
related duties" form. The signature and initials of all personal in charge of e-CRF completion 
should be recorded on this form. Each person involved in e-CRF completion, review, correction 
and / or validation will be trained and will have an individual login and access code to the e-CRF. 
Training sessions will be held by the subcontractor for all participants who will use this tool. An 
e-CRF user manual will be available for investigators and CRAs.  
All the information included into the e-CRF will be recorded from source documents onto the e-
CRF by an authorised person. 
The Investigator is responsible for the management and accuracy of the information on the  
e-CRF. At each monitoring visit, the e-CRF(s) should be at the CRA's disposition for review and 
validation. 
At the end of the study, a CD-ROM containing the pdf version of all e-CRF (including audit-trail) 
will be sent by the subcontractor to the Sponsor and to the investigational sites for archiving. The 
subcontractor must store all study data for at least 15 years after the end of the study and ensure 
their legibility and accessibility during all the storage period. 
11.1.2. Source Documents 
A source document is an original record or certified copy of an original record of clinical findings, 
observations or any other medical or paramedical activities performed during the clinical trial, 
necessary for the transcription and the verification of the collected data. 
Source documents along with all other trial-related documents (copies of all "informed consent" 
forms, e-CRFs CD-ROM, drug inventories and any correspondence related to the study) must be 
kept in the investigator's file throughout the study, and then, must be stored in the study centre's 
archives for a period of at least 15 years or as per local legal requirements, whatever is the 
longest.  
For further details see section 15.2. 
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11.2. 
STUDY MONITORING 
11.2.1. Monitoring visits 
On-site visits will be carried out by a representative of the Sponsor's staff (Study Manager or 
CRA) prior to study initiation and at regular intervals (every 4 to 6 weeks) throughout the study. 
Additional visits and communication by telephone fax or meeting may be performed if necessary. 
Any site visit performed by the Sponsor's representatives will be recorded in the Investigator's 
study file. 
11.2.1.1. 
Site Preselection Visit 
Before selecting a centre for the study, a visit will be carried out by the CRA and/or the Study 
Manager to ensure that the Investigator has the necessary capacities (availability, patient's 
recruitment, environment), technical means and staff to carry out the study. 
11.2.1.2. 
Initiation Visit 
Before the start of the study at all investigation sites, an initiation visit will be carried out by the 
CRA to check at the latest that: 
• The Investigator: 
− has received the technical protocol, administrative and financial agreement signed by all 
parties 
− has received the written statement of the Ethics Committee approval and the list of its 
members and their functions 
• The original dated and signed curriculum vitae of the investigator(s) has been collected 
• Laboratory normal ranges have been collected  
• All study materials are available on the study site 
• All participants agree with the monitoring procedures and know the study procedures 
• All participants are aware of a possible audit or inspection 
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The CRA has also to provide training on the study protocol requirements and study specific 
procedures. 
11.2.1.3. 
Follow-up Visits 
Throughout the study, regular follow-up visits will be carried out by the CRA to check 
compliance with GCP, patient’s informed consents, strict application of the protocol, conformity 
of the data entered on the e-CRF with the source documents and ensure its correct completion, 
adverse events reporting, proper retention, storage and management of the study medication, as 
well as the source and other trial-related documents. 
11.2.1.4. 
Closing Visit 
At the end of the study, a final visit will be carried out by the CRA to: 
• Verify that the e-CRFs CD-ROM with pdf files are correctly stored 
• Control the accountability of intact and used treatment units and return them to the Clinical 
Pharmacy Department of the IRPF for destruction 
• Obtain the last data clarifications and/or solutions if any 
• Collect the patient's consent forms in sealed envelopes (except in case of specific country 
requirements),  
• Make an on-site review of all study documentation and complete it if necessary 
• And finally, remind the Investigator of his regulatory obligations, study document archiving 
process and duration. 
11.2.2. Direct Access to Source Documents 
In accordance to the requirements of the GCP, all Sponsor representatives (Study Manager, CRA 
and Auditors) have to be given a direct access to all source and study data to perform quality 
monitoring/audit, thus ensuring accuracy and completeness of data).  
Investigators are reminded that all Sponsor representatives keep professional confidentiality with 
regards to the patient data. 
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11.3. 
INDEPENDENT DATA MONITORING COMMITTEE 
An Independent Data Monitoring Committee (IDMC) will be established to assess at intervals the 
progress of the clinical trial, the compliance with the inclusion criteria, the quality of follow up, 
the quality of measures of primary end point, the safety data and to recommend to the Sponsor 
whether to continue, modify, or to stop the study.  
The IDMC operating procedures will be described in an independent document.  
12. DATA MANAGEMENT  
All clinical data related to the study will be collected and saved in a computerised database by the 
Data Management Department of the subcontractor and under the supervision of the Data 
Manager of Pierre Fabre Biometry (PFB) according to the following procedures.  
12.1. DATA ENTRY 
All required data will be collected by the Investigator or authorised designee (duly identified into 
the delegation task list) on a e-CRF.  
The e-CRF used for this study will be developed and maintained by the Data Management 
Department of the subcontractor and approved by the Sponsor.  
Electronic data (Holter ECG, TTEM and DHA) will be transferred by the 3rd party vendor 
according to the specifications given by the Data Manager of the subcontractor. These data will be 
captured and handled in accordance with the European GCP ICH E6 guideline. 
12.2. 
DATA CLEANING 
The subcontractor will define in the Data Validation Plan for reviewing and querying data, 
descriptions of both manual and electronic edit checks. Upon Sponsor approval, the subcontractor 
will program the checks.  
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The subcontractor will review the data over the course of the study, working with the Sponsor to 
identify data inconsistencies. The Investigator will be asked to resolve queries by making changes 
directly into the e-CRF.  
12.3. 
DATA CODING 
Adverse events, concomitant diseases, medical/surgical histories will be coded by the 
subcontractor using the MedDRA dictionary (latest version in use). 
Concomitant medication will be coded by the subcontractor using the WHO-DRUG dictionary 
(latest version in use).  
The Sponsor Clinical Development Physician will validate coding. 
12.4. 
DATA STORAGE 
The computer data files, as well as their modifications, will be archived by the subcontractor and 
kept available upon request of the Sponsor. 
12.5. 
DATABASE LOCK 
The validated database will be locked by the subcontractor upon request of the Data Manager of 
PFB following the completion of all steps required, i.e.: data entry and check of all data, 
resolution of all queries, validation of the coding, Clinical and Products Safety databases 
reconciliation and validation committee.  
Then, the subcontractor will transfer the locked database in SAS format to the Data Manager of 
PFB who assume storage on the PFB secured server. 
13. STATISTICAL ANALYSIS 
After the database lock and the randomisation code release, the statistical analysis will be 
performed by Pierre Fabre Biométrie (PFB) or under the supervision of the statistician of PFB 
using SAS® software, according to the Statistical Analysis Plan (SAP) approved by the Validation 
Committee. 
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13.1. 
GENERAL CONSIDERATIONS 
The main objective of the study is to assess the efficacy of F373280 versus placebo on the 
maintenance of sinus rhythm after direct electrical cardioversion in patients with persistent atrial 
fibrillation and chronic heart failure. 
Only the primary analysis of the primary efficacy criterion, on which is based the sample size 
justification, may lead to a causal interpretation. All other statistical results are to be regarded 
within a descriptive perspective. 
The statistical significance level of the various two sided tests of all analyses will be 5 %. 
13.2. 
SAMPLE SIZE 
Assuming an AF recurrence rate of 85% under placebo and 65% under active group, i.e. a 
clinically relevant difference ∆ of 20%, a sample size of 64 evaluable patients per group is 
required, using a log-rang test of survival curves with a 80 % power and a 5 % two-sided 
significance level. 
According to the previous assumptions and assuming a rate of not assessable patients of 15%, a 
minimum of 76  patients will have to be randomised per group. 
13.3. PROTOCOL DEVIATIONS 
Prior to the database lock and the randomisation code release, the Validation Committee members 
will review the protocol deviations and will classify them as either minor or major. A protocol 
deviation will be considered major when it is likely to bias significantly the treatment effect 
estimate based on the primary efficacy criterion. 
Patients with major deviation(s) will be excluded from the Per Protocol data set (see section 13.4). 
A listing of all protocol deviations will be provided for all randomised patients, including the type 
(major/minor) of protocol deviations according to the decisions made by the members of the 
Validation Committee. 
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The number and percentage of patients with major protocol deviations will be tabulated by 
treatment group and type of major protocol deviations on the Full Analysis Set defined in section 
13.4. 
13.4. DATA SETS ANALYSED 
The following 2 data sets will be analysed (as defined by the Validation Committee):  
 
• The Safety Set composed of all randomised patients having received at least one dose of the 
study treatment. This data set will be used to perform analyses of Safety 
• The Full Analysis Set (FAS) composed of all randomised patients having received at least one 
dose of the study treatment and with a successful cardioversion observed at visit 3. This data set 
will be used to perform analyses of Efficacy.  
• The Per Protocol Set (PP) which is the subset of the Full Analysis Set composed of all patients 
with a primary efficacy criteria available and without any major protocol deviation or other source 
of bias for primary criteria analyses. 
13.5. 
HANDLING OF DROPOUTS AND MISSING DATA 
13.5.1. Dropouts 
The number of patients who withdraw from the study after their randomisation will be provided 
by treatment group for all treated patients (Safety Set). All withdrawn patients will be further 
described regarding their time to dropout and reasons for withdrawal. 
13.5.2. Repositioning of Visits 
No repositioning of visits will be done. 
13.5.3. Missing Data 
Missing values will not be substituted by estimated values, but considered as missing in statistical 
analysis. 
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13.6. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Before the first trial drug intake, patient’s background, medical and surgical history, demographic 
data and disease characteristics will be described by treatment group on the Safety Set. 
- Quantitative parameters will be described by treatment group and overall using the 
following: number of patients, number of missing data, mean, standard deviation, 
minimum, median and maximum values. 
- Qualitative parameters will be described by treatment group and overall using 
frequencies. 
Concomitant diseases, as well as medical and surgical histories will be tabulated descriptively by  
treatment group and overall using the MedDRA codes of System Organ Classes and preferred 
terms. 
If more than 10% of patients are excluded from the FAS and PP set, the description of patients by 
treatment group at selection and inclusion will be repeated on the FAS and PP set for all 
parameters. 
No statistical test of comparability of treatment groups at baseline will be performed.  
13.7. 
EFFICACY ANALYSIS  
13.7.1. Primary Criterion  
13.7.1.1. 
Primary Analysis 
The primary criteria, time to first recurrence, will be analysed using the Kaplan Meier method and 
compared with the Log rank test. Hazard ratios and 95% confidence intervals will be estimated 
with the Cox regression model. 
The primary analysis will be performed on the FAS. 
13.7.1.2. 
Supportive Analysis 
The primary analysis will be repeated on the PP set. 
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13.7.2. Secondary Criteria 
All secondary analyses will be performed on the FAS. If more than 10% of patients are excluded 
from the PP set, the secondary analyses will be repeated on the PP set.  
13.7.2.1. Numbers of Atrial Fibrillation Episodes 
Both the numbers of AF episodes (symptomatic or not) lasting for at least 10 minutes and with 
duration less than 10 minutes (NSup10 and NInf10) will be described by treatment group and 
compared by the chi-square test (or CMH test adjusted for centre) or Fisher’s exact Test. 
13.7.2.2. Duration of Atrial Fibrillation Episodes 
The duration of all AF Episodes will be described by treatment group and compared using the 
Student t (or using an ANOVA with treatment and centres effects) or Wilcoxon test. 
13.7.2.3. Time to first AF recurrence less than 10 minutes or symtomatic 
The time to the first AF recurrence less than 10 minutes and the time to the first symptomatic AF 
recurrence will be analysed as the primary analysis.  
13.7.2.4. Clinical parameters evaluation 
The EHRA score will be described by treatment group and analysed using a chi-squared test (or 
CMH test adjusted for centre) or Fisher’s exact Test.  
The frequency of presumed arrhythmia will be described by treatment group. 
The number of recurrence of symptomatic AF, of hospitalizations (for cardiovascular events, for 
thromboembolic stroke and for all causes), of spontaneous cardioversion, of successful 
cardioversion (including number of shocks distribution) and the number of patients needing 
cardioversion after initial ECV will be described by treatment group and compared using a chi-
square test or a Fisher Test (if the numbers are relevant).  
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The duration of hospitalizations for cardiovascular events, for thromboembolic stroke and for any 
cause will be described by treatment group and compared using the Student t (or using an 
ANOVA with treatment and centre effects) or Wilcoxon test. 
The echocardiographic parameters values will be described at each time (V1, V2, V4, V6 and V9) 
and changes described from V4 to V9 and from V2 to V9. 
13.7.2.5. Biomarker analysis: red blood cell concentrations of DHA 
Values and changes from baseline for red blood cell concentration of DHA will be performed by 
treatment group and assessment time. 
13.8. 
SAFETY ANALYSIS 
The Safety Set will be used to perform all analyses of the safety criteria. 
13.8.1. Adverse Events 
Any adverse event having been reported during the study for a given patients will be classified by 
preferred term and corresponding system organ class using the MedDRA terminology. 
Adverse events will be classified as: 
• Treatment emergent adverse events, i.e., any adverse event which occurs or worsens on study 
treatment during the randomised period. 
• Or non treatment emergent adverse events, i.e., any adverse event which occurs during the 
run-in period (before V2) or is reported as concomitant disease with the same intensity. 
For each study period, any patient with at least one reported adverse event will be classified as a 
patient: 
• With at least one adverse event 
• With at least one treatment emergent adverse event 
• With one TEAE 
• With two TEAE 
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• With at least three TEAE 
• With at least one related TEAE 
• With an adverse event leading to the study treatment discontinuation (definitive or 
temporary) 
• With an adverse event leading to withdrawal 
• With at least one serious adverse event. 
• 
Numbers and percentages of patient with at least one reported treatment emergent adverse 
event will be tabulated by treatment group: 
• By system organ class 
• By system organ class and preferred term 
• By system organ class and preferred term, taking into consideration its most severe 
intensity 
• And by system organ class and preferred term, taking into consideration the most severe 
relationship to the study treatment. 
Recurring adverse events (i.e., adverse events classified with the same preferred term) for a given 
patient will only be counted once and only their most severe intensity or most severe relationship 
to the study treatment will be tabulated. 
"The number and percentage of patient with at least one most common (reported in 1% patients in 
any group) drug related TE AE ("not excluded or unassessable") will be tabulated by Preferred 
Term and Treatment group in decreasing order for the treatment group (for all patient). 
The number and percentage of patients with at least one reported most common treatment 
emergent adverse event will also be plotted by treatment group. This graphical representation will 
highlight the frequencies of the most severe intensities reported by system organ class and 
preferred term. 
Serious adverse events will also be described on an individual basis: treatment group, patient's 
code, sex and age, Investigator's reported term, preferred term, time of onset according to the time 
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of the first study treatment administration, duration, action taken regarding the study treatment 
administration, use of a corrective treatment, outcome and relationship to the study treatment in 
the Investigator’s opinion. 
13.8.2. Clinical Laboratory Evaluation  
For each laboratory parameter, data will be tabulated by treatment group and assessment time. 
The absolute changes post-trial drug administration - baseline (the baseline value being the value 
measured on the last blood sample collected before the first trial drug administration) will be 
calculated and tabulated by parameter, treatment group and post-trial drug administration 
assessment time. Results of retests performed post-trial drug administration will not be analysed 
and tabulated. They will only be displayed in individual data listings. 
For all biochemistry parameters, scatter plots highlighting individual results will display the 
baseline and week 24 of the laboratory measurements for each patient by locating the point 
defined by the baseline value on the abscissa and respectively week 24 value in the ordinate.  
For all haematology parameters, scatter plots highlighting individual results will display the 
baseline and week 4, week 12 and week 24 of the laboratory measurements for each patient by 
locating the point defined by the baseline value on the abscissa and respectively week 4, week 12 
and week 24 value in the ordinate.  
Each treatment group will be identified differently. The first bisecting line (45° line), the lines of 
lower and upper normal range, the lines of PSC range and CNALV range added on the plots (see 
Appendix 17.3). 
For all blood laboratory parameters, shift tables will be provided to depict the numbers of  patients 
with post-trial drug administration variations at each assessment time as compared to the baseline 
values (measured on the last blood sample collected before the first trial drug administration) by 
treatment group. A 3-point scale (low, normal, high) will be used as defined by the normal ranges 
in use in the laboratory in charge of the assays. 
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Clinically noteworthy abnormal laboratory values (CNALV) (see in Appendix 17.3) will be 
identified and described on an individual basis. If relevant, five separate individual data listings by 
treatment group will be provided: 
• CNALV for haemoglobin (including corresponding individual results of erythrocytes and 
haematocrit) 
• CNALV for neutrophils or leucocytes (including corresponding individual results of 
basophils, eosinophils, lymphocytes and monocytes) 
• CNALV for platelets (including corresponding individual results of erythrocytes and 
leucocytes) 
• CNALV for liver function parameters (including corresponding individual results of 
gamma-GT) 
• CNALV for serum creatinine  
13.8.3. Global Physical Examination 
Recorded data of the global physical examination performed will not be tabulated as any 
abnormal findings post-randomisation should be reported as AEs (if clinically significant). 
Physical examination assessments will be provided in the listings of individual data. 
13.8.4. Vital Signs, Physical Findings and Other Observations Related to Safety 
13.8.4.1. 
Vital Sign Measurements Over Time 
For each parameter (systolic blood pressure, diastolic blood pressure and heart rate in supine and 
standing positions), descriptive statistics over time of values and changes from baseline will be 
tabulated by treatment group and assessment time. 
13.8.4.2. 
Body weight 
Descriptive statistics over time of values and changes from baseline will be tabulated by treatment 
group and assessment time. 
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13.8.4.3. 
Individual Patient Changes 
The number and percentage of patient with at least one Predefined Potentially Clinically 
Significant Change (PSC) and with at least one PSC Leading to Clinically Significant Value 
(PSCV) will be tabulated by treatment group (see Table 1 in Appendix 17.3).  
According to the pharmacological drug profile mentioned previously in this Protocol, the changes 
from baseline to the maximum and/or minimum post-baseline value could be categorized and 
tabulated by treatment group with frequencies and decreasing cumulative percentages. 
If there is a signal of a drug effect toward one direction rather than the other, additionally shift 
tables of variations from baseline to the maximum or minimum post-baseline value could be also 
provided (see Table 2 to 4 in Appendix 17.3). 
An individual data listing of patients with symptomatic or asymptomatic orthostatic hypotension 
will be provided by treatment group (see Table 5 in Appendix 17.3). 
13.8.5. ECG 
Frequencies on the clinical interpretation (normal, abnormal CS or NCS) will be presented by 
treatment group and assessment time. Individual tabulated data for ECG abnormalities will be also 
displayed. 
13.8.6. Coagulation parameters 
Scatter plots highlighting individual results for coagulation parameters (prothrombin time/INR, 
activated partial thromboplastin time and thrombin clotting time) before and after study treatment 
administration will be produced. 
13.9. CONCOMITANT TREATMENTS 
Concomitant treatments will be tabulated by treatment group within a descriptive perspective. 
They will be classified by therapeutic area according to the WHO-DRUG dictionary using the 
"anatomical therapeutic chemical" (ATC) classification on the safety set. 
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13.10. 
COMPLIANCE 
 
The percentage of compliance will be described by treatment group using the quantity 
 
100
_
_
_
(%)
×
=
n
consumptio
l
Theoretica
n
consumptio
actual
Estimated
Compliance
 
 
 
with: Estimated actual consumption = number of tablets provided at the start of study (Visit 2) – 
number of tablets returned at the end of study (Visit 9) 
Theoretical consumption = number of days of treatment intake planned between the start and the 
end of study (168 days ± 7days). 
 
13.11. 
INTERIM ANALYSIS AND DATA MONITORING 
No interim analysis is planned. 
14. GENERAL ETHICAL CONSIDERATIONS  
14.1. 
ETHICAL CONDITIONS 
This study is performed in accordance with the principles stated in the Declaration of Helsinki 
(1964) and subsequent amendments and in accordance with the Good Clinical Practice Guideline 
(CPMP/ICH/135/95). 
14.2. 
ETHICS COMMITTEE AND LEGAL REQUIREMENTS 
All the documents required by National Regulations and any other informative documents that 
may be requested are submitted for review to an Ethics Committee whose procedures and 
operations meet the GCP and National Legal Requirements. 
Depending on National Regulations, the application is submitted to the Ethics Committee by the 
Sponsor (or representative) or by the Investigator. 
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A copy of the formal written approval from the Ethics Committee is provided to the Sponsor 
(directly by the Ethics Committee or via the Investigator) with a list of names and qualifications 
of its members. 
The request for authorisation by the Competent Authority or its notification if required (depending 
on National Regulations) is carried out by the Sponsor. 
The screening of patients does not start before the approval of the Ethics Committee has been 
obtained and the study authorised by the Competent Authority or notified to the Competent 
Authority (depending on National Regulations). 
14.3. 
PATIENT'S INFORMATION LEAFLET AND INFORMED CONSENT 
 
FORM 
An information must be given to the patients before their decision to participate or abstain from 
participation. 
This information is based on the elements set out in the Declaration of Helsinki and the ICH GCP 
Guidelines. It must also describe the measures taken to safeguard patient’s privacy and protection 
of personal data, according to European Directive 95/46 EC or other local regulation. 
Restraints and risks must be explained, as well as the right to discontinue participation in the 
study at any stage, without affecting their further relationship with the Investigator and/or their 
future care. 
The written information and consent form must be submitted to the patient with an oral 
explanation. It must be agreed and signed by the patient before any study-related procedure starts. 
This information and consent procedure is under the Investigator’s responsibility. 
The information and consent document are made in triplicate: the original copy is kept by the 
Investigator, one copy is given to the patient and the last copy is kept by the Clinical Quality 
Assurance Unit of the Sponsor in a sealed envelope at the end of study (except in case of specific 
country requirement). 
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Specific areas of the Sponsor’s copy are not triplicated to avoid the reading of the patient’s 
surname (except the first 3 letters), first name, address and signature.  
If any information becomes available during the trial that may be relevant to the patient’s 
willingness to keep on participating in the trial, an updated written informed consent must be 
submitted to the patient to confirm  agreement to continue participating. 
14.4. 
PERSONAL DATA PROTECTION 
All information from this study (excluding data from the informed consent) is entered into a 
computer under the Sponsor’s responsibility in accordance with the French law, "Loi 
Informatique et Libertés" (January 6, 1978, and subsequent amendments) and with the European 
Directive 95/46/CE. 
14.5. 
INSURANCE POLICY 
In accordance with the provisions of the law and the GCP, the Sponsor Pierre Fabre Médicament, 
has an insurance policy intended to guarantee against possible damage resulting from the research. 
The studies and/or experiments performed on behalf of the Sponsor Pierre Fabre Médicament, are 
specifically and expressly guaranteed. 
It is advisable to underline that non compliance with the Research Legal Conditions is a cause for 
guarantee exclusion. 
15. ADMINISTRATIVE PROCEDURES 
15.1. 
PROTOCOL AMENDMENT 
Neither the Investigator nor the Sponsor may alter the protocol without the authorisation of the 
other party.  
All changes to the protocol are subject to an amendment which must be dated and signed by both 
parties and must appear as an amendment to the protocol. 
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Substantial amendments are submitted for approval / authorisation to the Ethics Committees and 
Competent Authorities 
Urgent amendments are submitted for approval / authorisation to the Ethics Committees and 
Competent Authorities, but could be implemented immediately under specific conditions defined 
with the Sponsor. 
15.2. 
SOURCE DOCUMENTS, INVESTIGATOR'S FILE STORAGE 
The Investigator: 
• Keeps all trial-related documents in appropriate file folders. Records of patient, original 
informed consent forms, source documents, a CD Rom containing a pdf copy of e-CRF, drug 
inventory, Ethics Committees and Sponsor correspondence pertaining to the study must be kept 
on file. 
• Retains all documents relating to the screening (consent and investigation results) of all 
patients included in the trial or not 
• Retains a list of the patient’s names, addresses (and/or number of medical file), code numbers 
to allow checking of data reported on e-CRFs with those from source documents 
• Authorises direct access to source documents for monitoring, audits and inspections 
• The trial-related documents must be retained as strictly confidential at the Investigator’s site 
for at least 15 years or according to local requirements, whatever is the longest after the 
completion or discontinuation of the trial (European Directive 2003/63/EC). 
15.3. 
END OF THE STUDY 
15.3.1. Definition of the End of Study 
The end of study is the last visit of the last patient undergoing the trial. 
Any change to this definition during the study, for whatever reason, must be notified as a 
substantial amendment. 
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15.3.2. Early Study Termination 
15.3.2.1. 
Early Study Termination Decided by the Sponsor 
The Sponsor may discontinue the study at any time for any of the following reasons: 
• Lack of recruitment 
• Deviations from good clinical practice and/or regulations 
• Poor product safety 
• New information that could jeopardise the patient’s safety 
• Stopping of the development … 
15.3.2.2. 
Early Study Termination Decided by the Competent Authorities 
The Competent Authorities may suspend or prohibit a study if it considers that the conditions of 
authorisation are not being met or has doubt about the safety or scientific validity of the study. 
15.4. 
AUDIT 
The 
Sponsor 
is 
responsible 
for 
making 
sure 
that 
both 
his 
representatives 
(Study Manager, CRA, ...) and the Investigator fulfil the requirements as specified by the GCP 
Guideline.  
An audit can be organised internally at Pierre Fabre Médicament and at the investigational site 
where the e-CRFs are matched against source documents. 
All study documentation must be directly accessible to auditors. 
The practical conditions for the audit are discussed between the Investigator and the Clinical 
Quality Assurance Department. 
Oral information about the audit results are given to the Investigator. 
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15.5. INSPECTION 
The Health Authorities may inspect any investigation site or the Sponsor in the course of the study 
or after its completion, to verify the conduct of the study and quality of the data. The Investigator 
must provide to the inspectors direct access to study documents. 
15.6. CONFIDENTIALITY 
The present materials (protocol and related documentation, e-CRF, Investigator's Brochure) 
contain confidential information.  
Except if agreed to in writing with the Study Manager, the investigators must hold such 
information confidential, and must not disclose it to others (except where required by Applicable 
Law). 
15.7. CLINICAL STUDY REPORT 
Data analysis, and clinical study report writing are under the Sponsor’s responsibility.  
Upon completion of the data analysis, a final report, including a review of the objectives and 
methods, a presentation and discussion of the results are drawn up according to ICH Guidelines 
(Structure and Content of Clinical Study Reports, ICH-E3, CPMP/ICH/137/95). 
The report is a clinical and statistical integrated report. It must be signed by the Sponsor's 
representative(s) and the Coordinating Investigator. 
15.8. STUDY RESULTS COMMUNICATION 
Upon completion of the study, the global results of the Research are communicated to the 
investigator. According to the Local Regulation, the patient can ask the Investigator for the 
results. 
15.9. STUDY RESULTS PUBLICATION 
The information and data collected during the conduct of this clinical study are considered 
confidential and are used by the Sponsor in connection with the development of the study drug. 
This information may be disclosed if deemed necessary by the Sponsor. 
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To allow use of the information derived from this clinical study and to insure compliance with 
Current Regulations, the Investigator must provide the Sponsor with complete test results and all 
data collected during the study.  
Only the Sponsor may make study information available to physicians and to Regulatory 
Agencies, except as required by Current Regulations. 
All the results of this study including data, reports, discoveries and inventions resulting from the 
study, are the property of the Sponsor. 
In the event the Sponsor chooses to publish study data, the manuscript must be provided to the 
author(s) at least 30 days prior to the expected date of submission to the intended publisher. 
The investigator(s) can reserve the right to publish or present study data; if so, the manuscript or 
abstract must be provided to the Sponsor for review at least 30 days prior to the expected date of 
submission to the intended publisher or of planned presentation. 
In addition, if necessary, (the) investigator(s) shall withhold publication for an additional 60 days, 
to allow the filing of a patent application, or to allow the Sponsor to take any measures he deems 
appropriate to establish and preserve his proprietary rights. 
It is agreed that publication of study results by each site shall be made only as part of a 
publication of the study results obtained by all sites performing the protocol, once the study is 
completed and finalised.  
The authors list is agreed by all investigators prior to publication. The names of the authors are 
provided according to their participation in the design of the protocol as well as their recruitment 
of eligible and analysable patients. 
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16. REFERENCES 
 
[1] 
F373280 INVESTIGATOR'S BROCHURE, version January 2013 
 
[2] 
NODARI S., TRIGGIONAI M., CAMPIA U., MANERBA A., MILESI G., CESANA 
M.B., GHEORGHIADE M., DEI CAS L. 
n-3 Polyunsaturated Fatty Acids in the prevention of atrial Fibrillation Recurrences after 
electrical cardioversion. A prospective, Randomised study 
Circulation, 2011; 124:1100-1106 
 
[3] 
NODARI S., TRIGGIANI M., CAMPIA U., MANERBA A., MILESI G., CESANA 
M B., GHEORGHIADE M., DEI CAS L. 
Effects of n-3 polyunsaturated fatty acids on left ventricular function and functional 
capacity in patients with dilated cardiomyopathy 
J. Am. Coll. Cardiol. 2011;57;870-879 
 
[4] 
MOERTL D., HAMMER A., STEINER S., HUTULEAC R., VONBANK K., 
BERGER R. 
Dose-dependant effects of omega-3-polyunsaturated fatty acids on systolic left ventricular 
function, endothelial function, and markers of inflammation in chronic heart failure of non 
ischemic origin: A double-blind, placebo-controlled, 3-arm study  
American Heart Journal 2011; 161:915.e1-915.e9 - volume 161, number 5 
 
[5] 
GISSI-HF INVESTIGATORS 
Effects of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GSSI-
HF Trial): a randomised, double-blind, placebo-controlled trial 
The lancet on line - August 2008 
 
[6] 
CAMM A.J., KIRCHHOF P., LIP G.Y., SCHOTTEN U., SAVELIEVA I., ERNST S., 
VAN GELDER I.C., AL-ATTAR N., HINDRICKS G., PRENDERGAST B., 
HEIDBUCHEL H., ALFIERI O., ANGELINI A., ATAR D., COLONNA P., DE 
CATERINA R., DE SUTTER J., GOETTE A., GORENEK B., HELDAL M., 
HOHLOSER S.H., KOLH P., LE HEUZEY J.Y., PONIKOWSKI P., RUTTEN F.H. 
Guidelines for the management of atrial fibrillation: the Task Force for the Management of 
Atrial Fibrillation of the European Society of Cardiology (ESC). 
European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery,  
Eur Heart J. 2010 Oct;31(19):2369-429 
 
 
[7] 
KOWEY PR, REIFFEL JA, ELLENBOGEN KA, NACCARELLI GV, PRATT CM. 
Efficacy and safety of prescription omega-3 fatty acids for the prevention of recurrent 
symptomatic atrial fibrillation: a randomised controlled trial. 
JAMA. 2010;304:2363–2372. 
 
 
 
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[8] 
BIANCONI L., CALO L., MENNUNI M., SANTINI L., MOROSETTI P., 
AZZOLINI P., BARBATO G., BISCIONE F., ROMANO P., SANTINI M.  
N-3 polyunsaturated fatty acids for the prevention of arrhythmia recurrence after electrical 
cardioversion of chronic persistent atrial fibrillation: a randomised, double-blind, 
multicentre study  
Europace (2011) 13, 174-181 
 
[9] 
OMACOR® SUMMARY PRODUCT CARACTERISTICS (SPC) dated 17/02/2012 
 
[10] 
BEPANTHENE ® SUMMARY PRODUCT CARACTERISTICS (SPC) 
 
[11] 
TOUBOUL P, BRUGADA J, CAPUCCI A, CRIJNS HJ, EDVARDSSON N, 
 
HOHNLOSER SH.  
Dronedarone for prevention of atrial fibrillation: a dose-ranging study.  
Eur Heart J 2003;24(16):1481-7. 
 
[12] LE HEUZEY JY AND ALL.  
A Short-Term, Randomised, Double-Blind, Parallel-Group Study to Evaluate the Efficacy 
and Safety of Dronedarone versus Amiodarone in Patients with Persistent Atrial 
Fibrillation: The DIONYSOS Study. 
J Cardiovasc Electrophysiol. 
 
[13] METCALF G.R., JAMES J.M., GIBSON A.R., EDWARDS J., STUBBERFIELD J., 
STUKLIS R., YOUNG D.G., ROBERTS-THOMSON K. & CLELAND G.L.M.L. & 
OKEN H. 
Effects of fish-oil supplementation on myocardial fatty acids in humans.  
Am J Clin Nutr (2007); 85 : 1225. 
 
[14] ARTERBURN M.L. & OKEN H. 
Distribution, interconversion and dose response of n-3 fatty acids in humans.  
Am J Clin Nutr (2006);83 : 1469-1473S. 
 
[15] TIELEMAN RG, VAN GELDER IC, CRIJNS HJ, DE KAM PJ, VAN DEN BERG 
MP, HAAKSMA J, VAN DER WOUDE HJ, AND ALLESSIE MA. 
Early recurrences of atrial fibrillation after electrical cardioversion: a result of 
fibrillation-induced electrical remodelling of the atria? 
J. Am. Coll. Cardiol. 1998;31;167-173 
 
[16] 
SALM P, TAYLOR PJ, KOSTNER K 
Simultaneous quantification of total eicosapentaenoic acid, docosahexaenoic acid and 
arachidonic acid in plasma by high-performance liquid chromatography-tandem mass 
spectrometry.  
Biomed Chromatogr 2011 Jun;25(6):652-9. 
 
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[17] LEGRAND P., SCHMITT B., MOUROT J., CATHELINE D., CHESNEAU G., 
MIREAUX M., KERHOAS N., WEILL P. 
The consumption of food products from linseed-fed animals maintains erythrocyte omega-3 
fatty acids in obese human 
Lipids, 2010, 45, 11-19. 
 
[18] HARRIS WS, VON SCHACKY C. 
The Omega-3 Index: a new risk factor for death from coronary heart disease? 
Prev Med. 2004 Jul; 39(1):212-20 
 
[19] ABSTRACT: P5161 . 
NODARI S, MANERBA A., MADURERI A., BERLINGHIERI N., PULCINI E., 
FRATTINI S., METRA M, DEI CAS L. 
Effects of Polyunsaturated Fatty Acids n-3 (PUFA n-3) in the prophylaxis of atrial 
fibrillation relapses after external electric cardioversion 
World Congress of Cardiology 2006, 2-6 September, Barcelona – Spain 
 
[20] 
KIRCHHOF P., AURICCHIO A., BAX J., CRIJNS H., CAMM J., DIENER HC., 
 
GOETTE A., HINDRICKS G., HOHNLOSER S., KAPPENBERGER L., KUCK 
 
KH., LIP HYG., OLSSON B., MEINERTZ T., PRIORI S., RAVENS U., 
 
STEINBECK G., SVERHAGE E., TIJSSEN J., VINCENT A., BREITHARDT G. 
 
Outcome parameters from a consensus conference organized by the German Atrial 
 
Fibrillation Competence NETwork and the European Heart Rhythm Association. 
 
Europace 2007, 9, 1006-1023 
 
[21] 
EUROPEAN MEDICINES AGENCY 
 
Addendum to the guideline on antiarrhythmics on atrial fibrillation and atrial flutter. 
 
EMA/CHMA/EWP/213056/2010 
 
[22] 
OWEN AJ, PETER-PRZYBOROWSKA BA, HOY AJ, MCLENNAN PL. 
Dietary fish oil dose- and time-response effects on cardiac phospholipid fatty acid 
composition. 
Lipids. 2004;39:955–961 
 
[23] 
ROBERTO M. LANG, MICHELLE BIERIG, RICHARD B. DEVEREUX, FRANK 
A. FLACHSKAMPF*, ELYSE FOSTER, PATRICIA A. PELLIKKA, MICHAEL H. 
PICARD, MARY J. ROMAN, JAMES SEWARD, JACK SHANEWISE, SCOTT 
SOLOMON, KIRK T. SPENCER, MARTIN ST. JOHN SUTTON, WILLIAM 
STEWART. 
 
Recommendations for chamber quantification 
 
Eur J Echocardiography (2006) 7, 79-108 
 
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17. APPENDICES 
 
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17.1. DECLARATION OF HELSINKI 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
ETHICAL PRINCIPLES FOR MEDICAL RESEARCH INVOLVING 
HUMAN SUBJECTS 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 29th WMA 
General Assembly, Tokyo, Japan, October 1975 35th WMA General Assembly, Venice, Italy, October 1983 41st 
WMA General Assembly, Hong Kong, September 1989 48th WMA General Assembly, Somerset West, Republic of 
South Africa, October 1996 52nd WMA General Assembly, Edinburgh, Scotland, October 2000 53th WMA General 
Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 55th WMA General Assembly, Tokyo 
2004 (Note of Clarification on Paragraph 30 added) 59th WMA General Assembly, Seoul, October 2008 
 
A. INTRODUCTION  
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of 
ethical principles for medical research involving human subjects, including research on identifiable 
human material and data. The Declaration is intended to be read as a whole and each of its constituent 
paragraphs should not be applied without consideration of all other relevant paragraphs.  
2. Although the Declaration is addressed primarily to physicians, the WMA encourages other participants 
in medical research involving human subjects to adopt these principles.  
3. It is the duty of the physician to promote and safeguard the health of patients, including those who are 
involved in medical research. The physician's knowledge and conscience are dedicated to the fulfilment 
of this duty.   
4. The Declaration of Geneva of the WMA binds the physician with the words, “The health of my patient 
will be my first consideration,” and the International Code of Medical Ethics declares that, “A physician 
shall act in the patient's best interest when providing medical care.”  
5. Medical progress is based on research that ultimately must include studies involving human subjects. 
Populations that are underrepresented in medical research should be provided appropriate access to 
participation in research.  
6. In medical research involving human subjects, the well-being of the individual research subject must 
take precedence over all other interests.  
7. The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic interventions 
(methods, procedures and treatments). Even the best current interventions must be evaluated continually 
through research for their safety, effectiveness, efficiency, accessibility and quality.  
8. In medical practice and in medical research, most interventions involve risks and burdens.  
9. Medical research is subject to ethical standards that promote respect for all human subjects and protect 
their health and rights. Some research populations are particularly vulnerable and need special 
protection. These include those who cannot give or refuse consent for themselves and those who may be 
vulnerable to coercion or undue influence.  
10. Physicians should consider the ethical, legal and regulatory norms and standards for research involving 
human subjects in their own countries as well as applicable international norms and standards. No 
national or international ethical, legal or regulatory requirement should reduce or eliminate any of the 
protections for research subjects set forth in this Declaration.  
 
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B. PRINCIPLES FOR ALL MEDICAL RESEARCH  
11. It is the duty of physicians who participate in medical research to protect the life, health, dignity, 
integrity, right to self-determination, privacy, and confidentiality of personal information of research 
subjects.  
12. Medical research involving human subjects must conform to generally accepted scientific principles, be 
based on a thorough knowledge of the scientific literature, other relevant sources of information, and 
adequate laboratory and, as appropriate, animal experimentation. The welfare of animals used for 
research must be respected.   
13. Appropriate caution must be exercised in the conduct of medical research that may harm the 
environment.  
14. The design and performance of each research study involving human subjects must be clearly described 
in a research protocol. The protocol should contain a statement of the ethical considerations involved 
and should indicate how the principles in this Declaration have been addressed. The protocol should 
include information regarding funding, sponsors, institutional affiliations, other potential conflicts of 
interest, incentives for subjects and provisions for treating and/or compensating subjects who are 
harmed as a consequence of participation in the research study. The protocol should describe 
arrangements for post-study access by study subjects to interventions identified as beneficial in the 
study or access to other appropriate care or benefits.   
15. The research protocol must be submitted for consideration, comment, guidance and approval to a 
research ethics committee before the study begins. This committee must be independent of the 
researcher, the sponsor and any other undue influence. It must take into consideration the laws and 
regulations of the country or countries in which the research is to be performed as well as applicable 
international norms and standards but these must not be allowed to reduce or eliminate any of the 
protections for research subjects set forth in this Declaration. The committee must have the right to 
monitor ongoing studies. The researcher must provide monitoring information to the committee, 
especially information about any serious adverse events. No change to the protocol may be made 
without consideration and approval by the committee.  
16. Medical research involving human subjects must be conducted only by individuals with the appropriate 
scientific training and qualifications. Research on patients or healthy volunteers requires the 
supervision of a competent and appropriately qualified physician or other health care professional. The 
responsibility for the protection of research subjects must always rest with the physician or other health 
care professional and never the research subjects, even though they have given consent.  
17. Medical research involving a disadvantaged or vulnerable population or community is only justified if 
the research is responsive to the health needs and priorities of this population or community and if 
there is a reasonable likelihood that this population or community stands to benefit from the results of 
the research.   
18. Every medical research study involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and communities involved in the research in 
comparison with foreseeable benefits to them and to other individuals or communities affected by the 
condition under investigation.  
19. Every clinical trial must be registered in a publicly accessible database before recruitment of the first 
subject.  
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20. Physicians may not participate in a research study involving human subjects unless they are confident 
that the risks involved have been adequately assessed and can be satisfactorily managed. Physicians 
must immediately stop a study when the risks are found to outweigh the potential benefits or when 
there is conclusive proof of positive and beneficial results.  
21. Medical research involving human subjects may only be conducted if the importance of the objective 
outweighs the inherent risks and burdens to the research subjects.  
22. Participation by competent individuals as subjects in medical research must be voluntary. Although it 
may be appropriate to consult family members or community leaders, no competent individual may be 
enrolled in a research study unless he or she freely agrees.  
23. Every precaution must be taken to protect the privacy of research subjects and the confidentiality of 
their personal information and to minimize the impact of the study on their physical, mental and social 
integrity.   
24. In medical research involving competent human subjects, each potential subject must be adequately 
informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional 
affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort 
it may entail, and any other relevant aspects of the study. The potential subject must be informed of the 
right to refuse to participate in the study or to withdraw consent to participate at any time without 
reprisal. Special attention should be given to the specific information needs of individual potential 
subjects as well as to the methods used to deliver the information. After ensuring that the potential 
subject has understood the information, the physician or another appropriately qualified individual 
must then seek the potential subject’s freely-given informed consent, preferably in writing. If the 
consent cannot be expressed in writing, the non-written consent must be formally documented and 
witnessed.  
25. For medical research using identifiable human material or data, physicians must normally seek consent 
for the collection, analysis, storage and/or reuse. There may be situations where consent would be 
impossible or impractical to obtain for such research or would pose a threat to the validity of the 
research. In such situations the research may be done only after consideration and approval of a 
research ethics committee.   
26. When seeking informed consent for participation in a research study the physician should be 
particularly cautious if the potential subject is in a dependent relationship with the physician or may 
consent under duress. In such situations the informed consent should be sought by an appropriately 
qualified individual who is completely independent of this relationship.  
27. For a potential research subject who is incompetent, the physician must seek informed consent from the 
legally authorized representative. These individuals must not be included in a research study that has 
no likelihood of benefit for them unless it is intended to promote the health of the population 
represented by the potential subject, the research cannot instead be performed with competent persons, 
and the research entails only minimal risk and minimal burden.   
28. When a potential research subject who is deemed incompetent is able to give assent to decisions about 
participation in research, the physician must seek that assent in addition to the consent of the legally 
authorized representative. The potential subject’s dissent should be respected.  
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29. Research involving subjects who are physically or mentally incapable of giving consent, for example, 
unconscious patients, may be done only if the physical or mental condition that prevents giving 
informed consent is a necessary characteristic of the research population. In such circumstances the 
physician should seek informed consent from the legally authorized representative. If no such 
representative is available and if the research cannot be delayed, the study may proceed without 
informed consent provided that the specific reasons for involving subjects with a condition that renders 
them unable to give informed consent have been stated in the research protocol and the study has been 
approved by a research ethics committee. Consent to remain in the research should be obtained as soon 
as possible from the subject or a legally authorized representative.  
30. Authors, editors and publishers all have ethical obligations with regard to the publication of the results 
of research. Authors have a duty to make publicly available the results of their research on human 
subjects and are accountable for the completeness and accuracy of their reports. They should adhere to 
accepted guidelines for ethical reporting. Negative and inconclusive as well as positive results should 
be published or otherwise made publicly available. Sources of funding, institutional affiliations and 
conflicts of interest should be declared in the publication. Reports of research not in accordance with 
the principles of this Declaration should not be accepted for publication.  
 
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE  
31. The physician may combine medical research with medical care only to the extent that the research is 
justified by its potential preventive, diagnostic or therapeutic value and if the physician has good 
reason to believe that participation in the research study will not adversely affect the health of the 
patients who serve as research subjects.   
32. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the 
best current proven intervention, except in the following circumstances:  
• 
The use of placebo, or no treatment, is acceptable in studies where no current proven intervention 
exists; or  
• 
Where for compelling and scientifically sound methodological reasons the use of placebo is 
necessary to determine the efficacy or safety of an intervention and the patients who receive 
placebo or no treatment will not be subject to any risk of serious or irreversible harm.  Extreme 
care must be taken to avoid abuse of this option.  
33. At the conclusion of the study, patients entered into the study are entitled to be informed about the 
outcome of the study and to share any benefits that result from it, for example, access to interventions 
identified as beneficial in the study or to other appropriate care or benefits.  
34. The physician must fully inform the patient which aspects of the care are related to the research. The 
refusal of a patient to participate in a study or the patient’s decision to withdraw from the study must 
never interfere with the patient-physician relationship.  
35. In the treatment of a patient, where proven interventions do not exist or have been ineffective, the 
physician, after seeking expert advice, with informed consent from the patient or a legally authorized 
representative, may use an unproven intervention if in the physician's judgement it offers hope of 
saving life, re-establishing health or alleviating suffering. Where possible, this intervention should be 
made the object of research, designed to evaluate its safety and efficacy. In all cases, new information 
should be recorded and, where appropriate, made publicly available.  
 
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17.2. SAE REPORT FORM 
 
 
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N O T I F I C A T I O N  O F  S E R I O U S  A D V E R S E  E V E N T  ( S A E )  O R  P R E G N A N C Y    
TO PIERRE FABRE PRODUCT SAFETY DEPARTMENT 
 
TO BE TRANSMITTED TO THE MONITOR BY FAX WITHIN 24H : M. GUIRAUD  .............. Fax n° +33 5 34 50 65 92 
Transmission date  
 
 
  
 
  
 
 
 
(ddmmyyyy) 
Country :  
........................................
 
 
 
   SAE N° 
 
 
 
                      FIRST NOTIFICATION           FOLLOW-UP   
 
 SUBJECT CHARACTERISTICS  
 
     Surname    
 
 
 
          First name 
 
 
Birth date  
 
 
 
 
 
 
 
 
  
 
 
Gender 
 
1=M,    2=F 
   Height 
 
 
 
cm 
 Weight 
 
 
 
 
 
kg 
 
 
 DESCRIPTION OF THE EVENT 
The serious adverse event resulted in : 
 Death (whatever may be the cause) 
 Hospitalisation (*) or extension thereof 
 Life threatening 
 Invalidity or disability 
 
 Congenital abnormality or abnormal pregnancy outcome 
 Cancer 
 Other  (any other serious clinical or laboratory event 
     according to the investigator or the protocol, overdosage 
      meeting seriousness criteria, suicide attempts) 
Other fact to be notified : 
 Pregnancy exposure 
Nature of the event (if clinical nature, indicate the diagnosis or the major symptom) : 
........................................................................................................................................................................................................... 
........................................................................................................................................................................................................... 
........................................................................................................................................................................................................... 
AE onset date  |__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
 
Seriousness onset date  |__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
 
Summary description (if clinical cause, significant history, progression of event, available laboratory results, etc...) : 
 
 
 
 
 
 
(*) Except hospitalisations with durations and goals planned in the protocol 
 
 THE SAE IN RELATION TO THE TRIAL 
                                                      TREATMENT NUMBER         |___|___|___|___|___|___| 
• Time of occurrence of SAE 
 
 During the selection or run-in period 
 
 During the administration phase of the study treatment 
 
 After the administration phase of the study treatment 
• Date of first study treatment administration 
• Date of last study treatment administration 
   before the occurence of SAE 
|__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
 
|__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
• Was the blind broken ?       Yes         No          Not applicable 
   If yes, or if this is an open study, drug(s) administered : 
 
 
 
 
 
  Conditions of administration (cycles(s), daily dose(s), route(s) of administration, etc..) :  
 
 
 
 
 
 
 
 
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Transmission date 
 
 
  
 
  
 
 
 
  (ddmmyyyy) 
Country : ............................................ 
 
 
 
  SAE N° 
 
 
 
                     FIRST NOTIFICATION           FOLLOW-UP   
 
 CONCOMITANT MEDICATION SINCE TRIAL INITIATION and UP UNTIL THE OCCURRENCE OF THE SAE 
     (EXCEPT THE TREATMENTS GIVEN FOR THE SAE)  
 
INN or trade name 
 
 
Daily dose 
 
Start date 
(ddmmyy) 
Ongoing at 
occurence of the 
event 
 
Stop date 
(ddmmyy) 
Route of 
admin. 
 
Indication 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 MEASURES TAKEN FOLLOWING THE SAE 
• Study treatment 
 
 No change 
 
 Dosage modification, specify :……………………………..….      Modification Date : 
 
 Temporarily discontinued                                                       Readministration date : 
 
 Withdrawn                                                                                                  End date : 
 
 Not applicable 
 
 
 
 
 ____/____/_____ 
 ____/____/_____ 
 ____/____/_____ 
• The event led to : 
 
 Prescription of corrective or symptomatic treatments (specify names and dosages) : 
 
 
 
 Discontinuation of concomitant treatments (specify names) : 
 
 
 
 Others, specify : 
 
 
 OUTCOME 
         Not recovered/Not resolved                  Recovering/Resolving               Recovered/Resolved 
         Recovered/Resolved with sequelae     Fatal                                          Unknown 
 
                In case of death, has an autopsy been conducted ?       Yes         No 
 
 INVESTIGATOR CAUSALITY ASSESSMENT (investigator’s assessment to be done as soon as possible) 
 Not Suspected                          Suspected                    Insufficient data 
comments : ............................................................................................................................................................. 
 
Enclose in the notification the results of carried out examinations, reports of hospitalisation, etc... 
 
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17.3. PREDEFINED LIMITS OF LABORATORY AND VITAL SIGN 
POTENTIALLY CLINICALLY SIGNIFICANT CHANGES AND VALUES  
 
List of Predefined Potentially Clinically Significant Change For Laboratory Values(¤) 
 
 
PARAMETERS 
UNIT 
PSC 
 
 
 
Decrease 
Increase 
MUSCLE 
Creatine  Phosphokinase 
U / l 
- 
236 
KIDNEY 
Creatinine 
Urea 
Uric acid 
Phosphate 
Calcium 
µmol/l 
mmol/l 
µmol/l 
mmol/l 
mmol/l 
- 
- 
- 
0.39 
0.30 
35 
3.2 
119 
0.39 
0.30 
ELECTROLYTES 
Sodium 
Potassium 
Chloride 
Bicarbonate 
mmol/l 
mmol/l 
mmol/l 
mmol/l 
8 
1.1 
8 
7 
8 
1.1 
7 
8 
METABOLISM/ 
NUTRITIONAL 
Glucose (random) 
Albumin 
Protein 
Cholesterol 
HDL cholesterol 
LDL cholesterol 
Triglycerides 
mmol/l 
g/l 
g/l 
mmol/l 
mmol/l 
mmol/l 
mmol/l 
3 
6 
11 
- 
0.91 
2.17 
- 
3.7 
6 
10 
1.97 
0.85 
2.04 
2.91 
ERYTHROCYTES 
Erythrocyte count 
Haemoglobin 
Haematocrit 
MCV  
MCH (Fe) 
MCHC (Fe) 
T/l 
g/l 
1 
fl 
fmol 
mmol/l 
0.7 
20 
0.06 
7 
0.19 
2 
0.7 
- 
0.06 
7 
0.19 
2 
LEUKOCYTES 
Leukocyte count 
G/l 
4.2 
3.8 
DIFFERENTIAL 
COUNT 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
G/l 
G/l 
G/l 
G/l 
G/l 
3.47 
1.76 
- 
- 
- 
3.19 
1.63 
0.49 
0.41 
0.14 
URINE 
Specific gravity 
pH 
- 
- 
0.017 
2 
0.015 
2 
LIVER 
Total bilirubin 
ASAT (SGOT) 
ALAT (SGPT) 
Gamma GT 
Alkaline phosphatase 
µmol/l 
U/l 
U/l 
U/l 
U/l 
- 
- 
- 
- 
-- 
10 
N x (23/36) 
N x (28/45) 
N x (25/38) 
N x (30/95) 
 
N = upper limit of normal range 
 
(¤) Delta-limits from « Routine Laboratory Tests in Clinical Trials » W. Leigh Thompson, Rocco 
L. Brunelle, Gregory G. Enas, Patrick J. Simpson and Randy L. Walker Lilly Research 
Laboratories, Lilly Corporate Centre, Indianapolis, Indiana in « Clinical Trials and Tribulations » 
1988. 
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Definition of Clinically Noteworthy Abnormal Laboratory Values (CNALV) 
 
 
PARAMETERS 
CNALV 
HAEMOGLOBIN 
 
• Decrease of at least 2g/dl and value < 10 g/dl whatever the baseline 
value 
• If missing baseline : value <10g/dl 
NEUTROPHILS 
• < 1 500/mm3 whatever the baseline value 
WBC 
(if missing value for neutrophils) 
• < 3 000/mm3 whatever the baseline value 
PLATELETS 
• < 100 000/mm3 whatever the baseline value 
SERUM CREATININE 
• Increase of at least 30 % as compared to baseline value and 
value > 150 µmol/l whatever the baseline value 
• If missing baseline : value > 150 µmol/l 
LIVER FUNCTION TESTS 
 
 
ALAT 
 
 If normal baseline :  
 
 
•ALAT > 2 N 
 If abnormal baseline : 
→if baseline value ≤ 2.5 N : 
  
• increase of at least 100 % as compared to baseline value 
→ if baseline value > 2.5 N :  
 
 
• value > 5 N 
and/or 
ASAT 
 
  If normal baseline :  
 
 
• ASAT > 2 N 
  If abnormal baseline : 
→ if baseline value ≤ 2.5 N : 
  
• increase of at least 100 % as compared to baseline value 
→ if baseline value > 2.5 N :  
 
 
• value > 5 N 
and/or 
Alkaline phosphatase (AP) 
 
  If normal baseline :  
 
 
• AP > 1.25 N 
  If abnormal baseline :  
 
 
• AP > 2 N 
and/or 
Total bilirubin (TB) 
  If normal baseline :  
 
 
• TB > 1.5 N 
  If abnormal baseline :  
 
 
• TB > 2 N 
N=upper limit of normal range 
International consensus Meeting. International Journal of Clinical Pharmacology, Therapy and Toxicology, 1990;28:317-322 
Standardisation of definitions and criteria of causality assessment of adverse drug reactions: drugs-induced liver disorders: report 
of an Standardisation of definitions and criteria of causality assessment of adverse drug reactions: drugs-induced cytopenia. 
International Journal of Clinical Pharmacology, Therapy and Toxicology, 1991;29:75-81 
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Cardiovascular Safety 
 
Table 1: Predefined Limits for Potentially Clinically Significant Changes (PSC) and PSC 
Leading to Clinically Significant Values (PSCV) 
 
Parameter 
PSC 
PSCV 
SBP 
Increase ≥ 20 mmHg 
Decrease ≥ 20 mmHg 
SBP ≥ 160 mmHg and increase ≥ 20 mmHg 
SBP ≤ 90 mmHg and decrease ≥ 20 mmHg 
DBP 
Increase ≥ 10 mmHg 
Decrease ≥ 10 mmHg 
DBP ≥ 100 mmHg and increase ≥ 10 mmHg 
DBP ≤ 50 mmHg and decrease ≥ 10 mmHg 
HR 
Increase ≥ 10 bpm 
Decrease ≥ 10 bpm 
HR ≥ 110 bpm and increase ≥ 10 bpm 
HR ≤ 50 bpm and decrease ≥ 10 bpm 
 
Table 2: Predefined Classes for changes from Baseline to the Maximum (and/ or Minimum) 
Post-baseline Value 
Classes of Change from Baseline to the Maximum 
Post-baseline Value 
Classes of Change from Baseline to the 
Minimum Post-baseline Value 
SBP  mmHg 
DBP  mmHg 
HR bpm 
SBP  mmHg 
DBP  mmHg 
HR bpm 
All 
All 
All 
All 
All 
All 
≥  0 
≥  0 
≥  0 
≤  0 
≤  0 
≤  0 
>  0 
>  0 
>  0 
<  0 
<  0 
<  0 
≥ 10 
≥  5 
≥ 10 
≤ -10 
≤ - 5 
≤ -10 
≥ 20 
≥ 10 
≥ 20 
≤ -20 
≤ -10 
≤ -20 
≥ 30 
≥ 15 
≥ 30 
≤ -30 
≤ -15 
≤ -30 
≥ 40 
≥ 20 
 
≤ -40 
≤ -20 
 
 
≥ 25 
 
 
≤ -25 
 
 
≥ 30 
 
 
≤ -30 
 
 
Table 3: Classes for Vital Signs Maximum or Minimum Values 
Classes  for  the Maximum Post-baseline Value 
for each parameter 
Classes  for  the Minimum Post-baseline Value 
for each parameter 
SBP  mmHg 
DBP  mmHg 
HR bpm 
SBP  mmHg 
DBP  mmHg 
HR bpm 
< 120 
< 80 
≤ 50 
≤ 90 
≤ 50 
≤ 50 
[120 ;140[ 
[80;90[ 
]50 ;75[ 
[90 ;120[ 
[50;80[ 
]50 ;75[ 
[140;160[ 
 [90;100[ 
[75;100[ 
[120;140[ 
 [80;90[ 
[75;100[ 
≥ 160 
≥ 100 
≥ 100 
≥ 140 
≥ 90 
≥ 100 
 
Table 4: Classes for Maximum or Minimum of BP in its entirety 
Classification of Maximum Values for Blood 
Pressure (mmHg) 
Classification of Minimum Values Blood 
Pressure (mmHg) 
SBP < 140 and DBP < 90 
SBP > 90 and DBP > 50 
SBP [140;160[ and DBP < 100 
or DBP [90;100[ and SBP < 160 
SBP ≤  90 or DBP ≤  50 
SBP ≥ 160 or DBP ≥ 100 
 
 
Table 5: Definition of orthostatic hypotension 
Orthostatic Hypotension * 
SBP Decrease ≥ 20 mmHg or DBP Decrease ≥ 10 mmHg between supine and standing positions 
* Consensus Committee of the American Autonomic Society and the American Academy of Neurolog :Consensus statement on the definition of 
orthostatic hypotension, pure autonomic failure and multiple system atrophy. Neurology 1996;46:1470-3. 
 
 
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16.1.1.4. 
Protocol amendment n° PA02  
General and non-substantial dated on 28 March 2013 linked 
to Protocol and appendices (version 4: 28 March 2013) 
 
 
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CLINICAL STUDY PROTOCOL AMENDMENT n° PA02 – Version 1 
General – Non Substantial 
 
 
Final version
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Pierre Fabre Médicament 
Represented by : Institut de Recherche Pierre Fabre 
45, Place Abel Gance 
F-92100 Boulogne 
 
 
 
 
CLINICAL STUDY PROTOCOL AMENDMENT n° PA02 – Version 1 
 
General – Non Substantial 
 
 
 
 
Efficacy and safety study of F373280 for maintenance of sinus rhythm after electrical 
cardioversion in patients with persistent Atrial Fibrillation and Chronic Heart Failure. 
 
International, multicentric, randomised, double-blind, placebo controlled study 
 
 
 
 
Pierre Fabre Study Code: 
F373280 CA 2 01 
EudraCT Number: 
2012-003487-48 
Sponsor’s Representative: 
Gaëlle ALCARAZ 
Coordinating Investigator: 
Pr Savina NODARI 
Date of amendment PA02: 
28 March 2013 
 
 
Final version
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Final version
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Clinical Study Protocol Amendment n° PA 02 – Version 1 
General – Non substantial 
COUNTRY COORDINATING INVESTIGATOR SIGNATURE FORM 
 
 
Country Coordinating Investigator: 
Date:  
Signature: 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Clinical Study Protocol Amendment n° PA 02 – Version 1 
General – Non Substantial 
INVESTIGATOR SIGNATURE FORM 
 
 
By my signature below, I, Dr _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _, hereby confirm that I have read, taken 
note of (and will apply) the modifications brought by the protocol amendment n° PA 02, dated 28 MAR 
2013 and I will conduct the trial according to these new modalities. 
 
 
Date: 
Signature: 
 
 
 
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HISTORY OF PROTOCOL VERSIONS 
 
 
 
PROTOCOL VERSIONS 
DATE 
MODIFICATIONS 
COMMENTS 
Version 1 
09/11/2012 
Initial version 
General 
Version 2 
(General) 
15/01/2013 
Following French CA request 
(ANSM) : 
- Add of a non inclusion criteria : 
“Breast-feeding female patient” 
- Add of haematology 
examination at visit 3 and 6 
General 
Version 3 
(Local Italy) 
01/03/2013 
Following to the Italian Central 
Ethics Committee and Competent 
Authority requirements and, in 
order to harmonise the protocol 
and the Informed Consent Form, 
the following changes have been 
done to the study protocol :  
- adjustment of the selection 
criteria n°10 related to the 
contraception method  
- addition of a letter that is given 
by the patient to his/her general 
practitioner (GP) 
- precision that the sponsor can 
not collect a copy of the Informed 
Consent Form  
- precision that the patient card is 
in Italian language only (without 
any English mention)      
Local Italy 
 
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N° 
DATES 
TYPE 
APPLICATION 
AREA 
MODIFICATIONS 
PROTOCOL 
VERSIONS  
NA 
_____ 
NA 
General 
________________________________________________ 
Version 1 
09/11/2012 
NA 
_____ 
NA 
General 
Following French CA request (ANSM) : 
- Add of a non inclusion criteria : “Breast-feeding female 
patient” 
- Add of haematology examination at visit 3 and 6 
Version 2 
15/01/2013 
PA01 
01.03.2013 
Substantial 
Local (Italy) 
Following to the Italian Central Ethics Committee and 
Competent Authority requirements and, in order to 
harmonise the protocol and the Informed Consent Form, the 
following changes have been done to the study protocol :  
- Integration of the modification included in the protocol 
version 2 
- Harmonisation of the protocol and the Informed Consent 
Form : 
* adjustment of the selection criteria n°10 related to the 
contraception method  
* addition of a letter that is given by the patient to his/her 
general practitioner (GP) 
* precision that the sponsor can not collect a copy of the 
Informed Consent Form  
* precision that the patient card is in Italian language only 
(without any English mention)      
 
Version 3 
01/03/2013 
 
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1. AMENDMENT RATIONALE 
 
The clinical study protocol is updated with the following changes :  
 
- change of Sponsor’s Representative (Clinical Study Manager),  
 
- modification of the technical handling of the blood samples for determination of red blood cells 
concentration of DHA : the centrifugation is no more needed, 
 
- precision on the function and address of the International Study Coordinator Pr Nodari,  
 
- add of address and contacts details of two CRO newly involved in the study : Theradis (in 
charge of transportation of blood samples to the Analytical centre and material supply) and 
“Clinact” (in charge of refund of patients expenses linked to the study), 
  
- adjustment of the wording, in agreement with the commitment to the French Ethics Committee. 
In the paragraphe 8.3.2.1, the wording "hematology examination” is replaced by "standard 
hematologic dosage", 
   
- precision of the full title in the study synopsis (in agreement with the commitment to the Spanish 
Ethics Committee),  
 
- correction of a mistake in section 8.1.1.3 (related to TTEM transmission) and sections 3, 9 and 
study synopsis (related to the definition of INR not stabilized). 
 
- addition of the changes included in the local italian substantial protocol amendment (i.e : 
contraception method,  letter to General Practionner, patient card in Italian and no collection of 
the consent form by the sponsor in Italy). 
 
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2. CHANGES DESCRIPTION 
 
PREVIOUS VERSION 
MODIFIED VERSION 
Sponsor's Representative: 
Marlène GUIRAUD, Pharm D  
INSTITUT DE RECHERCHE PIERRE FABRE - 
Centre de R&D Pierre Fabre - BP 13562  
3 avenue Hubert Curien  
31035 TOULOUSE Cédex 1 
Phone: +33 5 34 50 63 48  
Fax:+33 5 34 50 65 92  
E-mail:marlene.guiraud@pierre-fabre.com 
 
Study Coordinating Investigator: 
Pr Savina NODARI 
Section of Cardiology  
Department of Experimental and Applied 
Sciences 
University of Brescia 
BRESCIA, ITALY 
Phone: +39 030 3996 587 - Fax: +39 030 3700 359 
E-mail: savinanodari@gmail.com 
Sponsor's Representative: 
Gaëlle ALCARAZ 
INSTITUT DE RECHERCHE PIERRE FABRE - 
Centre de R&D Pierre Fabre - BP 13562  
3 avenue Hubert Curien  
31035 TOULOUSE Cédex 1 
Phone: +33 5 34 50 62 16  
Fax:+33 5 34 50 XX XX (TBC)  
E-mail:gaelle.alcaraz@pierre-fabre.com  
 
Study Coordinating Investigator: 
Pr Savina NODARI –  
Associate Professor of Cardiology 
Department of Clinical and Surgical Specialities, 
Radiological Science and Public Health 
Section of Cardiovascular Diseases 
University Medical School and Spedali Civili 
Hospital of Brescia 
c/o Spedali Civili di Brescia 
Piazzale Spedali Civili, 1 
25123 - BRESCIA, ITALY 
Phone: +39 030 3996 587 – +39 030 393849 
Fax:+39 030 3700359 
E-mail: savinanodari@gmail.com ; 
nodari@med.unibs.it 
 
 
 
 
 
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PREVIOUS VERSION 
MODIFIED VERSION 
CONTRACT RESEARCH 
ORGANISATIONS 
.... 
 
For intra erythrocyte DHA dosage: 
Agrocampus Ouest 
Laboratoire de Biochimie 
65 rue de Saint Brieuc – CS 84215 
35042 RENNES Cedex - FRANCE 
Phone: +33 2 23 48 55 49 - Fax: +33 2 23 48 55 50 
E-mail: daniel.catheline@agrocampus-ouest.fr 
 
 
 
CONTRACT RESEARCH 
ORGANISATIONS 
.... 
 
For intra erythrocyte DHA dosage: 
Agrocampus Ouest 
Laboratoire de Biochimie 
65 rue de Saint Brieuc – CS 84215 
35042 RENNES Cedex - FRANCE 
Phone: +33 2 23 48 55 49 - Fax: +33 2 23 48 55 50 
E-mail: daniel.catheline@agrocampus-ouest.fr 
 
For transportation of blood sample to the 
Analytical centre (Agrocampus) and 
material supply : 
Theradis Pharma 
41, chemin des Presses 
06800 CAGNES-SUR-MER – France 
Phone : +33 (0)4 97 02 07 07 
Fax : +33 (0)4 97 10 08 78 
E-mail: chantal.raffy@theradis.pharma.com 
 
For refund of patients expenses linked to the  
patients expenses linked to the study:   
CLINACT 
6-10 rue TROYON 
92310 SEVRES – FRANCE 
Phone : +33 1 46 90 27 27 
Fax : +33 1 46 23 01 56 
Email : sebastien.beaumont@clinact.com 
 
 
 
Final version
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PREVIOUS 
VERSION 
MODIFIED VERSION 
STUDY 
SYNOPSIS 
AND 5.1 
INCLUSION 
CRITERIA 
Demographic 
Characteristics 
and 
Other 
Baseline 
Characteristics: 
10. 
For 
female 
patient 
of 
child-
bearing potential:  
use 
of 
an 
effective 
method 
of 
contraception 
(hormonal 
contraception 
or 
intra-
uterine 
device) 
assessed 
by 
the 
investigator, 
for at least 2 
months before 
the selection 
in the study 
and 
agreement to 
go on using it 
during 
the 
whole 
duration 
of 
the study and 
up to 1 month 
after the last 
dose of the 
study 
treatment or 
- 
documented 
as 
surgica
lly 
STUDY SYNOPSIS AND 5.1 INCLUSION CRITERIA 
Demographic Characteristics and Other Baseline Characteristics: 
10. For female patient of child-bearing potential:  
• 
in all the countries except Italy:  
- 
use of an effective method of contraception (hormonal contraception or intra-uterine 
device) assessed by the investigator, for at least 2 months before the selection in the 
study and agreement to go on using it during the whole duration of the study and up to 
1 month after the last dose of the study treatment or 
- 
documented as surgically sterilized 
 
• 
in Italy only:  
 
-  
absolute abstention from sexual intercourse during the whole duration of the study 
and for a month after the end of the study or 
-  
use of double barrier contraception method (use of effective medical contraception 
method)  from at least 2 months before the start of the study to the entire duration of the 
study and for a month after the end of the study or 
- 
documented as surgically sterilized 
11. For female patient of child-bearing potential: negative urine pregnancy test at inclusion 
 
12. For male with a childbearing potential partner (In Italy only): 
- 
absolute abstention from sexual intercourse during the whole duration of the study 
and for a month after the end of the study or 
- 
use of double barrier contraception method (use of condom for male and effective 
contraception method for the partner) from the entire duration of the study to a month 
after the end of the study. 
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steriliz
ed 
 
 
 
 
 
 
 
 
 
 
 
 
 
11. 
For 
female 
patient 
of 
child-
bearing 
potential: 
negative 
urine 
pregnancy 
test 
at 
inclusion 
 
 
 
 
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PREVIOUS VERSION 
MODIFIED VERSION 
STUDY 
SYNOPSIS, SECTION 
3. 
Ethical 
CONSIDERATIONs 
RELATING 
TO 
THE 
STUDY and section 9. Study procedures : 
 
Patients not stabilized for INR (i.e. values between 
2 and 3) on at least 3 consecutive weekly tests 
performed before ECV will be excluded from the 
study, unless the presence of atrial thrombosis may 
be excluded with ECHO –TE (trans-esophageal 
echocardiograph) performed  in the same day 
(before ECV) 
 
5.9 Study CARD 
The patient will receive from the Investigating 
Centre at Visit 1 - Selection Visit, a personal card to 
be kept all along the study duration and providing 
the following information: patient's name, sponsor's 
name, study code, EUDRACT number, start date 
and expected end date of the study, complete 
address of the Investigating Centre with the name 
and phone number of the Investigator and a sponsor 
24H/24 phone contact number in case of emergency 
(French and English languages): 33 (0)5 63 35 25 
83. 
 
STUDY SYNOPSIS, SECTION 3. Ethical 
CONSIDERATIONs 
RELATING 
TO 
THE 
STUDY and section 9. Study procedures : 
 
Patients not stabilized for INR (i.e. values not 
between 2 and 3) on at least 3 consecutive weekly 
tests performed before ECV will be excluded from 
the study, unless the presence of atrial thrombosis 
may be excluded with ECHO –TE (trans-
esophageal echocardiograph) performed  in the 
same day (before ECV) 
 
5.9 Study CARD and LETTER FOR GENERAL 
PRACTITIONERS (GP) 
The patient will receive from the Investigating 
Centre at Visit 1 - Selection Visit :  
- a personal card to be kept all along the study 
duration and providing the following information: 
patient's name, sponsor's name, study code, 
EUDRACT number, start date and expected end 
date of the study, complete address of the 
Investigating Centre with the name and phone 
number of the Investigator and a sponsor 24H/24 
phone contact number in case of emergency (French 
and English languages): 33 (0)5 63 35 25 83. For 
Italy, this card will be in Italian without any 
English mention. 
- a letter to be given to his/her general 
practitioner. This letter intends to inform the GP 
(and any other doctors who take care of the 
patient) that the patient participates to this 
clinical study. It describes the study treatment 
and includes some information on the forbidden 
treatment during the study.   
 
 
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PREVIOUS VERSION 
MODIFIED VERSION 
8.1. PRIMARY EFFICACY 
CRITERION:  
8.1.1.3. Evaluation Methods 
• 
Trans Telephonic ECG Monitoring (TTEM): 
Thus, the follow up will be documented using the 
TTEM: daily transmission from visit 4 to visit 6. 
Then, every two days from visit 6 to visit 9.              
 
8.2 BIOMARKER ASSESSMENT: RED 
BLOOD CELL CONCENTRATIONS 
OF DHA 
8.2.2.2 Technical handling 
Two blood samples will be collected containing 
EDTA. They will be gently shaken and centrifuged 
at 3000g for 15 min at room temperature, within 30 
minutes after collection. Plasma and white blood 
cells will be discarded. Red blood cells will be 
stored at +4°C (no freezing will be allowed) and 
sent to Analytical Centre in refrigerated conditions 
(between +2°C and +8°C) within 3 weeks following 
collection. Analysis will be performed within 2 
weeks following reception at the Analytical centre. 
 
8.1. PRIMARY EFFICACY 
CRITERION:  
8.1.1.3. Evaluation Methods 
• 
Trans Telephonic ECG Monitoring (TTEM): 
Thus, the follow up will be documented using the 
TTEM: daily transmission from visit 4 (week 6) to 
visit 5 (week 8). Then, every two days from visit 5 
(week 8) to visit 9 (week 24 – End of study). 
 
8.2 BIOMARKER ASSESSMENT: RED 
BLOOD CELLCONCENTRATIONS 
OF DHA 
8.2.2.2 Technical handling 
Two blood samples will be collected containing 
EDTA. They will be gently shaken, stored at +4°C 
(no freezing will be allowed) and sent to Analytical 
Centre in refrigerated conditions (between +2°C 
and +8°C). Analysis will be performed within 2 
weeks following reception at the Analytical centre. 
 
 
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PREVIOUS VERSION 
MODIFIED VERSION 
8.3 SAFETY ASSESSMENT 
8.3.2 Laboratory Investigations 
Laboratory investigations will be performed at 
visit 1 (before treatment) and visit 9 (end of 
treatment) or End of Treatment visit. 
At visit 3 and 6, only an haematology 
examination will be performed.  
10.2 Reporting of SAE 
Marlène GUIRAUD, Pharm D 
INSTITUT 
DE 
RECHERCHE 
PIERRE 
FABRE,  
Centre de R&D Pierre Fabre – BP 13562 
3 Avenue Hubert Curien 
31035 TOULOUSE Cedex 1 
Phone: +33 5 35 50 63 48 
Fax: + 33 5 34 50 65 92 
Email: marlene.guiraud@pierre-fabre.com 
 
8.3 SAFETY ASSESSMENT 
8.3.2 Laboratory Investigations 
Laboratory investigations will be performed at 
visit 1 (before treatment) and visit 9 (end of 
treatment) or End of Treatment visit. 
At visit 3 and 6, only a standard haematologic 
dosage will be performed.  
10.2 Reporting of SAE 
Gaëlle ALCARAZ 
INSTITUT 
DE 
RECHERCHE 
PIERRE 
FABRE,  
Centre de R&D Pierre Fabre – BP 13562 
3 Avenue Hubert Curien 
31035 TOULOUSE Cedex 1 
Phone: +33 5 35 50 62 16 
Fax: + 33 5 34 50 65 92 
Email: gaelle.alcaraz@pierre-fabre.com 
 
 
 
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PREVIOUS VERSION 
MODIFIED VERSION 
11.2. STUDY MONITORING 
11.2.1.4. Closing Visit 
At the end of the study, a final visit will be carried 
out by the CRA to: 
• 
Verify that the e-CRFs CD-ROM with pdf files 
are correctly stored 
• 
Control the accountability of intact and used 
treatment units and return them to the Clinical 
Pharmacy Department of the IRPF for destruction 
• 
Obtain the last data clarifications and/or 
solutions if any 
• 
Collect the patient's consent forms in sealed 
envelopes,  
 
• 
Make 
an 
on-site 
review 
of 
all 
study 
documentation and complete it if necessary 
• 
And finally, remind the Investigator of his 
regulatory obligations, study document archiving 
process and duration. 
 
 
11.2. STUDY MONITORING 
11.2.1.4. Closing Visit 
At the end of the study, a final visit will be carried 
out by the CRA to: 
• 
Verify that the e-CRFs CD-ROM with pdf files 
are correctly stored 
• 
Control the accountability of intact and used 
treatment units and return them to the Clinical 
Pharmacy Department of the IRPF for destruction 
• 
Obtain the last data clarifications and/or 
solutions if any 
• 
Collect the patient's consent forms in sealed 
envelopes (except in case of specific country 
requirement),  
• 
Make 
an 
on-site 
review 
of 
all 
study 
documentation and complete it if necessary 
• 
And finally, remind the Investigator of his 
regulatory obligations, study document archiving 
process and duration. 
 
 
 
 
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PREVIOUS VERSION 
MODIFIED VERSION 
14.3 PATIENT'S INFORMATION 
LEAFLET AND INFORMED 
CONSENT FORM 
The information and consent document are made in 
triplicate: the original copy is kept by the 
Investigator, one copy is given to the patient and the 
last copy is kept by the Clinical Quality Assurance 
Unit of the Sponsor in a sealed envelope at the end 
of study. 
 
14.3 PATIENT'S INFORMATION 
LEAFLET AND INFORMED 
CONSENT FORM 
The information and consent document are made in 
triplicate: the original copy is kept by the 
Investigator, one copy is given to the patient and the 
last copy is kept by the Clinical Quality Assurance 
Unit of the Sponsor in a sealed envelope at the end 
of study (except in case of specific country 
requirement). 
 
 
Final version
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F 373280 CA 2 01 
 
 
 
 
 
 
 
Final version
353/1185


 
 
Pierre Fabre Médicament 
Represented by: Institut de Recherche Pierre Fabre 
45, Place Abel Gance 
F-92100 Boulogne 
CLINICAL STUDY PROTOCOL 
 
Efficacy and safety study of F373280 for maintenance of sinus rhythm after 
electrical cardioversion in patients with persistent Atrial Fibrillation and 
Chronic Heart Failure. 
International, multicentric, randomised, double-blind, placebo controlled study 
F373280 / Soft Capsules / 1g  
Pierre Fabre Study Code: 
EudraCT Number: 
 
Sponsor's Representative: 
 
 
 
 
 
 
 
 
Study Coordinating Investigator 
F 373280 CA 2 01  
2012 – 003487 - 48 
 
Gaëlle ALCARAZ 
INSTITUT DE RECHERCHE PIERRE FABRE - Centre de 
R&D Pierre Fabre - BP 13562  
3 avenue Hubert Curien  
31035 TOULOUSE Cédex 1 
Phone: +33 5 34 50 62 16  
Fax:+33 5 34 50 65 92  
E-mail:gaelle.alcaraz@pierre-fabre.com  
 
Pr Savina NODARI –  
Associate Professor of Cardiology 
Department of Clinical and Surgical Specialities, 
Radiological Science and Public Health 
Section of Cardiovascular Diseases 
University Medical School and Spedali Civili Hospital of 
Brescia 
c/o Spedali Civili di Brescia 
Piazzale Spedali Civili, 1 
25123 - BRESCIA, ITALY 
Phone: +39 030 3996 587 – +39 030 393849 
Fax: +39 030 3700 359 
E-mail: savinanodari@gmail.com ; nodari@med.unibs.it 
 
Version 4– 28 MAR 2013 
 
The information contained in this document is confidential and is the property of the Sponsor, Pierre Fabre 
Medicament. This information is given for the needs of the study and must not be disclosed without prior written 
consent of the Sponsor Pierre Fabre Medicament. Persons to whom this information is given for the needs of the 
study must be informed that it is confidential and must not be disclosed. 
Final version
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SPONSOR PERSONNEL 
PIERRE FABRE MEDICAMENT 
represented by 
Institut de Recherche Pierre Fabre 
 
Clinical Study Manager (Monitor) 
Gaëlle ALCARAZ 
Phone: +33 5 34 50 62 16  
Fax: + 33 5 34 50 65 92 
E-mail: gaelle.alcaraz@pierre-
fabre.com 
Institut de Recherche Pierre Fabre 
Centre de R&D Pierre Fabre 
BP 13 562 
3, Avenue Hubert Curien 
31035 TOULOUSE Cedex 1 
 
 
Medical Director 
Richard ROCHE, MD 
Phone: +33 5 34 50 61 94 
Fax: +33 5 34 50 65 92 
E-mail: richard.roche@pierre-
fabre.com 
Institut de Recherche Pierre Fabre 
Centre de R&D Pierre Fabre 
BP 13 562 
3, Avenue Hubert Curien 
31035 TOULOUSE Cedex 1 
 
 
 
 
 
 
 
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CONTRACT RESEARCH ORGANISATIONS 
 
 
For Feasibility, Monitoring and Regulatory issues: 
Pharmaceutical Service Network (PSN) 
Rufino Gonzalez 
28 037 Madrid - SPAIN 
Phone: +34 91 375 6930 - Fax: +34 91 375 6931 
E-mail: www.psnglobal.org 
 
 
For Centralised Randomisation and Electronic Case Report Form 
S-Clinica 
6, Chaussée de Boondael 
B-1050 Brussels - BELGIUM 
Phone: +32 2 645 0567 - Fax: +32 2 645 0569 
E-mail: irena.seredina@s-clinica.com 
 
 
For Centralised Reading of Holder ECG and TTEM and equipment supply: 
Biomedical System 
1945 Chaussée de Wavre 
B-1160 Brussels - BELGIUM 
Phone: +32 2 661 20 70 - Fax: +32 2 661 20 71 
E-mail: sjacobs@biomedsys.com 
 
 
For intra erythrocyte DHA dosage: 
Agrocampus Ouest 
Laboratoire de Biochimie 
65 rue de Saint Brieuc – CS 84215 
35042 RENNES Cedex - FRANCE 
Phone: +33 2 23 48 55 49 - Fax: +33 2 23 48 55 50 
E-mail: daniel.catheline@agrocampus-ouest.fr 
 
 
For transportation of blood sample to the Analytical centre (Agrocampus) and material 
supply : 
Theradis Pharma 
41, chemin des Presses 
06800 CAGNES-SUR-MER – France 
Phone : +33 (0)4 97 02 07 07 
Fax : +33 (0)4 97 10 08 78 
E-mail: chantal.raffy@theradis.pharma.com 
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CONTRACT RESEARCH ORGANISATIONS 
 
 
For refund of patients expenses linked to the study (in France): 
CLINACT 
6-10 rue TROYON 
92310 SEVRES – FRANCE 
Phone : +33 1 46 90 27 27 
Fax : +33 1 46 23 01 56 
Email : sebastien.beaumont@clinact.com 
Final version
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Final version
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Protocol F 373280 CA 2 01 
COUNTRY COORDINATING  INVESTIGATOR  
SIGNATURE FORM 
Protocol Version 4 – 28 MAR 2013 
 
 
Country: …………………….. 
 
Country Coordinating Investigator:  
"Name"  
Date:   
 
 
 
 
 
 
Signature:  
 
 
 
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Protocol F 373280 CA 2 01 
INVESTIGATOR SIGNATURE FORM 
Protocol Version 4 – 28 MAR 2013 
 
 
 
By my signature below, I, Dr / Pr "                                         ", hereby confirm that I agree: 
♦ to conduct the trial described in the protocol F 373280 CA 2 01, dated 28 March 2013 in 
compliance with GCP, with applicable regulatory requirements and with the protocol 
agreed upon by the Sponsor Pierre Fabre Médicament and given approval / favourable* 
opinion by the Ethics Committee; 
♦ to document the delegation of significant study-related tasks and to notify the Sponsor of 
changes in site personnel involved in the study; 
♦ to comply with the procedure for data recording and reporting; 
♦ to allow monitoring, auditing and inspection; 
♦ to retain the trial-related essential documents until the Sponsor informs that these documents 
are no longer needed. 
Furthermore, I hereby confirm that I will have and will use the available adequate resources, 
personnel and facilities for conduct this trial. 
 
I have been informed that certain regulatory authorities require the Sponsor Pierre Fabre 
Médicament to obtain and supply details about the investigator’s ownership interest in the 
Sponsor or the study drug, and more generally about his/her financial relationships with the 
Sponsor. The Sponsor will use and disclose the information solely for the purpose of complying 
with regulatory requirements. 
Hence I agree: 
♦ to supply the Sponsor with any information regarding ownership interest and financial 
relationships with the Sponsor (including those of my spouse and dependent children); 
♦ to promptly update this information if any relevant changes occur during the course of the 
study and for 1 year following completion of the study; 
♦ that the Sponsor may disclose this information about such ownership interests and financial 
relationships to regulatory authorities. 
* To be adapted  
 
Date:  
Signature:  
 
 
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TABLE OF CONTENTS OF CLINICAL STUDY PROTOCOL 
 
1. 
INTRODUCTION AND STUDY RATIONALE ................................................................ 23 
1.1. 
TARGET PATHOLOGY AND THERAPY ........................................................................ 23 
1.2. 
INFORMATION ON THE TEST PRODUCT .................................................................... 25 
1.2.1. 
Chemical and pharmaceutical characteristics .................................................................... 26 
1.2.1.1. 
Nomenclature and structure ............................................................................................ 26 
1.2.1.2. 
Physical and chemical general properties ...................................................................... 26 
1.2.2. 
Non-clinical Data .............................................................................................................. 27 
1.2.2.1. 
Pharmacological profile ................................................................................................. 27 
1.2.2.2. 
Safety pharmacology ...................................................................................................... 28 
1.2.2.3. 
Toxicology profile .......................................................................................................... 28 
1.2.2.4. 
Pharmacokinetic data ..................................................................................................... 28 
1.2.3. 
Clinical data ....................................................................................................................... 28 
1.3. 
STUDY RATIONALE ......................................................................................................... 31 
1.4. 
OVERALL RISK AND BENEFIT ASSESSMENT ............................................................ 31 
2. 
STUDY OBJECTIVES ......................................................................................................... 34 
2.1. 
PRIMARY OBJECTIVE ..................................................................................................... 34 
2.2. 
SECONDARY OBJECTIVES ............................................................................................. 34 
3. 
ETHICAL CONSIDERATIONS RELATING TO THE STUDY .................................... 34 
4. 
STUDY DESIGN ................................................................................................................... 36 
4.1. 
OVERALL DESCRIPTION ................................................................................................ 36 
4.2. 
DISCUSSION OF THE STUDY DESIGN .......................................................................... 37 
4.2.1. 
Choice of the Study Population ......................................................................................... 37 
4.2.2. 
Choice of the Study Design ............................................................................................... 38 
4.2.3. 
Choice of the Dose ............................................................................................................ 39 
4.2.4. 
Choice of the Sample Size ................................................................................................. 40 
5. 
STUDY POPULATION ........................................................................................................ 40 
5.1. 
INCLUSION CRITERIA ..................................................................................................... 40 
5.2. 
NON INCLUSION CRITERIA ........................................................................................... 41 
5.3. 
NUMBER OF  PATIENTS .................................................................................................. 42 
5.4. 
RECRUITMENT MODALITIES ........................................................................................ 42 
5.5. 
PATIENTS IDENTIFICATION .......................................................................................... 42 
5.6. 
WITHDRAWAL CRITERIA ............................................................................................... 42 
5.7. 
REPLACEMENT OF PATIENTS ....................................................................................... 43 
5.8. 
POST-STUDY EXCLUSION PERIOD .............................................................................. 44 
5.9. 
STUDY CARD ..................................................................................................................... 44 
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6. 
STUDY TREATMENT ......................................................................................................... 44 
6.1. 
SOURCE, PRESENTATION AND COMPOSITION OF  INVESTIGATIONAL 
PRODUCT ........................................................................................................................... 44 
6.2. 
PACKAGING AND LABELLING ..................................................................................... 45 
6.2.1. 
Packaging .......................................................................................................................... 45 
6.2.2. 
Labelling ............................................................................................................................ 45 
6.3. 
DISTRIBUTION TO CENTRE AND STORAGE .............................................................. 46 
6.4. 
ALLOCATION OF TREATMENTS AND DISPENSATION TO PATIENT ................... 47 
6.5. 
DRUG ADMINISTRATION ............................................................................................... 48 
6.5.1. 
Duration of Treatment ....................................................................................................... 48 
6.5.2. 
Dose Schedule ................................................................................................................... 48 
6.5.3. 
Route and Conditions of Administration ........................................................................... 48 
6.6. 
ACCOUNTABILITY ON SITE AND RETURN/DESTRUCTION OF  
INVESTIGATIONAL PRODUCT ...................................................................................... 49 
6.7. 
RECALL OF INVESTIGATIONAL PRODUCTS ............................................................. 49 
7. 
CONCOMITANT TREATMENTS ..................................................................................... 49 
7.1. 
ANTI-VITAMIN K TREATMENT ..................................................................................... 50 
7.2. 
PROHIBITED TREATMENTS ........................................................................................... 50 
7.3. 
AUTHORISED TREATMENTS ......................................................................................... 51 
8. 
EVALUATION CRITERIA ................................................................................................. 51 
8.1. 
PRIMARY EFFICACY CRITERION: ................................................................................ 51 
8.1.1. 
Time to the first Atrial Fibrillation Recurrence ................................................................. 51 
8.1.1.1. 
Definition ........................................................................................................................ 51 
8.1.1.2. 
Schedule ......................................................................................................................... 51 
8.1.1.3. 
Evaluation Methods ........................................................................................................ 51 
8.1.2. 
Secondary Efficacy Criteria .............................................................................................. 52 
8.1.2.1. 
Numbers of Atrial Fibrillation episodes in the first week following visit 3   (ECV 
visit) ................................................................................................................................ 52 
8.1.2.2. 
Duration of Atrial Fibrillation episodes in the first week following visit 3   (ECV 
visit) ................................................................................................................................ 53 
8.1.2.3. 
Clinical parameters evaluation ....................................................................................... 53 
8.1.2.4. 
Cardioversion assessment ............................................................................................... 54 
8.1.2.5. 
Evolution of echocardiographic parameters ................................................................... 55 
8.2. 
BIOMARKER ASSESSMENT: RED BLOOD CELL   CONCENTRATIONS OF 
DHA ..................................................................................................................................... 55 
8.2.1. 
Definition ........................................................................................................................... 55 
8.2.2. 
Blood samples ................................................................................................................... 56 
8.2.2.1. 
Collection schedule ........................................................................................................ 56 
8.2.2.2. 
Technical handling ......................................................................................................... 56 
8.2.3. 
DHA concentration measurement ..................................................................................... 56 
8.3. 
SAFETY ASSESSMENT .................................................................................................... 57 
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8.3.1. 
Adverse Events .................................................................................................................. 57 
8.3.2. 
Laboratory Investigations .................................................................................................. 57 
8.3.2.1. 
Schedule ......................................................................................................................... 57 
8.3.2.2. 
Technical Procedures and Parameters ............................................................................ 57 
8.3.3. 
Global Physical Examination ............................................................................................ 58 
8.3.4. 
Vital Signs ......................................................................................................................... 58 
8.3.4.1. 
Schedule ......................................................................................................................... 59 
8.3.4.2. 
Technical Procedure and Parameters.............................................................................. 59 
8.3.5. 
Electrocardiogram (ECG) .................................................................................................. 59 
8.3.5.1. 
Schedule ......................................................................................................................... 59 
8.3.5.2. 
Technical Procedure and Parameters.............................................................................. 59 
8.3.6. 
Coagulation parameters ..................................................................................................... 60 
8.3.7. 
Concomitant Treatments ................................................................................................... 60 
8.4. 
COMPLIANCE .................................................................................................................... 60 
9. 
STUDY PROCEDURES ....................................................................................................... 61 
10. ADVERSE EVENTS: DEFINITION AND REPORTING ............................................... 66 
10.1. ADVERSE EVENTS ........................................................................................................... 66 
10.1.1. Definition of Adverse Events ............................................................................................ 66 
10.1.2. Grading of Adverse Events ............................................................................................... 67 
10.1.3. Reporting of Adverse Events ............................................................................................ 67 
10.2. SERIOUS ADVERSE EVENTS (SAE) .............................................................................. 67 
10.2.1. Definition ........................................................................................................................... 67 
10.2.2. Reporting of SAE .............................................................................................................. 68 
10.2.3. Follow-up of SAE ............................................................................................................. 69 
10.2.4. SAE Occurring After the Study ......................................................................................... 69 
10.3. REPORTING OF OVERDOSAGE TO THE SPONSOR ................................................... 69 
10.4. REPORTING OF PREGNANCY TO THE SPONSOR ...................................................... 69 
10.5. SPONSOR'S RESPONSIBILITIES FOR SAFETY REPORTING  PURPOSES ............... 70 
11. DATA COLLECTION AND STUDY MONITORING ..................................................... 70 
11.1. DATA COLLECTION ......................................................................................................... 70 
11.1.1. Case Report Form .............................................................................................................. 70 
11.1.2. Source Documents ............................................................................................................. 71 
11.2. STUDY MONITORING ...................................................................................................... 72 
11.2.1. Monitoring visits ............................................................................................................... 72 
11.2.1.1. Site Preselection Visit .................................................................................................... 72 
11.2.1.2. Initiation Visit ................................................................................................................. 72 
11.2.1.3. Follow-up Visits ............................................................................................................. 73 
11.2.1.4. Closing Visit ................................................................................................................... 73 
11.2.2. Direct Access to Source Documents ................................................................................. 73 
11.3. INDEPENDENT DATA MONITORING COMMITTEE ................................................... 74 
12. DATA MANAGEMENT ...................................................................................................... 74 
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12.1. DATA ENTRY ..................................................................................................................... 74 
12.2. DATA CLEANING ............................................................................................................. 74 
12.3. DATA CODING .................................................................................................................. 75 
12.4. DATA STORAGE ............................................................................................................... 75 
12.5. DATABASE LOCK ............................................................................................................. 75 
13. STATISTICAL ANALYSIS ................................................................................................. 75 
13.1. GENERAL CONSIDERATIONS ........................................................................................ 76 
13.2. SAMPLE SIZE ..................................................................................................................... 76 
13.3. PROTOCOL DEVIATIONS ................................................................................................ 76 
13.4. DATA SETS ANALYSED .................................................................................................. 77 
13.5. HANDLING OF DROPOUTS AND MISSING DATA ..................................................... 77 
13.5.1. Dropouts ............................................................................................................................ 77 
13.5.2. Repositioning of Visits ...................................................................................................... 77 
13.5.3. Missing Data ...................................................................................................................... 77 
13.6. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ............................... 78 
13.7. EFFICACY ANALYSIS ...................................................................................................... 78 
13.7.1. Primary Criterion ............................................................................................................... 78 
13.7.1.1. Primary Analysis ............................................................................................................ 78 
13.7.1.2. Supportive Analysis ....................................................................................................... 78 
13.7.2. Secondary Criteria ............................................................................................................. 79 
13.7.2.1. Numbers of Atrial Fibrillation Episodes ........................................................................ 79 
13.7.2.2. Duration of Atrial Fibrillation Episodes ......................................................................... 79 
13.7.2.3. Time to first AF recurrence less than 10 minutes or symtomatic .................................. 79 
13.7.2.4. Clinical parameters evaluation ....................................................................................... 79 
13.7.2.5. Biomarker analysis: red blood cell concentrations of DHA ........................................... 80 
13.8. SAFETY ANALYSIS .......................................................................................................... 80 
13.8.1. Adverse Events .................................................................................................................. 80 
13.8.2. Clinical Laboratory Evaluation ......................................................................................... 82 
13.8.3. Global Physical Examination ............................................................................................ 83 
13.8.4. Vital Signs, Physical Findings and Other Observations Related to Safety ....................... 83 
13.8.4.1. Vital Sign Measurements Over Time ............................................................................. 83 
13.8.4.2. Body weight ................................................................................................................... 83 
13.8.4.3. Individual Patient Changes ............................................................................................. 84 
13.8.5. ECG ................................................................................................................................... 84 
13.8.6. Coagulation parameters ..................................................................................................... 84 
13.9. CONCOMITANT TREATMENTS ..................................................................................... 84 
13.10. COMPLIANCE .................................................................................................................... 85 
13.11. INTERIM ANALYSIS AND DATA MONITORING ........................................................ 85 
14. GENERAL ETHICAL CONSIDERATIONS .................................................................... 85 
14.1. ETHICAL CONDITIONS ................................................................................................... 85 
14.2. ETHICS COMMITTEE AND LEGAL REQUIREMENTS ................................................ 85 
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14.3. PATIENT'S INFORMATION LEAFLET AND INFORMED CONSENT  FORM ........... 86 
14.4. PERSONAL DATA PROTECTION ................................................................................... 87 
14.5. INSURANCE POLICY ........................................................................................................ 87 
15. ADMINISTRATIVE PROCEDURES ................................................................................ 87 
15.1. PROTOCOL AMENDMENT .............................................................................................. 87 
15.2. SOURCE DOCUMENTS, INVESTIGATOR'S FILE STORAGE ..................................... 88 
15.3. END OF THE STUDY ......................................................................................................... 88 
15.3.1. Definition of the End of Study .......................................................................................... 88 
15.3.2. Early Study Termination ................................................................................................... 89 
15.3.2.1. Early Study Termination Decided by the Sponsor ......................................................... 89 
15.3.2.2. Early Study Termination Decided by the Competent Authorities.................................. 89 
15.4. AUDIT .................................................................................................................................. 89 
15.5. INSPECTION ....................................................................................................................... 90 
15.6. CONFIDENTIALITY .......................................................................................................... 90 
15.7. CLINICAL STUDY REPORT ............................................................................................. 90 
15.8. STUDY RESULTS COMMUNICATION .......................................................................... 90 
15.9. STUDY RESULTS PUBLICATION ................................................................................... 90 
16. REFERENCES ...................................................................................................................... 92 
17. APPENDICES ....................................................................................................................... 95 
17.1. DECLARATION OF HELSINKI ........................................................................................ 96 
17.2. SAE REPORT FORM ........................................................................................................ 100 
17.3. PREDEFINED LIMITS OF LABORATORY AND VITAL SIGN POTENTIALLY 
CLINICALLY SIGNIFICANT CHANGES AND VALUES ............................................ 103 
 
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SYNOPSIS 
 
Name of Sponsor: 
Pierre Fabre Médicament represented by the Institut de Recherche Pierre Fabre (IRPF) 
Name of Finished Product: 
Not applicable 
Name of Active Substance:  
F373280 (Panthenyl-Ester of DHA) 
Title of the Study: 
Efficacy and safety study of F373280 for maintenance of sinus rhythm after electrical 
cardioversion in patients with persistent Atrial Fibrillation and Chronic Heart Failure. 
International, multicentric, randomised, double-blind, placebo controlled study 
Abbreviated Title: 
Not applicable 
Study Coordinating Investigator: 
Pr Savina NODARI 
 
Study Centres: 
International, multicentric 
Publication / Rationale: 
F373280 is a new therapy based on DHA delivery (pro-drug) developed for the maintenance 
of sinus rhythm after electrical cardioversion in persistent atrial fibrillation (AF) patients with 
chronic heart failure. 
The results of a pharmacological study performed in animals evidenced that DHA reduces the 
duration of Atrial Fibrillation (AF) induced by burst pacing.[1] 
Moreover, the effectiveness of PUFA (PolyUnsaturated Fatty Acid) has been proven in the 
following conditions: 
− 
prevention of Atrial Fibrillation recurrence in patients with persistent Atrial 
Fibrillation, in co-administration with amiodarone (add on therapy) [2]  
− 
Improvement of ventricular functional parameters, morbi-mortality and duration 
of hospitalisation in patients with heart failure [3, 4, 5] 
Taking into account these studies, it seems that DHA might be of therapeutic interest in the 
treatment of patients with both persistent atrial fibrillation and chronic heart failure. 
This phase IIa study is designed to assess the efficacy and the safety of the investigational 
product (F373280) for maintenance of sinus rhythm after electrical cardioversion (ECV) in 
patients with persistent atrial fibrillation and chronic heart failure. 
Planned Study Period: 
January 2013 –  April 2014 
Clinical Phase: IIa 
 
Objectives: 
Primary: 
- Efficacy of F373280 on the maintenance of sinus rhythm after direct electrical 
cardioversion in patients with persistent atrial fibrillation and chronic heart failure 
Secondary: 
- Efficacy of F373280 on the efficiency of direct electrical  cardioversion 
- Effect of F373280 on echocardiographic parameters 
- Safety and tolerability of F373280 
Methodology: 
- International, multicentre, randomised, double-blind, placebo-controlled 
- Selection period 
- Start of treatment 4 weeks before ECV 
• 
Condition to ECV:  
− 
INR 2-3 (anti-vitamin K should be given at least 3 weeks before ECV) 
− 
No spontaneous cardioversion before ECV 
- Follow-up 20 weeks after visit 3  (ECV visit) 
• 
Condition: successful ECV or spontaneous CV 
- Cardiac monitoring: 
• 
7-days continuous ECG ambulatory recording (Holter ECG)  between visit 3 (ECV 
visit) and visit 4  (week 5) in patients with sinusal rhythm 
• 
TTEM: daily transmission from week 6 to week 8; then every two days from week 
9 to week 24, and in case of AF symptoms 
- Treatment duration: 24 weeks 
Study Schedule 
9 visits will be scheduled: 
- V1/ W-4 to W-1: selection visit (7 to 28 days before the inclusion visit)  
- V2/ D1: Inclusion visit (start of treatment) 
- V3/ W4 (D28 -2/+7 days): cardioversion visit (Outpatient or hospitalization according to 
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clinical practice of the centre) (installation of the Holter device) 
- V4/ W5 (D35± 2 days): follow-up visit (removing of the Holter device and installation of 
the TTEM) 
- V5/ W8 (D56± 7 days): follow-up visit 
- V6/ W12 (D84 ± 7 days): follow-up visit 
- V7/ W16 (D112 ± 7 days): follow-up visit 
- V8/ W20 (D140 ± 7 days): follow-up visit 
- V9/ W24 (D168 ± 7 days): final study visit 
 
Number of  Patients: 
76 x 2 patients  
Diagnosis and Criteria for Inclusion: 
Inclusion Criteria: 
Demographic Characteristics and Other Baseline Characteristics: 
1. 
Men or women aged more than 18 years (inclusive), 
2. 
Patients with persistent AF between 7 days and 6 months duration for whom electrical 
cardioversion is warranted. 
3. 
History of first documented persistent AF less than 1 year 
4. 
History of ischemic or non ischemic heart failure  
5. 
NYHA class I or II chronic heart failure at selection and at inclusion 
6. 
Reduced left ventricular ejection fraction between 30% and 45% inclusive (using the 
two-dimensional echocardiography biplane Simpson’s rule) ) at selection and at 
inclusion 
7. 
On appropriate, stable medical treatments for heart failure, including a diuretic and/or 
angiotensin-converting enzyme, and/or angiotensin-receptor blocker and/or 
mineralocorticoid receptor (MR) antagonists, and/or betablockers 
8. 
Left atrial area ≤ 40 cm² ) at selection and at inclusion 
9. 
Patients treated or having to be treated by anti-vitamin K 
10. For female patient of child-bearing potential:  
• 
in all the countries except Italy:  
- 
use of an effective method of contraception (hormonal contraception or intra-
uterine device) assessed by the investigator, for at least 2 months before the 
selection in the study, and agreement to go on using it during the whole duration of 
the study and up to 1 month after the last dose of the study treatment 
- 
documented as surgically sterilized 
 
• 
in Italy only:  
- 
absolute abstention from sexual intercourse during the whole duration of the study 
and for a month after the end of the study or 
- 
use of double barrier contraception method (use of effective medical contraception 
method) from at least 2 months before the start of the study to the entire duration of 
the study and for a month after the end of the study or 
- 
documented as surgically sterilized 
 
11. For female patient of child-bearing potential: negative urine pregnancy test at inclusion 
12. For male with a child-bearing potential partner (In Italy only): 
- 
Absolute abstention from sexual intercourse during the whole duration of the study 
and for a month after the end of the study or 
- 
 use of double barrier contraception method (use of condom for male and effective 
contraception method for the partner) from the entire duration of the study to a 
month after the end of the study. 
 
Ethical /legal considerations: 
13. Having signed his/her written informed consent, 
14. Affiliated to a social security system, or is beneficiary (if applicable in the national 
regulation) 
 
Non-Inclusion Criteria: 
Criteria related to pathologies: 
1. 
History of first documented episode of persistent AF more than 1 year 
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2. 
More than two successful cardioversions (electrical or pharmacological) in the last 6 
months 
3. 
Secondary Atrial Fibrillation due to alcohol or severe valvular heart disease (grade III to 
IV) 
4. 
NYHA class III or IV heart failure at selection or at inclusion 
5. 
Thyroid disease uncontrolled by treatment: TSH ± T4L ± T3L to be checked in case of 
treatment for thyroid disease 
6. 
Myocardial infarction or unstable angina or presence of unstable ischemic 
coronaropathy assessed by coronarography or cardiac stress test (Echo stress, exercice 
stress test, nuclear or MR perfusion evaluation methods) within 6 months before 
selection 
7. 
Severe chronic kidney disease (creatinine ≥ 25 mg/L or estimated glomerular filtration 
rate < 30 mL/min) at selection 
8. 
Bradycardia (HR ≤ 50 bpm) 
9. 
Hyperkalemia or hypokalemia (K>5.5 mEq/L or K < 3.5 mEq/L) at selection  
10. Cardiac surgery within 3 months before selection or planned during the study duration 
 
 
Criteria related to treatments: 
11. Previously ineffective pharmacological or electrical cardioversion 
12. Concomitant treatment with any anti-arrhythmic drug (within 7 days prior to selection), 
except stable dose of digoxin, betablockers, calcium-blockers 
13. Previous treatment with oral amiodarone within 12 months prior to inclusion 
14. Previous treatment with intravenous amiodarone within 6 months prior to inclusion 
15. Patient requiring a cardiac resynchronization therapy (CRT) or having undergone CRT 
implantation within the last 6 months  
16. Treatment with any Polyunsaturated Fatty Acid (PUFA) within the last 3 months 
17. Dietary supplement with ω3 or ω6 according to investigator’s judgement 
18. Having undergone any form of ablation therapy for AF 
19. Patient treated with other anticoagulant treatment than antivitamin K: thrombin inhibitor 
such as Dabigatran or treated with antiaggregant P2Y12 inhibitors such as Clopidogrel 
or Prasugrel 
 
Other criteria: 
20. Patient liable not to comply with protocol instructions and/or with treatment, in the 
investigator’s opinion 
21. Patient having taken part in a clinical trial in the preceding 2 months or taking part in a 
trial at the time of selection 
22. Patient linguistically or mentally unable to understand the nature, objectives and 
possible consequences of the trial, or refusing to patient himself/herself to its constraints 
23. Patient family member or work associate (secretary, nurse, technician,..) of the 
Investigator 
24. Patient having forfeited his / her freedom by administrative or legal award or being 
under guardianship 
25. Breastfeeding female patient 
 
Exclusion criteria before V3: 
Patients not stabilized for INR (i.e. values not between 2 and 3) on at least 3 consecutive 
weekly tests performed before ECV will be excluded from the study, unless the presence of 
atrial thrombosis may be excluded with ECHO –TE (trans-esophageal echocardiograph) 
performed  in the same day (before ECV) 
ECV will be performed in patients without dyskalemia 
If necessary for obtaining stabilized INR between 2 and 3, the ECV (and following visits) 
could be postponed by 7 days. 
Test Product:  
F373280  
Soft Capsules  
Dose: 
Arm with 1g of F373280 
Mode of Administration: 
Oral, one capsule each evening with dinner. 
Duration of Treatment: 
24 weeks of treatment exposure with F373280 (25 weeks if ECV postponed by 1 week) 
Reference Therapy 
Placebo soft capsules 
Placebo will be administered in the same conditions as the tested product. 
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Mode of Administration: 
Oral, one capsule each evening with dinner 
Evaluation Criteria: 
Efficacy evaluation variables: 
 
Primary evaluation variable: 
- Time to first Atrial Fibrillation recurrence defined by the first episode of Atrial Fibrillation 
lasting for at least 10 minutes (Follow up of 20 weeks after  visit 3 (ECV visit) 
Handling of AF recurrences: 7-day continuous ECG (5-leads/2 or 3 channels) ambulatory 
recording (holter ECG) between visit 3 (ECV visit) and visit 4 (week 5). Then, the follow 
up will be documented using the TTEM: daily transmission from week 6 to week 8. Then, 
every two days from week 9 to week 24. 
For randomised patients with spontaneous cardioversion before ECV, the recurrence of AF 
will be assessed after visit 3 (week 5).  
Moreover, during this TTEM period, if patient experiences any AF symptoms, it should be 
recorded and documented using the TTEM.  
All ECG traces will be evaluated by a Central Reading Laboratory. 
 
Secondary evaluation variables: 
During the 7-day continuous ECG monitoring, 
• 
Numbers of AF episodes 
• 
Duration of AF episodes 
 
Clinical parameters: 
During the whole study: 
• 
Number of recurrence of symptomatic AF episodes 
• 
EHRA score 
• 
Hospitalization for cardiovascular events 
• 
Hospitalization for thromboembolic stroke 
• 
All cause of hospitalization 
 
Cardioversion: 
• 
Assessment of spontaneous cardioversion 
• 
Assessment of successful cardioversion 
• 
Number of patients needing an other cardioversion after the initial ECV 
 
Other: 
• 
Evolution of echocardiographic parameters (from V4 to V6 and V9) (Left atrial 
diameter (mm), Left atrial area (cm²), Left atrial volume (mL), Left atrial 
volume/BSA (mL/m2), Left ventricular ejection fraction (%),Left ventricular 
volume (mL), Left ventricular volume/BSA(mL/m2, Left ventricular end diastolic 
diameter (mm), Left ventricular end diastolic volume (mL) Left ventricular end 
systolic diameter (mm), Left ventricular end systolic volume (mL)) 
• 
Evolution of omega 3 index and intra erythrocyte DHA (For this assessment 
samples will be centralized). 
 
Safety criteria: 
- Adverse events (observed and / or spontaneously reported) 
- Vital signs (Blood pressure (supine and standing), heart rate 
-  Physical examination (body weight),  
- Standard 12-lead ECG: heart rate (bpm), PR (ms), QRS (ms), QT (ms), repolarisation 
patterns (ECG not centralized). 
- Haematology: haematocrit, haemoglobin, RBC, WBC, differential count, platelets 
- Biochemistry: sodium, potassium, bicarbonate, chloride, alkaline phosphatase, gamma 
GT, albumin, total bilirubin, conjugated bilirubin, creatinin, aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), fasting glucose, total cholesterol, cholesterol 
(HDL, LDL), triglycerides, creatin phosphokinase (CPK) fibrinogen (local laboratory) 
- Coagulation parameters: Activated partial thromboplastin time (aPTT), thrombin clotting 
time (TCT), INR (local laboratory), Prothrombine Time (PT) 
Statistical Methods: 
Sample Size: 
Assuming an AF recurrence rate under placebo of 85%, a power of 80%, an alpha risk of 5% 
and a rate of not assessable patients of 15%, 76 randomised patients per group will be 
necessary, using a log-rank test of survival curves, a difference between groups of 20%.  
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Primary Efficacy Analysis 
The primary analysis, performed on the Full Analysis Set (FAS: all randomised patients with 
at least one dose of treatment and with a successful cardioversion observed at visit 3), will be 
a survival analysis using the Kaplan Meier method and Cox regression model. 
Secondary Analyses  
All secondary efficacy criteria will be described and compared using appropriate tests on the 
FAS. 
Safety Analyses 
Descriptive statistics will be performed on the Safety Set (all randomised patients with at 
least one dose of treatment)  
 
 
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STUDY FLOW-CHART 
 
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F373280 CA 201
V1
V2
V3
V4
V5
V6
V7
V8
V9
Weeks
W-4 to W-1
D1
W4
 (28 -2D/+7 D) 
W5
 (35 +/-2 D)
W8 
(56+/-7D)
W12 
(84+/-7D)
W16 
(112+/-7D)
W20 
(140+/-7D) 
W24 
(168+/-7D)
Outpatient or Hospitalization (1)
X
Informed consent
X
Demographic characteristics
X
Medico-surgical history
X
Concomitant disease
X
Concomitant treatment
X
X
X
X
X
X
X
X
X
Habits
X
Global physical examination (body weight)
X
X
X
X
X
X
X
X
Echocardiography
X
X
X
X
X
Eligibility criteria check
X
X
Blood pressure, heart rate 
X
X
X
X
X
X
X
X
X
12-Lead  ECG Recording
X
X
X
X
X
X
X
X
INR 
 
 
 (2)
X
X
X
X
X
aPTT, TCT 
X
X
X
X
X
X
X
X
Biochemistry
X
X
Hematology
X
X
X
X
Urinary pregnancy test
X
X
Red Blood Cell concentrations of DHA 
X
X
X
X
Treatment allocation
X
X
IVRS
X
X
X
X
ECV (3)
X
Drug administration 
 
 
 
 
 
 
 
 
Adverse events recording
X
X
X
X
X
X
X
X
Holter ECG 
 (4)
 
 (5)
TTEM (6)
 
 
 
 
(3) In patients with AF
(1) Outpatient or hospitalization according to clinical practice of the centre (less or more than 24 hours)
(6) TTEM everyday from week 6 to week 8. Then every 2 days from week 9 to week 24. In case of AF symptoms. In case of AF recurrence for at least 10 minutes and the patient does not 
stop  the study treatment then TTEM every 4 weeks
(2) In case of AVK introduction: INR 2 to 3 times a week, then weekly untill the ECV, then every 4 weeks after ECV.
(5) 7-day Holter ECG
(4) 24-hour Holter ECG
 
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LIST OF ABBREVIATIONS 
 
aPTT 
Activated partial thromboplastin time 
AE 
: 
Adverse event 
AERP 
Atrial effective refractory period 
AF 
: 
Atrial fibrillation 
ALA 
Alpha-linoleic acid 
ALT 
: 
Alanine aminotransferase 
AST 
: 
Aspartate aminotransferase 
AUC 
: 
Area under the plasma concentration versus time curve 
AUCinf 
: 
Total area under the curve extrapolated to infinity 
AVK 
Anti vitamin K 
βHCG 
: 
beta human chorionic gonadotrophin 
BLQ 
: 
Below the limit of quantification 
BMI 
: 
Body mass index 
BP 
Blood pressure 
BSA 
: 
Body Surface Area 
CEP 
Protocol evaluation committee 
CHF 
: 
Congestive heart failure 
CHMP 
: 
Committee for medicinal products for human use 
Cmax 
: 
Maximum concentration 
Cmin 
Minimum concentration 
CNALV 
: 
Clinically noteworthy abnormal laboratory value 
CPK 
Creatin phosphokinase 
CPP 
: 
Comité de protection des personnes  
CRA 
: 
Clinical research associate 
CRT 
Cardiac resynchronization therapy 
CSC 
: 
“Clinically Significant Change”, i.e., Predefined potentially clinically significant 
change leading to a potentially clinically significant value (vital signs) 
CV 
: 
Coefficient of variation 
DBP 
: 
Diastolic blood pressure 
DHA 
: 
Docosahexaenoic acid 
EC 
: 
Ethics committee 
ECG 
: 
Electrocardiogram 
ECHO –TE 
Trans-esophageal echocardiograph 
ECV 
: 
Electrical cardioversion 
EHRA 
European heart rhythm association 
EPA 
Eicosapentaenoic acid 
eCRF 
Electronic case report form 
FAS 
: 
Full analysis set 
Fe 
: 
Fraction of the administered drug excreted in urine 
GCP 
: 
Good clinical practice 
GFR 
:  Glomerular Filtration Rate 
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HBs 
: 
Hepatitis B antigen 
HCV 
: 
Hepatitis C virus 
HDL 
High density lipoprotein 
HF 
Heart failure 
HIV 
: 
Human immunodeficiency virus 
HR 
: 
Heart rate 
ICH 
: 
International conference on harmonisation of technical requirements for 
registration of pharmaceuticals for human use 
IDMC 
: 
Independent data monitoring committee 
INR 
International normalized ratio 
IRPF 
: 
Institut de Recherche Pierre Fabre 
IVRS 
Interactive voice response system 
LAA 
Left atrial area 
LC/MS-MS : 
Liquid chromatography with tandem mass spectrometry 
LDL 
Low density lipoprotein 
LOQ 
: 
Limit of quantification 
LVEF 
Left ventricular ejection fraction 
MedDRA 
: 
Medical dictionary for regulatory activities 
MR 
Mineralocorticoid receptor 
MR perfusion 
Magnetic Resonance perfusion 
MTD 
: 
Maximum tolerated dose 
N 
: 
Number of determinations or replicates 
NOAEL 
: 
No observed adverse effect level 
NYHA 
New York heart association 
od 
: 
Once a day 
PC 
: 
“Predefined Change”, i.e., Predefined potentially clinically significant change (lab 
or vital signs) 
PCA 
: 
PC leading to an out-of-range value (lab values) 
PFB 
: 
Pierre Fabre Biométrie 
POC 
Proof of concept 
PUFA 
: 
PolyUnsaturated fatty acid 
PK 
: 
Pharmacokinetics 
p.o. 
: 
Per os 
PP 
: 
Per protocol data set 
RBC 
: 
Red blood cells 
SAE 
: 
Serious adverse event 
SBP 
: 
Systolic blood pressure 
SD 
: 
Standard deviation 
T1/2 
: 
Terminal half-life 
T0 
: 
Time of drug administration 
Tmax 
: 
Time to reach the maximal concentration 
TCT 
Thrombin clotting time 
TEAEs 
Treatment emergent adverse events 
TTEM 
TransTelephonic ECG monitoring 
VTP 
: 
Ventricular tachypacing 
WBC 
White blood cells 
WHO-DRUG : 
World health organization drug reference list 
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1. INTRODUCTION AND STUDY RATIONALE 
1.1. 
TARGET PATHOLOGY AND THERAPY 
Atrial Fibrillation (AF) is a supraventricular arrhythmia characterized by uncoordinated atrial 
electric activity with consequent deterioration of atrial mechanical function. It is the most 
common sustained cardiac rhythm disorder, increasing in prevalence with age. Haemodynamic 
impairment and thromboembolic events related to AF result in significant morbidity and mortality 
[7]. 
In 2009, Decision Resources estimated that there were 7.8 million diagnosed prevalent cases of 
atrial fibrillation (AF) in US, Europe and Japan. This age-related pathology should increase to 9.4 
million cases in 2019.  
Except for the conventional class I and class III anti-arrhythmic agents, the PUFAs 
(Polyunsaturated Fatty Acids) constitute one emerging antiarrhythmic therapy. These compounds 
potently address the AF substrate by directly targeting both the electrical and the structural 
remodelling of the deficient atria. The n-3 PUFAs, essential for human, are ALA, EPA and DHA. 
First, PUFAs specifically modulate ionic channels by fastening their inactivating mode which 
renders these compounds selective for pathological situations (such as AF) without any major 
effect in normal conditions. PUFAs are “open Kv1.5 channel blockers” leading to a lengthening of 
atrial action potential duration and are “persistent Nav1.5 channel blockers” leading to 
hyperpolarization of diastolic resting potential. Second, PUFAs influence structural remodelling 
through their anti-inflammatory effects as they directly compete with arachidonic acid in the 
production of inflammatory eicosanoids. In summary, PUFAs share unique, well-tolerated 
antiarrhythmic potential by interacting with the electrical and structural remodelling during 
sustained AF. In animal studies, it was recently demonstrated that DHA is particularly effective in 
pathologic conditions such as ischemia and/or atrial fibrillation. 
The potential anti-arrythmic effects of a PUFA was previously developed in atrial fibrillation: 
nicotinyl ester of DHA (pro-drug based on DHA delivery) were assessed in a two-week 
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ventricular tachypaced canine model. Dogs were subjected to 4 weeks of medication prior to 
undergoing an electrophysiology study, and received either placebo or nicotinyl ester of DHA. 
Dogs were tachypaced at 240 beats per min for the final two weeks of the treatment plan. The 
results showed that the tested PUFA reduced the duration of atrial fibrillation (AF) induced by 
burst pacing, and the incidence of sustained AF, compared to dogs treated with the placebo [1]. 
In clinical practice, Nodari and coll assessed n-3 Polyunsaturated Fatty Acids in the prevention of 
atrial fibrillation recurrences after electrical cardioversion. All included patients were treated with 
amiodarone and a renin-angiotensin-aldosterone system inhibitor. The 199 patients were assigned 
either to placebo or n-3 PUFAs 2 g/d and then underwent direct electrical cardioversion (ECV) 4 
weeks later. The primary end point was the maintenance of sinus rhythm at 1 year after 
cardioversion. At the 1-year follow up, the maintenance of sinus rhythm was significantly higher 
in the n-3 PUFAs treated patients compared with the placebo group (hazard ratio, 0.62 [95% 
confidence interval, 0.52 to 0.72] and 0.36 [95% confidence interval, 0.26 to 0.46], respectively; p 
= 0.0001). The study concludes that in patients with persistent atrial fibrillation on amiodarone 
and a renin-angiotensin-aldosterone system inhibitor, the addition of n-3 PUFAs 2 g/d improves 
the probability of the maintenance of sinus rhythm after direct current cardioversion [2]. 
Previously, during the World Congress of Cardiology in 2006, an abstract reported the 
effectiveness of PUFA on top of traditional treatment (amiodarone, beta blockers, renin-
angiotensin-aldosterone system inhibitor) in the prevention of AF relapses in patients having 
undergone ECV. In the PUFA group, AF relapses were significantly lower than placebo group at 
one month (3.3% vs 10%; p=0.043), at 3 months (10% vs 25%; p=0.004) and at 6 months (13.3% 
vs 40%; p<0.0001) [19]. 
In contrast, in the general AF population (paroxystic atrial fibrillation and persistent atrial 
fibrillation), PUFAs failed to prove their efficacy [7] because of the absence of cardiac 
remodelling or because of a short pre-treatment duration before ECV (1 week) [8].The effect of 
PUFAs were only observed in patients with persistent AF on add on therapy and after a sufficient 
pre-treatment before ECV. Persistent AF is commonly associated to heart failure. Previous studies 
performed in heart failure population demonstrated the benefit of PUFAs on the improvement of 
functional ventricular parameters and morbi-mortality, and on the reduction of hospitalisation [3, 
4, 5]. 
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Nodari and coll [3] performed a trial in patients with a chronic heart failure (NYHA I to III and 
LVEF< 45%). After a treatment of 133 patients with PUFAs (n=67) or placebo (n=66) at a dosage 
of 5 g/day for 1 month, then 2 g/day for 11 months, the n-3 PUFAs group and the placebo group 
differed significantly (p <0.001) in regard to:  
− LVEF (increased by 10.4% and decreased by 5.0%, respectively) 
− peak VO2 (increased by 6.2% and decreased by 4.5%, respectively) 
− exercise duration (increased by 7.5% and decreased by 4.8%, respectively) 
− mean New York Heart Association functional class (decreased from 1.88+/- 0.33 to 1.61 
+/- 0.49 and increased from 1.83+/- 0.38 to 2.14 +/- 0.65, respectively).  
The hospitalization rates for HF were 6% in the n-3 PUFAs and 30% in the placebo group  
(p <0.0002). 
Moertl and coll [4] performed a dose-ranging study in patients with a more severe chronic heart 
failure (NYHA III and IV and LVEF < 35%). It was a double-blind, randomised, controlled pilot 
trial in 43 patients treated with PUFAs or placebo for 3 months (1 g/d n3-PUFA (n = 14), 4 g/d 
n3-PUFA (n = 13), or placebo (n = 16)). After treatment, left ventricular ejection fraction 
increased in a dose-dependent manner (P = 0.01 for linear trend) in the 4 g/d (baseline vs 3 
months [mean ± SD]: 24% ± 7% vs 29% ± 8%, p = 0.005) and 1 g/d treatment groups (24% ± 8% 
vs 27% ± 8%, P = 0.02). 
No changes in any investigated parameters were noted with placebo. 
Taking into account these studies performed with PUFAs, it seems that the best target for DHA is 
persistent AF in patients with heart failure. The aim of this proof of concept study is to assess in 
stand alone therapy (without association of other anti-arrhythmic treatments), the effect of 
F373280 in patients with persistent atrial fibrillation and heart failure in the maintenance of sinus 
rhythm after electrical cardioversion. 
1.2. 
INFORMATION ON THE TEST PRODUCT 
F373280 or panthenyl ester of DHA (docosahexaenoic acid) is the mono-ester of panthotenic 
alcohol and DHA, selected to be developed for the management of atrial fibrillation.  
F373280 is a prodrug of DHA. 
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A brief summary of F373280 known characteristics is presented in this section. For further details, 
please refer to the F373280 Investigator’s Brochure. [1] 
1.2.1. 
Chemical and pharmaceutical characteristics 
1.2.1.1. 
Nomenclature and structure 
Chemical name (IUPAC):  
(4Z,7Z,10Z,13Z,16Z,19Z)-3-((R)-2,4-dihydroxy-3,3-diméthylbutanamido) 
propyl 
docosa-
4,7,10,13,16,19-hexaenoate 
Structural formula: 
O
O
O
O
NNHH
O
O
OHH
O
OHH
 
Laboratory code: F373280 
Molecular formula: C31H49NO5 
Molecular mass: 515.7 
1.2.1.2. 
Physical and chemical general properties 
Appearance: Clear oily viscous liquid 
Solubilities:  
− Water: Practically insoluble 
− Alcohol: Very soluble  
− Trimethylpentane: Slightly soluble  
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1.2.2. 
Non-clinical Data 
Non-clinical data are exhaustively detailed in the Investigator’s brochure [1]. A brief summary is 
provided below. 
1.2.2.1. 
Pharmacological profile 
F373280 (mono-ester of panthotenic alcohol and DHA) is a novel pro-drug of DHA which exerts 
antiarrhythmic properties by interacting with the electrical and structural remodelling of the atria.  
Experimental investigations were conducted in HEK293 cell line transfected with human Kv1.5 
channel using the whole cell patch clamp technique to evaluate whether F373280 could block the 
sustained component of IKv1.5. F373280 concentration-dependently reduced Kv1.5 channel activity 
with an IC50 value of 13.7 µM. 
The effects of F373280 on atrial effective refractory period (AERP) were investigated in 
anesthetized pig using a conventional pacing protocol through epicardial electrodes placed on the 
left atrium. F373280 administered as a bolus and an infusion (10 mg/kg) significantly increased 
AERP (23.8 ± 2.2 ms versus -7.3 ± 11.5 ms in the presence of vehicle, P<0.05). In addition, 
F373280 was devoid of significant effect on the hemodynamic and the ECG intervals.  
Proof of the pharmacological concept was performed with a different DHA derivative named: 
Nicotinyl ester of DHA (pro-drug based on DHA delivery). Ventricular tachypacing (VTP)-
induced congestive heart failure (CHF) provides a clinically-relevant animal model of AF 
associated with structural remodelling, as is often seen clinically. It has been shown that sustained 
oral PUFA administration suppresses CHF-induced AF-promotion and fibrosis in the VTP canine 
model. Nicotinyl ester of DHA was tested in this model, at 1g/day and 5g/day, during 4 weeks, to 
prevent CHF-related atrial structural remodelling and AF promotion in dogs. Nicotinyl ester of 
DHA dose dependently reduced heart failure-induced increases in atrial fibrillation duration (989 
± 111 sec, n=5 in the presence of placebo versus 637 ± 196 sec, n=5 in the presence of 1g/kg/d 
Nicotinyl ester of DHA and 79 ± 51 sec, n=5, in the presence of 5g/kg/d Nicotinyl ester of DHA 
The protective effect of Nicotinyl ester of DHA was associated with a marked increase of plasma 
level of DHA and important incorporation of DHA in the left atrial tissue. Because F373280 
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similarly to Nicotinyl ester of DHA increases plasma level of DHA, it could be estimated that the 
compound may exert a similar protective effect [1]. 
1.2.2.2. 
Safety pharmacology 
A battery of safety pharmacology studies was performed to evaluate the effects of F373280 on the 
central nervous, cardiovascular and respiratory systems. Data of these studies are exhaustively 
detailed in the Investigator’s brochure [1]. 
No particular alerts were evidenced with F373280. 
1.2.2.3. 
Toxicology profile 
 
Concerning the toxicological data, 4-week and 26-week repeat-dose studies in rat and dog were 
performed. Compared to the high administered doses of F373280 (500 to 2000 gm/kg/day), low 
circulating concentrations of F373280 were measured.  
During these toxicity studies , no toxicity was observed in rat after 4 and 26 weeks of dosing and 
in dog after 4 weeks of dosing. A NOAEL of 2000 mg/kg/day was established in these repeat 
toxicity studies.  
During the 26-week toxicity study in dogs, the NOAEL was set at 1000 mg/kg/day based on 
changes observed on red blood cell parameters. 
Based on toxicological profiles, F373280 is considered to support the proposed clinical trial. 
 
1.2.2.4. 
Pharmacokinetic data  
According to animal studies described in the Investigator’s brochure [1], the non-clinical 
pharmacokinetic profile of F373280 is not associated with particular alerts concerning the 
proposed clinical phase IIa study. 
1.2.3. 
Clinical data 
Part A: single dose 
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6 consecutive single ascending doses were tested (0.5g, 1g, 2g, 4g, 8g and 16g) on 6 independent 
cohorts of 8 subjects (6 verum + 2 placebo). 49 subjects were treated and 48 completed the study. 
No Serious Adverse Events occurred in the course of the study. 
Regarding the reported Treatment Emergent Adverse Events (TEAEs) that were judged by the 
Investigator as having a causal relationship with the study drug administration in the absence of 
an alternative explanation, 4 were observed in the placebo group (palpitation, dizziness in 
standing position , 2 symptomatic orthostatic hypotensions without loss of consciousness) and 4 in 
the group of F373280 at the dosage of 16g (meteorism, liquid stool, symptomatic orthostatic 
hypotension and dizziness in standing position). None of these adverse events were reported in the 
groups of F373280 at the dosages of 0.5g, 1g, 2g, 4g and 8g. 
After a single administration of the different tested doses no difference between the tested product 
and placebo has been reported, regarding vital signs (heart rate, systolic blood pressure and 
diastolic blood pressure), biological parameters (related to coagulation: platelets and fibrinogen) 
and coagulation parameters (bleeding time, prothrombin time/INR, activated partial 
thromboplastin time, thrombin clotting time). Variations of these parameters were within the 
physiological ranges. 
After single oral administration of F373280 from 0.5g to 16 g in 36 young male healthy subjects 
(6 per dose level), the following was observed: 
 
- F373280: Whatever the tested dose there is no circulating F373280 in plasma: only few, 
sparse and non consecutive samples with quantifiable level of F373280 close to LOQ were 
observed. This confirm that F373280 is a prodrug. 
- Panthenol: Cmax and AUC increased with the administered dose between 0.5 and 16g. 
Panthenol concentrations were rapidly cleared from plasma with a mean terminal half-life 
around 2 hours. 
- DHA: after 0.5 and 1g, low increased in DHA plasma concentrations compared to the 
baseline levels led to a high inter-individual variability of the corresponding PK parameters. 
Plasma exposure in DHA increased with the administered dose between 2 and 16g with no 
departure from proportionality (baseline corrected parameters). 
 
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Part B: Multiple dose  
Three consecutive repeated ascending doses (1, 2 and 4g) were tested on 3 independent cohorts of 
12 subjects (9 verum + 3 placebo, double blind). 36 subjects completed the study. Each treatment 
was administered over a period of 28 days. Pharmacokinetic parameters were assessed over a 
period of 14 days.  
Among the TEAE judged by the investigator as suspected to F373280 5/9 TEAE were classified 
according the SOC in vascular system disorder with orthostatic hypotension (2 in the 1 g group, 1 
in the 2 g group and 2 in the 4 g group) and 4/9 were classified in nervous system disorder with 3 
dizziness (2 in the 2 g group and 1 in the 4 g group) and 1 migraine (in the 1 g group). These 
TEAE have already been reported with Poly Unsaturated Fatty Acids and are commonly observed 
in phase I studies. 
After a repeated administration of the different tested doses, no difference between the tested 
products and placebo was reported regarding vital signs (heart rate, systolic blood pressure and 
diastolic blood pressure), biological parameters. The assessment of coagulation parameters and 
platelet function after administration of repeated dose of F373280 did not report any bleeding 
issue. The reported changes in coagulation parameters and platelet function were within 
physiological ranges. 
After a 14-day repeated oral administration of F373280 from 1 g to 4 g, the following was 
observed: 
 Panthenol: Cmax and AUC increased with the administered dose between 1 and 4 g. No 
accumulation of panthenol in plasma was observed. 
 
 DHA: Plasma exposure increased with dose. A 2-fold accumulation in total plasma exposure 
of DHA was observed after 14 days of administration, whatever the administered dose. 
 
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1.3. 
STUDY RATIONALE 
F373280 is a new therapy based on DHA delivery (pro-drug) developed for the maintenance of 
sinus rhythm after electrical cardioversion in persistent atrial fibrillation (AF) patients with 
chronic heart failure. 
The results of a pharmacological study performed in animals evidenced that DHA reduces the 
duration of atrial fibrillation (AF) induced by burst pacing [1]. 
Moreover, the effectiveness of PUFA has been proven in the following conditions: 
- 
Prevention of atrial fibrillation recurrence in patients with persistent atrial fibrillation in 
co-administration with amiodarone (add on therapy) [2], 
- 
Improvement of ventricular functional parameters, morbi-mortality and duration of 
hospitalisation in patients with heart failure [3, 4, 5]  
Taking into account these studies, it seems that DHA might be of therapeutic interest in the 
treatment of patients with both persistent atrial fibrillation and chronic heart failure. 
This phase IIa study is designed to assess the efficacy and the safety of the investigational product 
(F373280) for maintenance of sinus rhythm after electrical cardioversion in patients with 
persistent atrial fibrillation and chronic heart failure. 
1.4. 
OVERALL RISK AND BENEFIT ASSESSMENT 
F373280 is a new pro-drug of DHA.  
DHA is a well-known long chain PUFAs with a long-term clinical experience in cardiovascular 
diseases. DHA is contained in several medicinal products such as Omacor, (1g of Omacor 
contains about 320 mg of DHA acid) marketed by Laboratoires Pierre Fabre for 
hypertriglyceridemia and as an adjuvant treatment for secondary prevention after myocardial 
infarction. According to the summary product characteristics of Omacor, [9]: 
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- The frequencies of adverse reactions are ranked according to the following: common (> 
1/100, < 1/10); uncommon (>1/1000 < 1/100); rare (>1/10000, < 1/1000); very rare ( < 1/10000), 
not known (cannot be estimated from the available data). 
- The reported adverse events are: 
• Infection and infestations 
Uncommon: gastroenteritis 
• Immune system disorders: 
Uncommon: hypersensitivity 
• Metabolism and nutrition disorders: 
Rare: hyperglycaemia 
• Nervous system disorders: 
Uncommon: dizziness, dysgeusia 
Rare: headache 
• Vascular disorders: 
Very rare: hypotension 
• Respiratory thoracic and mediastinal disorders:  
Very rare: nasal dryness 
• Gastrointestinal disorders: 
Common: dyspepsia, nausea 
Uncommon: abdominal pain, gastrointestinal disorders, gastritis, abdominal pain upper 
Rare: gastrointestinal pain 
Very rare: lower gastrointestinal haemorrhage 
• Hepatobiliary disorders:  
Rare: hepatic disorders  
• Skin and subcutaneous tissue disorders:  
Rare: acne, rash pruritic 
Very rare: urticaria 
• General disorders and administration site conditions: 
Rare: malaise sensation 
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• Investigations: 
Very rare: white blood count increased, blood lactate dehydrogenase increased 
Moderate elevation of transaminases has been reported in patients with hypertriglyceridaemia. 
Panthenol is a well-known substance with a long-term experience in medical, nutraceutic and 
cosmetic uses. According to the summary product characteristics of a product such as 
Bépanthene (tablet indicated in alopecia) which contains panthenol (100 mg), adverse event 
observed are rare cases of urticaria and erythema [10]. Panthenol is metabolised in panthotenic 
acid, i.e. B5 vitamin. 
Concerning toxicological studies performed results can support the administration of F373280 in 
the proposed clinical phase II study without particular alert [1]. 
Any safety warning was reported during a phase I study performed with F373280 administered to 
84 healthy volunteers in single dose in a range between 500 mg and 16 g or in repeated dose 
during 28 days in a range between 1g and 4g. Adverse events reported and related to study 
treatment were minor to moderate. The adverse events were palpitations, orthostatic hypotension, 
dizziness, meteorism and liquid stool. Most were reported in both groups (placebo and F373280) 
without a dose relationship. The assessment of coagulation parameters and platelet function after 
administration of repeated dose of F373280 did not report any bleeding concern: the reported 
changes in coagulation parameters and platelet function were within physiological ranges. 
Moreover, DHA has been associated with anticoagulant products in Atrial Fibrillation studies [2, 
8]. The range of PUFAs doses tested was between 2g to 3g (640 mg to 960 mg of DHA) and the 
range of study durations between 6 to 12 months. This association did not report a significant side 
effect of bleeding. 
DHA has already been used in heart failure patients in several studies without safety concern [3, 
4, 5]. The range of PUFAs doses tested was between 1g to 5g (1g of the tested PUFAs contains 
about 320 mg of DHA acid) and the range of study durations was between 3 months to 3.9 years. 
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Thus, inclusion of patients with no specific antiarrhythmic treatment is acceptable. They will 
receive an anticoagulant treatment to prevent the thrombo-embolic complications of AF 
(particularly stroke) and the adequate treatments to control the heart rate and heart failure.   
In conclusion, the overall available data allow in safe conditions the treatment of patients with 
persistent AF and chronic heart failure with F373280 in safe conditions. 
2. STUDY OBJECTIVES 
2.1. 
PRIMARY OBJECTIVE 
The primary objective of the study is to assess the efficacy of F373280 on the maintenance of 
sinus rhythm after direct electrical cardioversion in patients with persistent atrial fibrillation and 
chronic heart failure. 
2.2. 
SECONDARY OBJECTIVES 
The secondary objectives of the study are to assess: 
• the efficacy of F373280 on the efficiency of direct electrical cardioversion 
• the effect of F373280 on echocardiographic parameters 
• the safety and tolerability of F373280 
3. ETHICAL CONSIDERATIONS RELATING TO THE STUDY 
The trial is conducted according to Good Clinical Practices (CPMP/ICH/135/95), the National 
regulations and the Declaration of Helsinki and its subsequent amendments (see Appendix 17.1). 
This protocol and the informed consent form will be submitted for approval to independent local 
or national Institutional Review Boards/Ethics Committees before the study set up, according to 
national regulation. 
All the protocol amendments or critical events liable to increase the risks incurred by the patients 
or to compromise the validity of the study or patients' rights will be submitted to the coordinator 
and to the Ethics Committees. 
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After being informed orally and in writing of all potential risks and constraints of the trial, as well 
as their freedom to withdraw their participation at any time, patients will then sign a consent.  
A time of reflection will be given to the patients, before giving a written consent and starting the 
study procedures. 
The use of a placebo is in accordance with EMA Addendum to the guideline on antiarrhythmics 
on atrial fibrillation and atrial flutter (EMA/CHMP/EWP/213056/2010) [21] and is acceptable 
because the included patients will remain under the standard treatment of atrial fibrillation and 
chronic heart failure. Except antiarrythmics, they will receive anticoagulant (AVK), rate control 
treatment, chronic heart failure treatment. During the study, in case of AF recurrence that would 
require a cardioversion or an introduction of an anti-arrhythmic because of intolerable and/or 
uncomfortable clinical symptoms, patients will be withdrawn and the tested product stopped. 
These patients will be considered as treatment failure. 
In this study, patients will be carefully screened, particularly for their cardiac condition, with 
ECG, 24-hour holter monitor and echocardiographic data, and their biologic and coagulation 
condition. 
The study will be addressed only to patients requiring an ECV due to their persistent AF, in the 
following conditions: 
- 
ECV in patients not presenting a contra-indication,  
- 
Anticoagulation  with anti-vitamin K for at least 3 weeks before ECV,  
- 
ECV in patients with stabilized INR (i.e. values between 2 and 3) on at least 3 
consecutive weekly tests performed. Patients not stabilized for INR (i.e. values not 
between 2 and 3) on at least 3 consecutive weekly tests performed before ECV will be 
excluded from the study, unless the presence of atrial thrombosis may be excluded 
with ECHO –TE (trans-esophageal echocardiograph) performed  in the same day 
(before ECV) 
 
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- 
Patients who do not revert to sinus rhythm or present an early relapse within the 
observation period after ECV will be withdrawn and the tested product stopped. 
During the whole study, patients will remain under medical control: visits in cardiology units will 
be scheduled at least every month. This follow up will include clinical signs, ECG, biological and 
coagulation parameters. Moreover, patient’s cardiac rhythm will be monitored between visits 
using daily, then every 2 days Trans Telephonic ECG Monitoring (TTEM) reviewed by a Central 
Reading Laboratory. 
Patients may withdraw from the study at any time without having to give a reason and can expect 
to receive regular conventional therapy. 
4. STUDY DESIGN 
4.1. 
OVERALL DESCRIPTION 
This phase IIa trial will be conducted as an international, multicentric, 24 weeks, double-blind, 
placebo-controlled, randomised, parallel group design, trial in 152 patients suffering from 
persistent atrial fibrillation and chronic heart failure. 
After a 1 to 4-week of run-in period without treatment, patients will be randomised into one of the 
following treatment groups: F373280 1g or placebo for 24 weeks.  
Nine visits are planned for the study: 
- 
Visit 1 (V1): W-4 to W-1: Selection visit (7 to 28 days before the Inclusion Visit) 
- 
Visit 2 (V2): D1: Inclusion visit (start of treatment)  
- 
Visit 3 (V3): W4 (D28 -2/+7D): cardioversion visit (outpatient or hospitalization 
according to clinical practice of the centre) (installation of the Holter ECG device) 
- 
Visit 4 (V4): W5 (D35 ± 2D): follow-up visit (removing of Holter ECG device and 
installation of the TTEM) 
- 
Visit 5 (V5): W8 (D56 ± 7D): follow-up visit 
- 
Visit 6 (V6): W12 (D84 ± 7D): follow-up visit 
- 
Visit 7 (V7): W16 (D112 ± 7D) : follow-up visit 
- 
Visit 8 (V8): W20 (D140 ± 7D): follow-up visit 
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- 
Visit 9 (V9): W24 (D168 ± 7D): final study visit 
4.2. 
DISCUSSION OF THE STUDY DESIGN 
4.2.1. 
Choice of the Study Population 
The target indication of F373280 will be the maintenance of sinus rhythm after cardioversion of 
patients with persistent atrial fibrillation and chronic heart failure. In the present proof of concept 
study, the evaluation will focus on patients within this indication. This target population is 
justified by: 
− The proved efficacy of PUFAs in patients with persistent atrial fibrillation with or 
without heart failure in co-administration with amiodarone (add on therapy) [2] 
− The proved efficacy of PUFAs on the improvement of ventricular functional parameters, 
morbi-mortality and duration of hospitalisation in patients with heart failure  [3, 4, 5] 
The study aim is to investigate the product effect in patients with: 
− early persistent atrial fibrillation history (less than one year) with a duration of a the 
current episode between 7 days to 6 months  
− a moderately abnormal moderately systolic heart failure (Left Ventricular Ejection 
Fraction (LVEF) between 30 to 45% as defined in the report from the American Society 
of Echocardiography’s Guideline). According to a sub-group analysis performed in 
patients with persistent atrial fibrillation associated to heart failure ( Nodari S. personnal 
data), PUFAs would be effective to prevent recurrence of AF after cardioversion in 
patients with moderately abnormal LVEF. 
 
− A Left Atrial Area (LAA) not severely abnormal (less than 40 cm2 as defined in the 
report from the American Society of Echocardiography’s Guideline). According to a 
sub-group analysis performed in patients with persistent atrial fibrillation associated to 
heart failure ( Nodari S. personnal data), PUFAs would not be effective to prevent 
recurrence of AF after cardioversion of patients with severely abnormal LAA. 
For the successful rate of electrical cardioversion, patients should have a stable medical 
treatment of heart failure and should not have myocardial infarction or unstable angina or 
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unstable ischemic coronaropathy (assessed by coronarography or cardiac stress test or effort 
test within 6 months before selection).  
4.2.2. 
Choice of the Study Design 
As the target indication would be the prevention of AF recurrence after ECV, the study design 
meets the requirements of EMA guideline on anti-arrhythmics on atrial fibrillation 
(EMA/CHMP/EWP/213056/2010) [21]. 
As F373280 aims to be developed as a safe treatment for the prevention of AF recurrence, it will 
not be tested as an add-on therapy during the study. To avoid any interaction with the tested 
product, anti-arhythmics class I and III will be forbidden during the study. 
The study design is defined in order to avoid methodological bias. A double blind study is 
appropriate to assess the efficacy and safety of the use of F373280 to prevent recurrence of AF 
episodes. Moreover, this study design is similar to the design of almost all trials that have assessed 
intervention for rhythm control [2, 8, 11, 12].  
According to the target indication, only patients with persistent atrial fibrillation and requiring an 
electrical cardioversion will be included in order to assess the time to first documented recurrence 
of atrial fibrillation since cardioversion. 
To confirm the persistent nature of atrial fibrillation, a 24-hour holter monitoring will be 
performed during the selection visit.  
Eligible participants will enter a selection phase in which anticoagulant treatment (anti-vitamin K) 
will be adjusted to achieve an International Normalized Ratio (INR) of 2.0 to 3.0 before electrical 
cardioversion. According to guidelines for the management of atrial fibrillation [6], anti-vitamin 
K should be given at least 3 weeks before cardioversion because of risk of thrombo-embolism due 
to post-cardioversion.  
Experimental data suggest that the maximal incorporation, of n-3 PUFAs in the myocardial cell 
membrane takes up to 28 days to occur [22]. In addition, as shown in Nodary study [2], the 
duration of pre-treatment with PUFA before cardioversion appears to be a contributing factor in 
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success.Therefore, before starting follow up for the assessment of AF recurrence, treatment with 
F373280 should be started 28 days before ECV.  
Detection of atrial fibrillation recurrence will be performed using systematic (scheduled) ECG 
recording, thus allowing detection of asymptomatic (about 50% of episodes) as well as 
symptomatic AF episodes. According to previous studies, most of atrial fibrillation recurrence 
occurred during the first days after cardioversion [11, 15]. So that, the heart rhythm will be 
closely monitored during the first week after successful cardioversion using an ambulatory 
continuous 7-day holter ECG recording in order to increase sensibility to detect asymptomatic AF 
episodes. Thereafter, to improve patient compliance, this follow up will be continued using  a 
more easy to carry and easy to use device, a TTEM.  
Finally, during the study, patients will be scheduled for a clinical visit every month (with an 
additional visit 7 days after visit 3 (ECV visit)) in order to ensure a close medical monitoring and 
to assess efficacy and safety parameters. 
4.2.3. 
Choice of the Dose  
According to a previous study in patients with atrial fibrillation [2], the tested PUFA product 
(Omacor) at the dose of 2 g (i.e. 640 mg of DHA acid) was effective in the prevention of atrial 
fibrillation after cardioversion. Moreover, PUFAs at dosage of 1g and 2g were also effective on 
the improvement of ventricular functional parameters, morbi-mortality and duration of 
hospitalisation in patients with heart failure [3, 4, 5].  
From the F373280 phase I study, after a 14-day repeated administration of F373280 (1g/day), 
observed plasma concentrations of DHA measured before treatment (Cmin) were similar to that of 
an effective dose of Omacor at 2 g/day (60 to 95mg/mL and 60 to 90mg/mL, respectively) 
(phase I study of F373280 and Salm and coll study) [16]. With regard to the rythm of 
administration, mean peak/trough fluctuation (baseline corrected) was around 0.3. This value 
supports a once-daily administration allowing a 24-hour plasma exposure in DHA.Therefore, a 
dose of 1 g daily of F373280 is considered to be appropriate to be tested in this POC study. 
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4.2.4. 
Choice of the Sample Size 
See chapter 13. 
5. STUDY POPULATION 
Each patient fulfilling all the inclusion criteria and none of the non inclusion criteria will be 
eligible. 
5.1. 
INCLUSION CRITERIA 
Demographic Characteristics and Other Baseline Characteristics: 
1. Men or women aged more than 18 years (inclusive), 
2. Patient with persistent AF between 7 days and 6 months duration for whom 
electrical cardioversion is warranted. 
3. History of first documented persistent AF less than 1 year 
4. History of ischemic or non ischemic heart failure 
5.  NYHA class I or II chronic heart failure at selection and at inclusion 
6. Reduced left ventricular ejection fraction between 30% and 45% inclusive (using the two-
dimensional echocardiography biplane Simpson’s rule) at selection and at inclusion 
7. On appropriate, stable medical treatments for heart failure, including a diuretic and/or 
angiotensin-converting 
enzyme, 
and/or 
angiotensin-receptor 
blocker 
and/or 
mineralocorticoid receptor (MR) antagonists, and/or betablockers 
8. Left atrial area ≤ 40 cm² at selection and at inclusion 
9. Patient treated or having to be treated by anti-vitamin K 
10. For female patient of child-bearing potential:  
• in all the countries except Italy: 
 
- 
use of an effective method of contraception (hormonal contraception or intra-uterine 
device) assessed by the investigator, for at least 2 months before the selection in the 
study and agreement to go on using it during the whole duration of the study and up to 
1 month after the last dose of the study treatment or 
- 
documented as surgically sterilized 
 
• in Italy only: 
- 
absolute abstention from sexual intercourse during the whole duration of the study and 
for a month after the end of the study or 
- 
use of double barrier contraception method (use of effective medical contraception 
method) from at least 2 months before the start of the study to the entire duration of the 
study and for a month after the end of the study or 
- 
documented as surgically sterilized  
 
11. For female patient of child-bearing potential: negative urine pregnancy test at inclusion 
12. For male with a child-bearing potential partner (In Italy only): 
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- 
absolute abstention from sexual intercourse during the whole duration of the study and 
for a month after the end of the study or 
 
 
Ethical /legal considerations: 
13. Having signed his/her written informed consent, 
14. Affiliated to a social security system, or is a beneficiary (if applicable in the national 
regulation), 
5.2. 
NON INCLUSION CRITERIA 
Criteria related to pathologies: 
1. History of first documented episode of persistent AF more than 1 year, 
2. More than two successful cardioversions (electrical or pharmacological) in the last 6 months, 
3. Secondary Atrial Fibrillation due to alcohol or severe valvular heart disease (grade III to IV), 
4. NYHA class III or IV heart failure at selection or at inclusion 
5. Thyroid disease uncontrolled by treatment: TSH ± T4L ± T3L to be check in case of treatment 
for thyroid disease  
6. Myocardial infarction or unstable angina or presence of unstable ischemic coronaropathy 
assessed by coronarography or cardiac stress test (Echo stress, exercice stress test, nuclear or 
MR perfusion evaluation methods) within 6 months before selection 
7. Severe chronic kidney disease (creatinine ≥ 25 mg/L or estimated glomerular filtration rate  
< 30 mL/min) at selection 
8. Bradycardia (HR ≤ 50 bpm) 
9. Hyperkalemia or hypokalemia (K > 5.5 mEq/L or K < 3.5 mEq/L) at selection 
10. Cardiac surgery within 3 months before selection or planned during the study duration 
Criteria related to treatments: 
11. Previously ineffective pharmacological or electrical cardioversion 
12. Concomitant treatment with any anti-arrhythmic drug (within 7 days prior to selection), except 
stable dose of digoxin, beta-blockers, calcium-blockers. 
13. Previous treatment with oral amiodarone within 12 months prior to inclusion 
14. Previous treatment with intravenous amiodarone within 6 months prior to inclusion 
15. Patient requiring a cardiac resynchronization therapy (CRT) or having undergone CRT 
implantation within the last 6 months 
16. Treatment with any Polyunsaturated Fatted Acid within the last 3 months 
Dietary supplement with ω3 or ω6 according to investigator’s judgment 
18. Having undergone any form of ablation therapy for AF 
19. Patient treated with other anticoagulant treatment than antivitamin K: thrombin inhibitor such 
as Dabigatran or treated with antiaggregant P2Y12 inhibitors such as Clopidogrel or Prasugrel 
Others criteria:  
20. Patient liable not to comply with protocol instructions and/or with treatment, in the 
investigator’s opinion, 
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21. Patient having taken part in a clinical trial in the preceding 2 months or taking part in a trial at 
the time of selection, 
22. Patient linguistically or mentally unable to understand the nature, objectives and possible 
consequences of the trial, or refusing to patient himself / herself to its constraints, 
23. Patient family member or work associate (secretary, nurse, technician…) of the Investigator, 
24. Patient having forfeited his / her freedom by administrative or legal award or being under 
guardianship, 
25. Breastfeeding female patient. 
5.3. 
NUMBER OF  PATIENTS 
76 x 2 patients (taking into account 15 % of non evaluable patients). 
5.4. 
RECRUITMENT MODALITIES 
Patients will be recruited within the medical consultation of each centre involved in the study. If 
necessary and when authorized by local and national regulation, some specific supports or tools 
will be used to improve the recruitment (announcement, mailing to general practitioners, leaflet, 
website including ClinicalTrials.gov, CRO,…). 
Before implementation, the documents will be submitted to and approved by the Ethics 
Committee. 
5.5. 
 PATIENTS IDENTIFICATION 
The patient's code will contain 7 digits: the 2 first digits corresponding to the country number, the 
following 2 digits corresponding to the centre number and the last 3 digits corresponding to the 
patient's chronological order once having signed the written informed consent. 
5.6. 
WITHDRAWAL CRITERIA 
The reasons for a patient's premature withdrawal from the study may be the following: 
• The patient's decision. A patient who wishes to withdraw from the study for any reason may 
do so at any time but must inform the investigator. In all cases, the Investigator should attempt to 
contact the patient as soon as possible for a final assessment in order to: 
− have the patient's decision written on the consent form 
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− obtain the reason(s) for withdrawal and report it/them in the case report form 
− evaluate the patient's clinical condition 
− if necessary, take appropriate therapeutic measures: management of an adverse effect or 
concomitant disease, prescription of another treatment. 
• The Investigator's decision in the patient's interest. Particularly, if a serious adverse event 
occurs and is considered by the Investigator liable to threaten the health of the patient. The 
monitor will be informed by phone or fax and a letter or report explaining the withdrawal will be 
forwarded to the monitor as soon as possible. 
• An erroneous inclusion according to the study protocol. Any inclusion not respecting 
inclusion / non inclusion criteria will immediately be withdrawn and an appropriate treatment will 
be instored by the investigator under his/her responsibility. Erroneous inclusions will not be paid 
to the investigator. 
• Patients who could not be treated with anti-vitamin K for at least 3 weeks before ECV, 
• Patients who will not stabilize INR between 2 and 3 on at least 3 consecutive weekly tests 
• Patients with only 2 consecutives INR tests between 2 and 3 in the last 3 week for whom  a 
trans-oesophagoal echocardiography can not be performed before ECV or for whom a trans-
oesophagoal echocardiography shows a thrombus in the atria.  
• Patients who will not revert to sinus rhythm or with early relapse within the observation 
period after ECV (i.e. unsuccessful ECV) will be considered to have finished follow-up. 
• An occurrence of AF recurrence that would require, at the investigator’s judgement, a 
cardioversion or an introduction of an anti-arrhythmic because of intolerable and uncomfortable 
clinical symptoms. 
5.7. 
REPLACEMENT OF PATIENTS 
Withdrawn patients will not be replaced. 
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5.8. 
POST-STUDY EXCLUSION PERIOD  
Patients will not be allowed to participate to another clinical trial during 3 months following the 
study termination. 
5.9. 
STUDY CARD AND LETTER FOR GENERAL PRACTITIONER(S) 
The patient will receive from the Investigating Centre at Visit 1 - Selection Visit,  
- a personal card to be kept all along the study duration and providing the following information: 
patient's name, sponsor's name, study code, EUDRACT number, start date and expected end date 
of the study, complete address of the Investigating Centre with the name and phone number of the 
Investigator and a sponsor 24H/24 phone contact number in case of emergency (French and 
English languages): 33 (0)5 63 35 25 83. For Italy, this card will be in Italian only, without any 
English mention. 
- in Italy, a letter to be given to his/her general practitioner. This letter intends to inform the 
general practitioner(s) (and any other doctors who take care of the patient) that the patient 
participates to the clinical study. It describes the study treatment and includes some information 
on the forbidden treatment during the study.  
 
6. STUDY TREATMENT 
The Clinical Pharmacy Department of the Institut de Recherche Pierre Fabre (IRPF) will supply 
the investigational centres with the treatment necessary for the conduct of the trial.  
6.1. 
SOURCE, PRESENTATION AND COMPOSITION OF 
 
INVESTIGATIONAL PRODUCT 
F373280 and placebo will be prepared in Soft Capsules similar presentation.  
• F373280 
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Formulation of F373280, 1g, Soft Capsules: oral administration, oblong size 20, off-white, Soft 
Capsules containing: Panthenyl ester of DHA, gelatine, glycerol, titanium, dioxide, purified water. 
• Placebo 
Formulation of placebo matching tested product, Soft Capsules: oral administration, oblong size 
20, off-white, Soft Capsules containing: paraffin liquid, fish flavour, gelatine, glycerol, titanium, 
dioxide, purified water. 
 
Placebo and F373280 capsules will be packaged in opaque blisters. 
6.2. 
PACKAGING AND LABELLING 
The treatment units will be packed and labelled by the Clinical Pharmacy Department of the IRPF 
according to European Directive and local requirements. 
6.2.1. 
Packaging 
Each treatment unit will be composed of 3 cases for a 12-week treatment period. 
The Investigator will provide the patient with the treatment according to the following schedule: 
At Inclusion Visit (V2): a 12-week treatment unit will contain 3 cases, each case containing: 
− 10 blister packs of four 1g F373280 soft capsules or placebo soft capsules each. 
At Visit 6 (V6): a 12-week treatment unit will contain 3 cases, each case containing: 
− 10 blister packs of four 1g F373280 soft capsules or placebo soft capsules each. 
6.2.2. 
Labelling 
Investigational Products will be labelled according to the following rules: 
Labelling should comply with the local requirements for Investigational Medicinal Products. 
On the treatment units and cases, the labels will bear the following indications:  
a) name and address of the sponsor 
b) protocol number, 
c) packaging batch number, 
d) the treatment number 
e) storage conditions 
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f) expiry date 
g) pharmaceutical dose form 
h) route of administration 
i) quantity of dosage units 
j) direction for use 
k) legal statements:  
− “for clinical trial only”, “keep out of the reach and the sight of children”, “please return 
to your doctor any unused product”, respect the prescribed dose”. 
On the treatment unit, another label will be affixed with the mention of the investigator name and 
patient number (completed by the investigator). 
In addition, on each case, will be mentioned the case number and a detachable label will bear the 
following indications: 
− Protocol number 
− Packaging batch number 
− Expiry date 
− Case number 
− Treatment number 
On the blister pack, the label will mention the protocol number, the packaging batch number, the 
case number and the treatment number. 
6.3. 
DISTRIBUTION TO CENTRE AND STORAGE 
The Clinical Pharmacy Department of the IRPF will supply the Investigational Centre with the 
treatment units along the study according to the need, upon request triggered by the patient’s 
selection.  
As soon as the Pharmacist or the Investigator receives the trial medication, he/she will check the 
contents and immediately acknowledges the receipt in the IVRS/IWRS. The copy of the 
acknowledgement will be kept in the Investigator’s file. The same procedure will be applied to all 
further supplies during the course of the trial. 
At the time of the delivery to the Centre, the following information will be provided: 
• Details of storage conditions that should be respected 
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• And, upon request and for the 1st delivery only, a letter of release for the Investigational 
Medicinal Product from the Sponsor's Qualified Person. 
The CRA will ensure during the monitoring visits that trial medications have been received in 
good conditions and the acknowledgment of receipt has been performed adequately. 
Treatment units should remain intact until dispensation to the patients. They should be kept at 
temperature below 30°C in an appropriate lockable room only accessible to the person authorised 
to dispense them, under the responsibility of the Pharmacist or the Investigator. 
In the case of undue delay in study execution, the Pharmacist or the Investigator should ensure 
that the expiry date has not been exceeded.  
6.4. 
ALLOCATION OF TREATMENTS AND DISPENSATION TO PATIENT 
A randomisation list will be established by the Clinical Pharmacy Department of the IRPF. This 
list will be computer-generated with internal software. The randomisation methodology is 
validated by the Biometry Department before generation. 
Treatments F373280 or placebo will be balanced in a 1:1 ratio. 
As the treatment units are prepared for 12-week treatment periods, the Investigator will have to 
allocate a treatment number at inclusion Visit and another one at Visit 6.  
For each patient, the treatment number given at Visit 6 will not be the same that the one given at 
inclusion visit (V2). 
The treatment numbers will be given through the IVRS/IWRS. 
Practically, once the patient’s eligibility is confirmed, at selection visit:  
• The Investigator: 
− Calls the vocal server  
− Answers the questions relating to the patient  
− In return, the treatment number to be allocated for the first 12-week period to the patient 
is given by the vocal server.  
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• The IVRS/IWRS company: 
− Confirms this information by fax/email to the Investigator 
− Fills the “Request for Delivery of Investigational Product” form and sends it by email 
and/or fax to the Clinical Pharmacy Department of the IRPF.  
• The Clinical Pharmacy Department of the IRPF sends the corresponding treatment unit to the 
Investigator within 5 days from reception of the email request form. 
The Investigator will dispense to the patient the case which label indicates the treatment number 
and the administration period. 
At visit 5, the Investigator will contact again the IVRS/IWRS to obtain for visit 6 the treatment 
number for the last 12-week period of treatment according to the same process as described 
above. 
6.5. 
DRUG ADMINISTRATION 
6.5.1. 
Duration of Treatment 
For a patient completing the study, the theoretical study treatment exposure will be 24 weeks, 
with F373280 or placebo. 
If the ECV is postponed by 1 week to allow INR stabilization, the treatment duration will be 25 
weeks. 
6.5.2. 
Dose Schedule 
One soft capsule of 1g of F373280 or placebo to be taken each day during 24 weeks. 
6.5.3. 
Route and Conditions of Administration 
The soft capsules are to be taken orally. One soft capsule is to be taken each evening with the 
dinner during 24 weeks.  
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6.6. 
ACCOUNTABILITY ON SITE AND RETURN/DESTRUCTION OF 
 
INVESTIGATIONAL PRODUCT 
The Investigator should maintain accurate written records of drug received, dispensed, returned 
and any remaining treatment units, on the drug accountability form. These records should be made 
available for Clinical Research Associate (CRA) monitoring. The packaging of the medication 
should remain intact until just before the dispensation. 
At each visit, the Investigator will record the number of soft capsules returned by each patient 
using the appropriate page of the e-CRF. 
At the end of the study, all used and unused treatments including packaging should be noted, and 
return is organised by the CRA to the Clinical Pharmacy Department of the IRPF for destruction. 
A copy of the drug accountability form should be provided by the Investigator to the CRA. 
6.7. 
RECALL OF INVESTIGATIONAL PRODUCTS  
In case of recall of investigational products (decided by the Competent Authorities or the 
Sponsor), the Investigator will immediately be informed by the Sponsor. 
The Investigator, in collaboration with the Sponsor representatives (Study Manager, CRA) must 
urgently: 
• Stop the delivery of the concerned investigational products to the patients. 
• Inform the concerned patients that they must immediately stop taking these investigational 
products and bring them back. 
The Study Manager/CRA organises the return of the recalled products to the Clinical Pharmacy 
Department of the IRPF, according to the Sponsor’s procedures. 
7. CONCOMITANT TREATMENTS 
Any existing concomitant treatment (Selection Visit), any new concomitant treatment or change 
in the dosage of an existing concomitant treatment during the course of the study must be noted 
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on e-CRF. All treatments should be evaluated by the investigator at selection and their 
prolongation during the study or their stop should be considered. 
For all concomitant treatments taken during the study, the following information must be noted in 
the relevant section(s) of the e-CRF: 
• The name of the treatment and its form 
• The reason for prescription 
• The route of administration 
• The daily dose 
• The duration of treatment. 
7.1. 
ANTI-VITAMIN K TREATMENT 
Anti-vitamin K should be given for at least 3 weeks before ECV and continued for the whole 
study duration. The anti-vitamin K used will be left to the decision of the each investigator 
according to his/her local practice. 
7.2. 
PROHIBITED TREATMENTS 
- 
Class I and class III antiarrhythmic treatments: 
− Class I  
- 
Class IA: Disopyramide, Procainamide, Quinidine 
- 
Class IB: Lidocaine, Mexiletine 
- 
Class IC: Flecainide, Propafenone 
 
− Class III: Dofetilide, Ibutilide, Sotalol, Amiodarone, Dronedarone.  
- 
Any Polyunsaturated Fatty Acid (PUFA) 
- 
Any anticoagulant treatment other than antivitamin K: thrombin inhibitor such as Dabigatran 
or antiaggregant P2Y12 inhibitors such as Clopidogrel or Prasugrel 
- 
Dietary supplement with Omega 3 or Omega 6 
Prohibited treatments at selection must not be prescribed for the duration of the study except in 
case of occurrence of an adverse event or AF episode that requires a corrective treatment in the 
interest of the patient’s health. 
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7.3. 
AUTHORISED TREATMENTS 
Other treatments will be authorised during the study duration. 
However, if medication other than study drugs is administered at any time from the start of the 
study, details must be recorded in the case report form. During the study, patients must be asked 
whether they have been on a course of prescribed drug treatment or have taken any OTC or herbal 
drugs since the visit. 
8. EVALUATION CRITERIA 
8.1. 
PRIMARY EFFICACY CRITERION:  
8.1.1. 
Time to the first Atrial Fibrillation Recurrence 
8.1.1.1. 
Definition 
Time to first Atrial Fibrillation recurrence is defined by the first episode of Atrial Fibrillation 
(symptomatic or not) lasting for at least 10 minutes. 
8.1.1.2. 
Schedule 
The heart rhythm follow up will be performed from the end of electrical cardioversion visit  
(visit 3) to the final study visit (visit 9).  
For randomised patients with spontaneous cardioversion before ECV, the recurrence of AF will be 
assessed after visit 3 (week 5). 
8.1.1.3. 
Evaluation Methods 
• 7-day holter monitor: 
The heart rhythm monitoring will be carried out  from visit 3 to visit 4 using a 7-day continuous 
ECG (5-leads/2 or 3 channels) ambulatory recording (holter ECG) fixed after ECV visit. 
Following holter monitoring the heart rhythm will be documented using Trans Telephonic ECG 
Monitoring (TTEM) 
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• Trans Telephonic ECG Monitoring (TTEM): 
Thus, the follow up will be documented using the TTEM: daily transmission from visit 4 (week 6) 
to visit 5 (week 8). Then, every two days from visit 5 (week 8) to visit 9 (week 24 – End of 
study). 
Moreover, during this TTEM period, if patient experiences AF symptoms, it should be 
documented using the TTEM. 
In case of AF recurrence, and provided that the patient does not required a cardioversion or an 
introduction of an anti-arrhythmic at the investigator’s judgement, he/she could be maintained in 
the study with the treatment, in order to assess a spontaneous cardioversion. For that purpose the 
patient will continue to transmit a TTEM once a week. 
The TTEM will be centralized by the Central Reading Laboratory. The patient will be requested 
to contact the Central Reading Laboratory for transmission of each stored TTEM. The TTEM will 
be validated by a trained technician, then analysed by a cardiologist. The cardiologist 
interpretation will be faxed to the site. The investigator will be asked to review and sign this 
document. 
The TTEM process will be fully described in a separate document. 
8.1.2. 
Secondary Efficacy Criteria 
8.1.2.1. 
Numbers of Atrial Fibrillation episodes in the first week following visit 3 
 
 
(ECV visit) 
8.1.2.1.1. 
Definition 
Number of Atrial Fibrillation episodes will consist in the assessment of episodes of AF with 
duration at least 10 minutes (NSup10) and of less than 10 minutes (NInf10), respectively. 
8.1.2.1.2. 
Schedule 
The heart rhythm follow up will be performed from the end of successful electrical cardioversion 
visit (visit 3) to the study visit 4.  
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8.1.2.1.3. 
Evaluation Methods 
• 7-day holter monitor: 
The heart rhythm monitoring will start using a 7-day continuous ECG (5-leads/2 or 3 channels) 
ambulatory recording (holter ECG) after ECV visit from visit 3 to visit 4. 
8.1.2.2. 
Duration of Atrial Fibrillation episodes in the first week following visit 3 
 
 
(ECV visit) 
8.1.2.2.1. 
Definition 
Duration of AF episodes will consist in the sum of duration of each AF episodes. 
8.1.2.2.2. 
Schedule 
The heart rhythm follow up will be performed from the end of successful electrical cardioversion 
visit (visit 3) to the follow up study visit (visit 4).  
8.1.2.2.3. 
Evaluation Methods 
Duration of AF episodes will be assessed using the 7-day continuous ECG (5-leads/2 or 3 
channels) ambulatory recording. 
8.1.2.3. 
Clinical parameters evaluation 
8.1.2.3.1. 
EHRA score assessment 
8.1.2.3.1.1. Definition: 
AF related symptoms will be evaluated by the EHRA (European Heart Rhythm Association) score 
[20]. The following items “during presumed arrhythmia episodes" are checked to determine the 
score: palpitation, fatigue, dizziness, dyspnea, chest pain and anxiety. 
Classification of AF-related symptoms (EHRA score) are as follows: 
• EHRA I          - ‘No symptoms’ 
• EHRA II         - ‘Mild symptoms’; normal daily activity not affected 
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• EHRA III       - ‘Severe symptoms’; normal daily activity affected 
• EHRA IV       - ‘Disabling symptoms’; normal daily activity discontinued  
This classification relates exclusively to the patient-reported symptoms. 
In addition to this score, the frequency will be classified in three groups, namely occasionally 
(less than once per month); intermediate (1/month to almost daily); and frequent at least daily. 
8.1.2.3.1.2. Schedule 
This evaluation will be performed in case of symptoms evocative of arrhythmia. 
8.1.2.3.1.3. Evaluation Methods 
This evaluation will be collected by Central Reading Laboratory during all the study period. 
8.1.2.3.2. 
Number of recurrence of symptomatic AF  
It consists of number of AF recurrence associated with a symptom (Palpitation, fatigue, dizziness, 
dyspnea, chest pain and anxiety) and confirmed by an ECG in atrial fibrillation. 
8.1.2.3.3. 
Number and duration of hospitalization 
• Number and duration of hospitalization for cardiovascular events 
− Hospitalization for AF treatment 
− Hospitalization for worsening of heart failure 
− Hospitalization for myocardial infarction 
− All cause of hospitalization 
• Number and duration of hospitalization for thromboembolic stroke  
8.1.2.4. 
Cardioversion assessment 
• Assessment of spontaneous cardioversion before visit 3 
• Assessment of successful cardioversion at visit 3 (i.e. return to sinus rhythm) 
• Shock distribution (1, 2 or 3 shocks) 
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• Number of patients needing another cardioversion after initial ECV 
8.1.2.5. 
Evolution of echocardiographic parameters 
8.1.2.5.1. 
Definition 
The following echocardiographic parameters will be assessed: Left atrial diameter (mm), Left 
atrial area (cm2), Left atrial volume (mL), Left atrial volume/BSA (mL/m2), Left ventricular 
ejection fraction (%),Left ventricular volume (mL), Left ventricular volume/BSA(mL/m2, Left 
ventricular end diastolic diameter (mm) Left ventricular end diastolic volume (mL), Left 
ventricular end systolic diameter (mm) and Left ventricular end systolic volume (mL), 
8.1.2.5.2. 
. Schedule 
The measurements will be performed at visit 1 and visit 2 to check the eligibility of the patient.  
The measurements performed at visit 4, visit 6 and visit 9 are done to follow the 
echocardiographic evolution of the patients in sinus rhythm. 
8.1.2.5.3. 
Evaluation method 
The echography evaluations will be carried out according to the recommendations for chamber 
quantification drawn up by the American Society of Echocardiography and the European 
Association of Echocardiography [23]. So, for volume measurements, the recommended method 
is to use the biplane method of discs (modified Simpson’s rule) from 2-D measurement. 
8.2. 
BIOMARKER ASSESSMENT: RED BLOOD CELL  
 
CONCENTRATIONS OF DHA 
8.2.1. 
Definition 
Because of the limited accessibility of human tissues for biopsy, red blood cell DHA contents is a 
marker for tissue DHA concentration [13], [14]. 
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8.2.2. 
Blood samples 
8.2.2.1. 
Collection schedule 
Blood samples will be collected for determination of red blood cells (RBC) concentrations of 
DHA.  
Blood samples will be performed as follows: 
• Visit 2 before treatment, visit 3, visit 6 and visit 9. 
Actual sampling times will be individually reported in the electronic Case Report Forms  
(e-CRFs). 
8.2.2.2. 
Technical handling 
Two blood samples (4ml) will be collected in tubes containing EDTA. They will be gently 
shaken, stored at +4°C (no freezing will be allowed) and sent to Analytical Centre in refrigerated 
conditions (between +2°C and +8°C). Analysis will be performed within 2 weeks following 
reception at the Analytical centre. 
8.2.3. 
DHA concentration measurement 
Analytical determination of RBC concentrations of DHA will be carried out by the Analytical 
Centre. 
Lipids will be extracted from red blood cells samples with a mixture of hexane/isopropanol, after 
acidification [17]. Total lipid extracts will be saponified and methylated. The fatty acid methyl 
esters (FAME) will be extracted and analyzed by Gas Chromatography. 
Identification of FAME will be based on retention times obtained for FAME prepared from fatty 
acid standards. The area under peaks will be determined using ChemStation Software (Agilent) 
and results will be expressed as % of total fatty acids. DHA concentration will be calculated using 
the internal standard and expressed as µg/g for red blood cells samples. Thus, omega-3 index will 
be assessed. The omega-3 index represents the content of EPA plus DHA in red blood cells 
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(expressed as a percent of total fatty acids). It is a biomarker considered as a new marker of risk 
for death from coronary disease [18]. 
Results of this analytical determination will be kept confidential by the dosing centre until the end 
of the study, and will be provided only at the end of the study (after database lock), in a separate 
file. 
8.3. 
SAFETY ASSESSMENT 
8.3.1. 
Adverse Events 
At selection, any concomitant disease will be reported on the e-CRF. At each further visit, the 
occurrence of adverse events (AEs) since the last visit will be based on the patient's spontaneous 
reporting, the investigator's non-leading questioning and his/her clinical evaluation. All AEs will 
be reported on the e-CRF (see section 10). 
8.3.2. 
Laboratory Investigations 
8.3.2.1. 
Schedule 
Laboratory investigations will be performed at visit 1 (before treatment) and visit 9 (end of 
treatment) or End of Treatment visit. 
At visit 3 and 6, only a standard haematologic dosage will be performed.  
Furthermore the kaliemia will be checked before electrical cardioversion at visit 3. 
The volume of blood samples complete haematology, biochemistry should not exceed 30 mL. 
8.3.2.2. 
Technical Procedures and Parameters 
The following tests will be performed: 
 
Haematology: 
Hematocrit, haemoglobin, Red blood cells (RBC) count, white blood cells 
(WBC) count, WBC differential counts (% and absolute), reticulocytes, 
platelets.  
 
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Chemistry: 
sodium, potassium, bicarbonate, chloride, alkaline phosphatase, gamma GT, 
albumin, total bilirubin, conjugated bilirubin, creatinin, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), fasting glucose, 
total cholesterol, cholesterol (HDL, LDL), triglycerides, creatine 
phosphokinase (CPK), fibrinogen. 
Blood samples will be taken in the morning, in fasting conditions.  
The estimation of GFR at selection relies on the measurement of serum creatinine and the 
Cockcroft- Gault formula 
Cockcroft-Gault formula 
- with serum creatinine expressed as mg/L:  
in men: 
GFR (mL/min) = [(140-age)] x weight / 7.2 x serum creatinine in mg/L], 
 
in women: 
GFR (mL/min) = [(140-age)] x weight / 7.2 x serum creatinine in mg/L] x 0.85 
 
- with serum creatinine expressed as μmol/l: 
GFR (mL/min) = [(140-age) x weight / serum creatinine in μmol/l] x k,where k = 1.23 for men, 
1.04 for women. 
 
(weight in kg, age in years) 
Additional tests may be done at the Investigator’s discretion, in the patients’ interest. In case of 
any abnormal or clinically significant results, the Investigator will order laboratory control tests. 
8.3.3. 
Global Physical Examination 
A global physical examination including the measurement of body weight will be carried out on 
each body system at visit 1, visit 2, visit 3, visit 5, visit 6, visit 7, visit 8 and visit 9. 
The physical examination will be globally evaluated as “normal/abnormal”. Further target 
inspection will be undertaken for any abnormal finding. 
8.3.4. 
Vital Signs 
Vital signs will consist in blood pressure and heart rate at rest.  
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8.3.4.1. 
Schedule 
Vital signs will be measured at each visit. 
8.3.4.2. 
Technical Procedure and Parameters 
Systolic (SBP) and diastolic (DBP), expressed in mmHg, will be measured after at least 5 minutes 
in supine position and after 2 minutes in standing position.  
The heart rate (HR), expressed in beats per minute (bpm), will be measured by auscultation, after 
at least 5 minutes in supine position and after 2 minutes in standing position by counting the beats 
for at least 30 seconds. 
Bodyweight will be measured in  patient in underwear and with the same balance at each visit.  
8.3.5. 
Electrocardiogram (ECG)  
8.3.5.1. 
Schedule 
An electrocardiogram will be recorded at visit 1, visit 2, visit 3, visit 5, visit 6, visit 7, visit 8 and 
visit 9 using an usual standardised 12-lead cardiograph. 
8.3.5.2. 
Technical Procedure and Parameters 
• Electrocardiogram (ECG): 
The global interpretation from manual reading (normality, clinical relevance) and heart rate 
(bpm), PR (ms), QRS (ms), QT (ms), repolarisation patterns will be reported in the e-CRF. Each 
print-out will include the patient’s code, date, time, technician's initials and investigator's 
signature. 
In case of thermic paper ECG print out, a photocopy will be made by the centre to ensure safe 
filing. 
• 24 hour-Holter - ECG 
An ambulatory continuous 24-hour ECG (5-leads/2 or 3 channels) will be recorded at selection 
visit using a holter ECG, in order to confirm persistent atrial fibrillation.  
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8.3.6. 
Coagulation parameters 
The assessment of coagulation will be evaluated by the following parameters: 
− Prothrombin Time/INR (PT/INR) 
− Activated Partial Thromboplastin Time (aPTT) 
− Thrombin Clotting Time (TCT) 
During the pre-cardioversion period, if the anticoagulation by AVK should be initiated, then the 
INR monitoring will be as follow:  
− INR 2-3 times a week for the first week of treatment 
− INR weekly up to ECV, 
− INR every 4 weeks after ECV 
For patients already treated with AVK, INR monitoring will be as follow: 
− INR weekly up to ECV, 
− INR every 4 weeks after ECV 
aPTT and TCT will be performed at visit 1, visit 2, visit 3, visit 5, visit 6, visit 7, visit 8 and  
visit 9. 
Anti-coagulation by anti-vitamin K should be given at least 3 weeks before ECV and continued 
for the whole study duration. 
The quantity of blood samples collected at each time for coagulation parameters will be 2 mL. 
8.3.7. 
Concomitant Treatments 
Concomitant treatments will be evaluated at each study visit. 
Requirements relating to patient's concomitant treatments started before screening visit and 
continued throughout the trial, or started during the trial can be found in section 7.  
8.4. 
COMPLIANCE 
The patient will be reminded at each visit to bring back any remaining soft capsules, blister, case 
(used or unused) at the following visit. 
At each visit, the Investigator will record the number of supplied and remaining Soft Capsules in 
the e-CRF. 
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9. STUDY PROCEDURES 
Visit 1 - Selection Visit (Week -4 to Week -1) 
The patient considered eligible for selection by the Investigator will be informed of the 
characteristics and the consequences of the trial both verbally and by reviewing the patient's 
information sheet and consent form (see section 14.3). If he/she accepts to participate in the study, 
he/she will sign the informed consent and will keep a copy. 
The patient will be assessed for the following: 
• Demographic characteristics (gender, age, height, body surface area) 
• Personal and medico-surgical history 
• Habits (Tobacco, alcohol consumption, dietary habits including fish consumption…) 
• Cardiovascular diseases, mainly detailed history of Heart Failure and Atrial Fibrillation 
characteristics  
• Echocardiography using a two-dimensional echocardiography.  
• 12-lead ECG 
• Concomitant diseases, adverse signs or symptoms (able to be used for treatment emergent AE 
determination) 
• Concomitant treatments (authorised, disallowed) 
• Global physical examination/bodyweight 
• Vital signs 
• Biology: haematology, biochemistry, assessment of coagulation parameters: Prothrombin 
Time/INR (PT/INR), Activated Partial Thromboplastin Time (aPTT), Thrombin Clotting Time 
(TCT) 
• Biology assessment of renal function: creatinine or estimated glomerular filtration rate 
If the results of the above assessments are compatible with the selection criteria 
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• A 24-hour continuous ECG ambulatory recording (Holter ECG) device will be installed on the 
patient to monitor the patient heart rhythm. The patient will be requested to bring back the device 
after the termination of 24 hours recording. The recording will be transmitted from the 
Investigational site to the Central Reading Laboratory (CRL). The CRL will send his/her 
assessment regarding the confirmation of persistent atrial fibrillation within 2 working days to the 
Investigator. 
• The patient will enter the selection period in which anticoagulant (anti-vitamin K) will be 
adjusted to achieve an International Normalized Ratio (INR) of 2 to 3 before electrical 
cardioversion.  
At the end of the visit, the Investigator will contact the IVRS/IWRS system to confirm the patient 
selection and order the treatment delivery and organise the appointment for the next visit.  
The patient will receive from the investigational centre the study card to be kept for the duration 
of the study. 
Visit 2 - Inclusion Visit (Day 1)  
If the patient's behaviour during the selection period and/or the result of complementary 
examinations particularly the confirmation of the presence of persistent atrial fibrillation by the 
CRL during this period, the INR and laboratory tests, are compatible with the inclusion criteria, 
the patient will be assessed for the following: 
• Adverse events 
• Concomitant treatments (authorised, disallowed) 
• Laboratory examination: red blood cell concentrations of DHA and coagulation parameters 
Prothrombin Time/INR (PT/INR), Activated Partial Thromboplastin Time (aPTT), Thrombin 
Clotting Time (TCT) 
• Global Physical examination/bodyweight 
• Vital signs 
• Echocardiography using a two-dimensional echocardiography. 
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• 12-lead ECG 
• Urine pregnancy test for women of child bearing potential. 
If the results of the above assessments are compatible with the inclusion criteria, the patient will 
be included and allocated a treatment number using the IVRS/IWRS system.  
Between this Inclusion visit and the next visit (V3), the INR will be closely monitored (refer to 
paragraph 8.3.6), in order to ensure that the INR is stable, between 2 to 3 before electrical 
cardioversion. 
At the end of the visit, the Investigator will organise the appointment for the next visit and give 
the treatment to be taken during the next 4-week period. 
Visit 3 (Week 4: D28 -2/+7 days) cardioversion 
Patient will be assessed for the following criteria: 
• Adverse events 
• Concomitant treatments (authorised, disallowed) 
• Laboratory examination: Haematology, Red Blood Cell concentrations of DHA, Prothrombin 
Time/INR (PT/INR), Activated Partial Thromboplastin Time (aPTT), Thrombin Clotting Time 
(TCT) 
• Global Physical examination /bodyweight 
• Vital signs  
• 12-lead ECG 
• Electrocardioversion (ECV): ECV has to be scheduled 4 weeks after randomization and after 
target international normalized ratio levels will be stabilized (between 2 and 3) on at least 3 
consecutive weekly tests in patients with AF. Patients not stabilized for INR (i.e. values not 
between 2 and 3) on at least 3 consecutive weekly tests performed before ECV will be excluded 
from the study, unless the presence of atrial thrombosis may be excluded with ECHO –TE (trans-
esophageal echocardiograph) performed  in the same day (before ECV). ECV will be performed 
in the morning, with the patient in the fasting state and without dyskalemia. Anesthesia will be 
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induced and patients will be cardioverted with administration of a synchronized, biphasic current. 
The initial shock will be set at 100 J if the body weight is less than 70 kg and at 150 J for higher 
body weights. Successful cardioversion will be defined as recovery of sinus rhythm lasting at least 
1 minute after the shock. If unsuccessful, a second 200-J shock, and eventually a third 200-J 
shock, will be administered. Failure of ECV is defined as the persistence of AF after the third 
attempt at cardioversion. After the procedure, patients will be monitored on telemetry for at least 
6 hours before discharge. Patients who will not revert to sinus rhythm or with early relapse within 
the observation period after ECV will be withdrawn from the study and will be considered to have 
finished their follow-up. 
At the end of the visit, a 7-day continuous ECG (5-leads/2 or 3 channels) ambulatory recording 
(holter ECG) will be installed on the patient in order to monitor the patient heart rhythm after 
ECV.  
At the end of the visit, the Investigator will organise the appointment for the next visit and give 
the treatment to be taken during the next 4-week period. 
Visit 4 (Week 5: D35 ± 2 days) 
After removal of the continuous ECG ambulatory device, the patient will be assessed for the 
following criteria: 
• Assessment of Adverse Events 
• Concomitant treatments (authorised, disallowed) 
• Vitals Signs 
• Echocardiography using a two-dimensional echocardiography 
At the end of the visit, the patient will be given the TTEM device (Trans Telephonic ECG 
Monitoring) for cardiac monitoring. The patient will be clearly instructed on the frequency and 
modalities of transmission. The patient will be requested to performed daily transmission from 
week 6 to week 8, then every 2 days from week 9 to week 24. Moreover, in case of AF symptoms 
additional transmission may be performed. 
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Visit 5 (Week 8: D56 ± 7 days) – Visit 6 (Week 12: D84 ± 7 days) - Visit 7 (Week 16: D112 ± 
7 days) - Visit 8 (Week 20: D140 ± 7 days) 
Patient will be assessed for the following criteria: 
• Adverse events 
• Concomitant treatments (authorised, disallowed) 
• Laboratory examination: Prothrombin Time/INR (PT/INR), Activated Partial Thromboplastin 
Time (aPTT), Thrombin Clotting Time (TCT). However, in case of discontinuation of 
anticoagulation after ECV, the monitoring of INR, aPTT and TCT should be stopped. 
• Global Physical examination/bodyweight  
• Vital signs  
• 12-lead ECG 
• The cardiac monitoring will be continued using a TTEM device (Trans Telephonic ECG 
Monitoring). The device will be given to the patient who will be requested to performed daily 
transmission from week 6 to week 8, then every 2 days from week 9 to week 24. Moreover, in 
case of AF symptoms additional transmission may be performed. 
The Investigator will collect all the cases, blisters and any unused soft capsules and count the 
unused capsules for each 4-week treatment period. 
At the end of the visit, the Investigator will organise the appointment for the next visit and give 
the treatment to be taken during the next 4-week treatment period. 
In addition: 
- at visit 5, the investigator will contact the IVRS/IWRS to obtain another treatment unit to be 
dispensed at visit 6 for the last 12-week period. 
- at visit 6, an echocardiography will be performed, an haematology examination will be done and 
the red blood cell concentration of DHA will be measured.  
 
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End-of-Study Visit - Visit 9 (Week 24: D168 ± 7 days) 
 Patient will be assessed for the following: 
• Adverse events 
• Concomitant treatments (authorised, disallowed) 
• Global Physical examination/bodyweight 
• Vital signs 
• 12-lead ECG 
• Laboratory examination: haematology, biochemistry, assessment of coagulation parameters: 
Prothrombin Time/INR (PT/INR), Activated Partial Thromboplastin Time (aPTT), Thrombin 
Clotting Time (TCT). Red blood cell concentration of DHA. 
• Urine pregnancy test for women of childbearing potential 
• Echocardiography using a two-dimensional echocardiography 
The Investigator will collect all the cases, blisters and any unused soft capsules and count the 
unused soft capsules. 
10. ADVERSE EVENTS: DEFINITION AND REPORTING 
10.1. 
ADVERSE EVENTS 
10.1.1. Definition of Adverse Events 
An adverse event is any adverse change from the patient's baseline condition, i.e. any subjective 
signs and symptoms or change in a concomitant disease present at the Selection Visit considered 
or not related to the treatment. 
This includes intercurrent signs, symptoms, illnesses and significant deviations from baseline for 
vital signs and laboratory values, which may occur during the course of the clinical study. 
All laboratory tests for which abnormal results are collected after study treatment initiation should 
be repeated until the values return to normal or to a stable status. Abnormal results are defined as 
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those falling out of the laboratory normal ranges and that are clinically significant. The frequency 
of such checks should be defined by the Investigator according to the degree of abnormality. 
In all cases, the aetiology should, as much as possible, be identified and Pierre Fabre Médicament 
notified. 
10.1.2. Grading of Adverse Events 
Adverse or intercurrent events are graded as follows: 
• Mild: awareness of signs or symptoms, but easily tolerated 
• Moderate: uncomfortable enough to cause interference with usual activity 
• Severe: incapacity with inability to work or do usual activity. 
10.1.3. Reporting of Adverse Events 
The records of adverse events in the electronic Case Report Form (e-CRF) describe the nature 
(diagnosis, signs and symptoms), severity, onset date, stop date, outcome and actions taken, and 
relationship to study treatment (in the Investigator's opinion). It must be specified whether the 
event is serious or not. 
10.2. 
SERIOUS ADVERSE EVENTS (SAE) 
10.2.1. Definition 
A serious adverse event (SAE) includes, but is not necessarily restricted to any event which: 
• Results in death (whatever may be the cause) 
• Is life-threatening 
• Results in persistent or significant disability/incapacity 
• Requires the patient's hospitalisation or prolongation of current hospitalisation * 
• Is a congenital anomaly or birth defect. 
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Other events such as cancer, and any additional adverse experience or abnormal laboratory values 
occurring during the study period, defined by the protocol as serious or which the Investigator 
considers significant enough, or that suggest a significant hazard, contra-indications, side effect or 
precaution, must be handled as serious adverse events. 
Any overdosage meeting a seriousness criteria should be reported as a SAE (see section 10.3). 
Any pregnancy occurring during/after exposure to the study drug(s) should be reported on the 
SAE notification form (see section 10.4). 
* any hospitalisation, or prolongation of hospitalisation due to the circumstances listed below: 
− planned (as per protocol) medical/surgical procedure, 
− preparation for routine health assessment/procedure (e.g. routine colonoscopy), 
− planned medical/surgical admission (planned prior to entry into study trial, appropriate 
documentation required), 
− administrative or social reasons (e.g. lack of housing, economic inadequacy, care-giver 
respite, family circumstances) 
will not be reported as a SAE. 
10.2.2. Reporting of SAE 
All serious adverse events, according to the above-mentioned definitions and regardless of 
treatment or relationship to study drug, must be recorded by the Investigator as soon as he/she is 
informed of the event. 
The Investigator must notify the Sponsor of this event by sending, within 24 hours, the 
"Notification of serious adverse event" form ("first notification") (see appendix 17.2) with all the 
available information about the event, to the Sponsor's representative: 
Gaëlle ALCARAZ 
INSTITUT DE RECHERCHE PIERRE FABRE,  
Centre de R&D Pierre Fabre – BP 13562 
3 Avenue Hubert Curien 
31035 TOULOUSE Cedex 1 
Phone: +33 5 35 50 62 16 
Fax: + 33 5 34 50 65 92 
Email: gaelle.alcaraz@pierre-fabre.com 
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In case of non-inclusion the reporting period ends when the non-inclusion is documented. 
10.2.3. Follow-up of SAE 
The Investigator must draw-up a specific clinical report and use the "Notification of serious 
adverse event" form ("follow-up") (see appendix 17.2) and collect the results of the carried out 
examinations and the reports of hospitalisation. 
The serious adverse events must be followed up until resolution or stabilisation. 
10.2.4. SAE Occurring After the Study 
Any SAE occurring during 30 days following the end of the study for the patient should be 
notified to the Sponsor. 
Must also be notified to the Sponsor any event occurring at any time after the end of the study for 
the patient which may be related to the study treatment in the Investigator's opinion. 
10.3. 
REPORTING OF OVERDOSAGE TO THE SPONSOR 
For the purpose of this trial an overdosage will be defined as any dose exceeding the planned 
prescribed dose of the study drug or the administration of any dose of an associated product that is 
considered both excessive and medically important. 
In the absence of seriousness criteria, the overdosage, and associated adverse event if any, are 
reported only on the Adverse Event page of the CRF. If the definition of seriousness criteria is 
met, the SAE notification form must be also transmitted to the sponsor. 
10.4. 
REPORTING OF PREGNANCY TO THE SPONSOR 
Pregnancies discovered in the period in between the informed consent form signed but before any 
study drug exposure are not to be reported to the sponsor unless associated to a seriousness 
criteria (e.g. serious adverse event study-protocol related procedure). If pregnancy is confirmed, 
the women must not be administered the study drug and be withdrawn immediately from the 
study.  
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If pregnancy is suspected while the patient is receiving study treatment, the study drug(s) should 
be discontinued immediately until the result of the pregnancy testing is known. If pregnancy is 
confirmed, then the study treatment is permanently discontinued in an appropriate manner and the 
patient is discontinued from the study.  
The investigators must report to the sponsor any pregnancy which occurs during or after the 
patient has been exposed to the study drug and until 30 days after the last study drug 
administration. The investigator must immediately notify the sponsor using the SAE notification 
form and also report the pregnancy on the AE page of the e-CRF. 
Women who become pregnant after exposure to the study drug must be followed by the 
investigator until the completion/termination of the pregnancy. If the pregnancy goes to term, the 
outcome will have to be reported to the sponsor (baby's healthy status). 
10.5. 
SPONSOR'S RESPONSIBILITIES FOR SAFETY REPORTING 
 
PURPOSES 
Sponsor will submit expedited and periodic reports to both Competent Authorities and Ethics 
Committees per corporate standard operating procedures as regards to the EU directive 
2001/20/EC taking into account local specific requirements. 
11. DATA COLLECTION AND STUDY MONITORING 
11.1. 
DATA COLLECTION 
11.1.1. Case Report Form 
An electronic Case Report Forms (e-CRF) will be used to record all patient data required by the 
protocol except the central ECG (Holter ECG, TTEM) and DHA data which will be transferred 
from vendors to the subcontractor as electronic data files and which will be loaded into the study 
database.  
The e-CRF should be fully validated, compliant with ICH-GCP requirements and European 
regulations and include a traceability system for data corrections and deletions (audit trail). 
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Prior to the start of the study, the Investigator will complete a "Delegation of significant study-
related duties" form. The signature and initials of all personal in charge of e-CRF completion 
should be recorded on this form. Each person involved in e-CRF completion, review, correction 
and / or validation will be trained and will have an individual login and access code to the e-CRF. 
Training sessions will be held by the subcontractor for all participants who will use this tool. An 
e-CRF user manual will be available for investigators and CRAs.  
All the information included into the e-CRF will be recorded from source documents onto the e-
CRF by an authorised person. 
The Investigator is responsible for the management and accuracy of the information on the  
e-CRF. At each monitoring visit, the e-CRF(s) should be at the CRA's disposition for review and 
validation. 
At the end of the study, a CD-ROM containing the pdf version of all e-CRF (including audit-trail) 
will be sent by the subcontractor to the Sponsor and to the investigational sites for archiving. The 
subcontractor must store all study data for at least 15 years after the end of the study and ensure 
their legibility and accessibility during all the storage period. 
11.1.2. Source Documents 
A source document is an original record or certified copy of an original record of clinical findings, 
observations or any other medical or paramedical activities performed during the clinical trial, 
necessary for the transcription and the verification of the collected data. 
Source documents along with all other trial-related documents (copies of all "informed consent" 
forms, e-CRFs CD-ROM, drug inventories and any correspondence related to the study) must be 
kept in the investigator's file throughout the study, and then, must be stored in the study centre's 
archives for a period of at least 15 years or as per local legal requirements, whatever is the 
longest.  
For further details see section 15.2. 
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11.2. 
STUDY MONITORING 
11.2.1. Monitoring visits 
On-site visits will be carried out by a representative of the Sponsor's staff (Study Manager or 
CRA) prior to study initiation and at regular intervals (every 4 to 6 weeks) throughout the study. 
Additional visits and communication by telephone fax or meeting may be performed if necessary. 
Any site visit performed by the Sponsor's representatives will be recorded in the Investigator's 
study file. 
11.2.1.1. 
Site Preselection Visit 
Before selecting a centre for the study, a visit will be carried out by the CRA and/or the Study 
Manager to ensure that the Investigator has the necessary capacities (availability, patient's 
recruitment, environment), technical means and staff to carry out the study. 
11.2.1.2. 
Initiation Visit 
Before the start of the study at all investigation sites, an initiation visit will be carried out by the 
CRA to check at the latest that: 
• The Investigator: 
− has received the technical protocol, administrative and financial agreement signed by all 
parties 
− has received the written statement of the Ethics Committee approval and the list of its 
members and their functions 
• The original dated and signed curriculum vitae of the investigator(s) has been collected 
• Laboratory normal ranges have been collected  
• All study materials are available on the study site 
• All participants agree with the monitoring procedures and know the study procedures 
• All participants are aware of a possible audit or inspection 
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The CRA has also to provide training on the study protocol requirements and study specific 
procedures. 
11.2.1.3. 
Follow-up Visits 
Throughout the study, regular follow-up visits will be carried out by the CRA to check 
compliance with GCP, patient’s informed consents, strict application of the protocol, conformity 
of the data entered on the e-CRF with the source documents and ensure its correct completion, 
adverse events reporting, proper retention, storage and management of the study medication, as 
well as the source and other trial-related documents. 
11.2.1.4. 
Closing Visit 
At the end of the study, a final visit will be carried out by the CRA to: 
• Verify that the e-CRFs CD-ROM with pdf files are correctly stored 
• Control the accountability of intact and used treatment units and return them to the Clinical 
Pharmacy Department of the IRPF for destruction 
• Obtain the last data clarifications and/or solutions if any 
• Collect the patient's consent forms in sealed envelopes (except in case of specific country 
requirements),  
• Make an on-site review of all study documentation and complete it if necessary 
• And finally, remind the Investigator of his regulatory obligations, study document archiving 
process and duration. 
11.2.2. Direct Access to Source Documents 
In accordance to the requirements of the GCP, all Sponsor representatives (Study Manager, CRA 
and Auditors) have to be given a direct access to all source and study data to perform quality 
monitoring/audit, thus ensuring accuracy and completeness of data).  
Investigators are reminded that all Sponsor representatives keep professional confidentiality with 
regards to the patient data. 
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11.3. 
INDEPENDENT DATA MONITORING COMMITTEE 
An Independent Data Monitoring Committee (IDMC) will be established to assess at intervals the 
progress of the clinical trial, the compliance with the inclusion criteria, the quality of follow up, 
the quality of measures of primary end point, the safety data and to recommend to the Sponsor 
whether to continue, modify, or to stop the study.  
The IDMC operating procedures will be described in an independent document.  
12. DATA MANAGEMENT  
All clinical data related to the study will be collected and saved in a computerised database by the 
Data Management Department of the subcontractor and under the supervision of the Data 
Manager of Pierre Fabre Biometry (PFB) according to the following procedures.  
12.1. DATA ENTRY 
All required data will be collected by the Investigator or authorised designee (duly identified into 
the delegation task list) on a e-CRF.  
The e-CRF used for this study will be developed and maintained by the Data Management 
Department of the subcontractor and approved by the Sponsor.  
Electronic data (Holter ECG, TTEM and DHA) will be transferred by the 3rd party vendor 
according to the specifications given by the Data Manager of the subcontractor. These data will be 
captured and handled in accordance with the European GCP ICH E6 guideline. 
12.2. 
DATA CLEANING 
The subcontractor will define in the Data Validation Plan for reviewing and querying data, 
descriptions of both manual and electronic edit checks. Upon Sponsor approval, the subcontractor 
will program the checks.  
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The subcontractor will review the data over the course of the study, working with the Sponsor to 
identify data inconsistencies. The Investigator will be asked to resolve queries by making changes 
directly into the e-CRF.  
12.3. 
DATA CODING 
Adverse events, concomitant diseases, medical/surgical histories will be coded by the 
subcontractor using the MedDRA dictionary (latest version in use). 
Concomitant medication will be coded by the subcontractor using the WHO-DRUG dictionary 
(latest version in use).  
The Sponsor Clinical Development Physician will validate coding. 
12.4. 
DATA STORAGE 
The computer data files, as well as their modifications, will be archived by the subcontractor and 
kept available upon request of the Sponsor. 
12.5. 
DATABASE LOCK 
The validated database will be locked by the subcontractor upon request of the Data Manager of 
PFB following the completion of all steps required, i.e.: data entry and check of all data, 
resolution of all queries, validation of the coding, Clinical and Products Safety databases 
reconciliation and validation committee.  
Then, the subcontractor will transfer the locked database in SAS format to the Data Manager of 
PFB who assume storage on the PFB secured server. 
13. STATISTICAL ANALYSIS 
After the database lock and the randomisation code release, the statistical analysis will be 
performed by Pierre Fabre Biométrie (PFB) or under the supervision of the statistician of PFB 
using SAS® software, according to the Statistical Analysis Plan (SAP) approved by the Validation 
Committee. 
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13.1. 
GENERAL CONSIDERATIONS 
The main objective of the study is to assess the efficacy of F373280 versus placebo on the 
maintenance of sinus rhythm after direct electrical cardioversion in patients with persistent atrial 
fibrillation and chronic heart failure. 
Only the primary analysis of the primary efficacy criterion, on which is based the sample size 
justification, may lead to a causal interpretation. All other statistical results are to be regarded 
within a descriptive perspective. 
The statistical significance level of the various two sided tests of all analyses will be 5 %. 
13.2. 
SAMPLE SIZE 
Assuming an AF recurrence rate of 85% under placebo and 65% under active group, i.e. a 
clinically relevant difference ∆ of 20%, a sample size of 64 evaluable patients per group is 
required, using a log-rang test of survival curves with a 80 % power and a 5 % two-sided 
significance level. 
According to the previous assumptions and assuming a rate of not assessable patients of 15%, a 
minimum of 76  patients will have to be randomised per group. 
13.3. PROTOCOL DEVIATIONS 
Prior to the database lock and the randomisation code release, the Validation Committee members 
will review the protocol deviations and will classify them as either minor or major. A protocol 
deviation will be considered major when it is likely to bias significantly the treatment effect 
estimate based on the primary efficacy criterion. 
Patients with major deviation(s) will be excluded from the Per Protocol data set (see section 13.4). 
A listing of all protocol deviations will be provided for all randomised patients, including the type 
(major/minor) of protocol deviations according to the decisions made by the members of the 
Validation Committee. 
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The number and percentage of patients with major protocol deviations will be tabulated by 
treatment group and type of major protocol deviations on the Full Analysis Set defined in section 
13.4. 
13.4. DATA SETS ANALYSED 
The following 2 data sets will be analysed (as defined by the Validation Committee):  
 
• The Safety Set composed of all randomised patients having received at least one dose of the 
study treatment. This data set will be used to perform analyses of Safety 
• The Full Analysis Set (FAS) composed of all randomised patients having received at least one 
dose of the study treatment and with a successful cardioversion observed at visit 3. This data set 
will be used to perform analyses of Efficacy.  
• The Per Protocol Set (PP) which is the subset of the Full Analysis Set composed of all patients 
with a primary efficacy criteria available and without any major protocol deviation or other source 
of bias for primary criteria analyses. 
13.5. 
HANDLING OF DROPOUTS AND MISSING DATA 
13.5.1. Dropouts 
The number of patients who withdraw from the study after their randomisation will be provided 
by treatment group for all treated patients (Safety Set). All withdrawn patients will be further 
described regarding their time to dropout and reasons for withdrawal. 
13.5.2. Repositioning of Visits 
No repositioning of visits will be done. 
13.5.3. Missing Data 
Missing values will not be substituted by estimated values, but considered as missing in statistical 
analysis. 
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13.6. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Before the first trial drug intake, patient’s background, medical and surgical history, demographic 
data and disease characteristics will be described by treatment group on the Safety Set. 
- Quantitative parameters will be described by treatment group and overall using the 
following: number of patients, number of missing data, mean, standard deviation, 
minimum, median and maximum values. 
- Qualitative parameters will be described by treatment group and overall using 
frequencies. 
Concomitant diseases, as well as medical and surgical histories will be tabulated descriptively by  
treatment group and overall using the MedDRA codes of System Organ Classes and preferred 
terms. 
If more than 10% of patients are excluded from the FAS and PP set, the description of patients by 
treatment group at selection and inclusion will be repeated on the FAS and PP set for all 
parameters. 
No statistical test of comparability of treatment groups at baseline will be performed.  
13.7. 
EFFICACY ANALYSIS  
13.7.1. Primary Criterion  
13.7.1.1. 
Primary Analysis 
The primary criteria, time to first recurrence, will be analysed using the Kaplan Meier method and 
compared with the Log rank test. Hazard ratios and 95% confidence intervals will be estimated 
with the Cox regression model. 
The primary analysis will be performed on the FAS. 
13.7.1.2. 
Supportive Analysis 
The primary analysis will be repeated on the PP set. 
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13.7.2. Secondary Criteria 
All secondary analyses will be performed on the FAS. If more than 10% of patients are excluded 
from the PP set, the secondary analyses will be repeated on the PP set.  
13.7.2.1. Numbers of Atrial Fibrillation Episodes 
Both the numbers of AF episodes (symptomatic or not) lasting for at least 10 minutes and with 
duration less than 10 minutes (NSup10 and NInf10) will be described by treatment group and 
compared by the chi-square test (or CMH test adjusted for centre) or Fisher’s exact Test. 
13.7.2.2. Duration of Atrial Fibrillation Episodes 
The duration of all AF Episodes will be described by treatment group and compared using the 
Student t (or using an ANOVA with treatment and centres effects) or Wilcoxon test. 
13.7.2.3. Time to first AF recurrence less than 10 minutes or symtomatic 
The time to the first AF recurrence less than 10 minutes and the time to the first symptomatic AF 
recurrence will be analysed as the primary analysis.  
13.7.2.4. Clinical parameters evaluation 
The EHRA score will be described by treatment group and analysed using a chi-squared test (or 
CMH test adjusted for centre) or Fisher’s exact Test.  
The frequency of presumed arrhythmia will be described by treatment group. 
The number of recurrence of symptomatic AF, of hospitalizations (for cardiovascular events, for 
thromboembolic stroke and for all causes), of spontaneous cardioversion, of successful 
cardioversion (including number of shocks distribution) and the number of patients needing 
cardioversion after initial ECV will be described by treatment group and compared using a chi-
square test or a Fisher Test (if the numbers are relevant).  
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The duration of hospitalizations for cardiovascular events, for thromboembolic stroke and for any 
cause will be described by treatment group and compared using the Student t (or using an 
ANOVA with treatment and centre effects) or Wilcoxon test. 
The echocardiographic parameters values will be described at each time (V1, V2, V4, V6 and V9) 
and changes described from V4 to V9 and from V2 to V9. 
13.7.2.5. Biomarker analysis: red blood cell concentrations of DHA 
Values and changes from baseline for red blood cell concentration of DHA will be performed by 
treatment group and assessment time. 
13.8. 
SAFETY ANALYSIS 
The Safety Set will be used to perform all analyses of the safety criteria. 
13.8.1. Adverse Events 
Any adverse event having been reported during the study for a given patients will be classified by 
preferred term and corresponding system organ class using the MedDRA terminology. 
Adverse events will be classified as: 
• Treatment emergent adverse events, i.e., any adverse event which occurs or worsens on study 
treatment during the randomised period. 
• Or non treatment emergent adverse events, i.e., any adverse event which occurs during the 
run-in period (before V2) or is reported as concomitant disease with the same intensity. 
For each study period, any patient with at least one reported adverse event will be classified as a 
patient: 
• With at least one adverse event 
• With at least one treatment emergent adverse event 
• With one TEAE 
• With two TEAE 
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• With at least three TEAE 
• With at least one related TEAE 
• With an adverse event leading to the study treatment discontinuation (definitive or 
temporary) 
• With an adverse event leading to withdrawal 
• With at least one serious adverse event. 
• 
Numbers and percentages of patient with at least one reported treatment emergent adverse 
event will be tabulated by treatment group: 
• By system organ class 
• By system organ class and preferred term 
• By system organ class and preferred term, taking into consideration its most severe 
intensity 
• And by system organ class and preferred term, taking into consideration the most severe 
relationship to the study treatment. 
Recurring adverse events (i.e., adverse events classified with the same preferred term) for a given 
patient will only be counted once and only their most severe intensity or most severe relationship 
to the study treatment will be tabulated. 
"The number and percentage of patient with at least one most common (reported in 1% patients in 
any group) drug related TE AE ("not excluded or unassessable") will be tabulated by Preferred 
Term and Treatment group in decreasing order for the treatment group (for all patient). 
The number and percentage of patients with at least one reported most common treatment 
emergent adverse event will also be plotted by treatment group. This graphical representation will 
highlight the frequencies of the most severe intensities reported by system organ class and 
preferred term. 
Serious adverse events will also be described on an individual basis: treatment group, patient's 
code, sex and age, Investigator's reported term, preferred term, time of onset according to the time 
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of the first study treatment administration, duration, action taken regarding the study treatment 
administration, use of a corrective treatment, outcome and relationship to the study treatment in 
the Investigator’s opinion. 
13.8.2. Clinical Laboratory Evaluation  
For each laboratory parameter, data will be tabulated by treatment group and assessment time. 
The absolute changes post-trial drug administration - baseline (the baseline value being the value 
measured on the last blood sample collected before the first trial drug administration) will be 
calculated and tabulated by parameter, treatment group and post-trial drug administration 
assessment time. Results of retests performed post-trial drug administration will not be analysed 
and tabulated. They will only be displayed in individual data listings. 
For all biochemistry parameters, scatter plots highlighting individual results will display the 
baseline and week 24 of the laboratory measurements for each patient by locating the point 
defined by the baseline value on the abscissa and respectively week 24 value in the ordinate.  
For all haematology parameters, scatter plots highlighting individual results will display the 
baseline and week 4, week 12 and week 24 of the laboratory measurements for each patient by 
locating the point defined by the baseline value on the abscissa and respectively week 4, week 12 
and week 24 value in the ordinate.  
Each treatment group will be identified differently. The first bisecting line (45° line), the lines of 
lower and upper normal range, the lines of PSC range and CNALV range added on the plots (see 
Appendix 17.3). 
For all blood laboratory parameters, shift tables will be provided to depict the numbers of  patients 
with post-trial drug administration variations at each assessment time as compared to the baseline 
values (measured on the last blood sample collected before the first trial drug administration) by 
treatment group. A 3-point scale (low, normal, high) will be used as defined by the normal ranges 
in use in the laboratory in charge of the assays. 
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Clinically noteworthy abnormal laboratory values (CNALV) (see in Appendix 17.3) will be 
identified and described on an individual basis. If relevant, five separate individual data listings by 
treatment group will be provided: 
• CNALV for haemoglobin (including corresponding individual results of erythrocytes and 
haematocrit) 
• CNALV for neutrophils or leucocytes (including corresponding individual results of 
basophils, eosinophils, lymphocytes and monocytes) 
• CNALV for platelets (including corresponding individual results of erythrocytes and 
leucocytes) 
• CNALV for liver function parameters (including corresponding individual results of 
gamma-GT) 
• CNALV for serum creatinine  
13.8.3. Global Physical Examination 
Recorded data of the global physical examination performed will not be tabulated as any 
abnormal findings post-randomisation should be reported as AEs (if clinically significant). 
Physical examination assessments will be provided in the listings of individual data. 
13.8.4. Vital Signs, Physical Findings and Other Observations Related to Safety 
13.8.4.1. 
Vital Sign Measurements Over Time 
For each parameter (systolic blood pressure, diastolic blood pressure and heart rate in supine and 
standing positions), descriptive statistics over time of values and changes from baseline will be 
tabulated by treatment group and assessment time. 
13.8.4.2. 
Body weight 
Descriptive statistics over time of values and changes from baseline will be tabulated by treatment 
group and assessment time. 
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13.8.4.3. 
Individual Patient Changes 
The number and percentage of patient with at least one Predefined Potentially Clinically 
Significant Change (PSC) and with at least one PSC Leading to Clinically Significant Value 
(PSCV) will be tabulated by treatment group (see Table 1 in Appendix 17.3).  
According to the pharmacological drug profile mentioned previously in this Protocol, the changes 
from baseline to the maximum and/or minimum post-baseline value could be categorized and 
tabulated by treatment group with frequencies and decreasing cumulative percentages. 
If there is a signal of a drug effect toward one direction rather than the other, additionally shift 
tables of variations from baseline to the maximum or minimum post-baseline value could be also 
provided (see Table 2 to 4 in Appendix 17.3). 
An individual data listing of patients with symptomatic or asymptomatic orthostatic hypotension 
will be provided by treatment group (see Table 5 in Appendix 17.3). 
13.8.5. ECG 
Frequencies on the clinical interpretation (normal, abnormal CS or NCS) will be presented by 
treatment group and assessment time. Individual tabulated data for ECG abnormalities will be also 
displayed. 
13.8.6. Coagulation parameters 
Scatter plots highlighting individual results for coagulation parameters (prothrombin time/INR, 
activated partial thromboplastin time and thrombin clotting time) before and after study treatment 
administration will be produced. 
13.9. CONCOMITANT TREATMENTS 
Concomitant treatments will be tabulated by treatment group within a descriptive perspective. 
They will be classified by therapeutic area according to the WHO-DRUG dictionary using the 
"anatomical therapeutic chemical" (ATC) classification on the safety set. 
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13.10. 
COMPLIANCE 
 
The percentage of compliance will be described by treatment group using the quantity 
 
100
_
_
_
(%)
×
=
n
consumptio
l
Theoretica
n
consumptio
actual
Estimated
Compliance
 
 
 
with: Estimated actual consumption = number of tablets provided at the start of study (Visit 2) – 
number of tablets returned at the end of study (Visit 9) 
Theoretical consumption = number of days of treatment intake planned between the start and the 
end of study (168 days ± 7days). 
 
13.11. 
INTERIM ANALYSIS AND DATA MONITORING 
No interim analysis is planned. 
14. GENERAL ETHICAL CONSIDERATIONS  
14.1. 
ETHICAL CONDITIONS 
This study is performed in accordance with the principles stated in the Declaration of Helsinki 
(1964) and subsequent amendments and in accordance with the Good Clinical Practice Guideline 
(CPMP/ICH/135/95). 
14.2. 
ETHICS COMMITTEE AND LEGAL REQUIREMENTS 
All the documents required by National Regulations and any other informative documents that 
may be requested are submitted for review to an Ethics Committee whose procedures and 
operations meet the GCP and National Legal Requirements. 
Depending on National Regulations, the application is submitted to the Ethics Committee by the 
Sponsor (or representative) or by the Investigator. 
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A copy of the formal written approval from the Ethics Committee is provided to the Sponsor 
(directly by the Ethics Committee or via the Investigator) with a list of names and qualifications 
of its members. 
The request for authorisation by the Competent Authority or its notification if required (depending 
on National Regulations) is carried out by the Sponsor. 
The screening of patients does not start before the approval of the Ethics Committee has been 
obtained and the study authorised by the Competent Authority or notified to the Competent 
Authority (depending on National Regulations). 
14.3. 
PATIENT'S INFORMATION LEAFLET AND INFORMED CONSENT 
 
FORM 
An information must be given to the patients before their decision to participate or abstain from 
participation. 
This information is based on the elements set out in the Declaration of Helsinki and the ICH GCP 
Guidelines. It must also describe the measures taken to safeguard patient’s privacy and protection 
of personal data, according to European Directive 95/46 EC or other local regulation. 
Restraints and risks must be explained, as well as the right to discontinue participation in the 
study at any stage, without affecting their further relationship with the Investigator and/or their 
future care. 
The written information and consent form must be submitted to the patient with an oral 
explanation. It must be agreed and signed by the patient before any study-related procedure starts. 
This information and consent procedure is under the Investigator’s responsibility. 
The information and consent document are made in triplicate: the original copy is kept by the 
Investigator, one copy is given to the patient and the last copy is kept by the Clinical Quality 
Assurance Unit of the Sponsor in a sealed envelope at the end of study (except in case of specific 
country requirement). 
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Specific areas of the Sponsor’s copy are not triplicated to avoid the reading of the patient’s 
surname (except the first 3 letters), first name, address and signature.  
If any information becomes available during the trial that may be relevant to the patient’s 
willingness to keep on participating in the trial, an updated written informed consent must be 
submitted to the patient to confirm  agreement to continue participating. 
14.4. 
PERSONAL DATA PROTECTION 
All information from this study (excluding data from the informed consent) is entered into a 
computer under the Sponsor’s responsibility in accordance with the French law, "Loi 
Informatique et Libertés" (January 6, 1978, and subsequent amendments) and with the European 
Directive 95/46/CE. 
14.5. 
INSURANCE POLICY 
In accordance with the provisions of the law and the GCP, the Sponsor Pierre Fabre Médicament, 
has an insurance policy intended to guarantee against possible damage resulting from the research. 
The studies and/or experiments performed on behalf of the Sponsor Pierre Fabre Médicament, are 
specifically and expressly guaranteed. 
It is advisable to underline that non compliance with the Research Legal Conditions is a cause for 
guarantee exclusion. 
15. ADMINISTRATIVE PROCEDURES 
15.1. 
PROTOCOL AMENDMENT 
Neither the Investigator nor the Sponsor may alter the protocol without the authorisation of the 
other party.  
All changes to the protocol are subject to an amendment which must be dated and signed by both 
parties and must appear as an amendment to the protocol. 
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Substantial amendments are submitted for approval / authorisation to the Ethics Committees and 
Competent Authorities 
Urgent amendments are submitted for approval / authorisation to the Ethics Committees and 
Competent Authorities, but could be implemented immediately under specific conditions defined 
with the Sponsor. 
15.2. 
SOURCE DOCUMENTS, INVESTIGATOR'S FILE STORAGE 
The Investigator: 
• Keeps all trial-related documents in appropriate file folders. Records of patient, original 
informed consent forms, source documents, a CD Rom containing a pdf copy of e-CRF, drug 
inventory, Ethics Committees and Sponsor correspondence pertaining to the study must be kept 
on file. 
• Retains all documents relating to the screening (consent and investigation results) of all 
patients included in the trial or not 
• Retains a list of the patient’s names, addresses (and/or number of medical file), code numbers 
to allow checking of data reported on e-CRFs with those from source documents 
• Authorises direct access to source documents for monitoring, audits and inspections 
• The trial-related documents must be retained as strictly confidential at the Investigator’s site 
for at least 15 years or according to local requirements, whatever is the longest after the 
completion or discontinuation of the trial (European Directive 2003/63/EC). 
15.3. 
END OF THE STUDY 
15.3.1. Definition of the End of Study 
The end of study is the last visit of the last patient undergoing the trial. 
Any change to this definition during the study, for whatever reason, must be notified as a 
substantial amendment. 
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15.3.2. Early Study Termination 
15.3.2.1. 
Early Study Termination Decided by the Sponsor 
The Sponsor may discontinue the study at any time for any of the following reasons: 
• Lack of recruitment 
• Deviations from good clinical practice and/or regulations 
• Poor product safety 
• New information that could jeopardise the patient’s safety 
• Stopping of the development … 
15.3.2.2. 
Early Study Termination Decided by the Competent Authorities 
The Competent Authorities may suspend or prohibit a study if it considers that the conditions of 
authorisation are not being met or has doubt about the safety or scientific validity of the study. 
15.4. 
AUDIT 
The 
Sponsor 
is 
responsible 
for 
making 
sure 
that 
both 
his 
representatives 
(Study Manager, CRA, ...) and the Investigator fulfil the requirements as specified by the GCP 
Guideline.  
An audit can be organised internally at Pierre Fabre Médicament and at the investigational site 
where the e-CRFs are matched against source documents. 
All study documentation must be directly accessible to auditors. 
The practical conditions for the audit are discussed between the Investigator and the Clinical 
Quality Assurance Department. 
Oral information about the audit results are given to the Investigator. 
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15.5. INSPECTION 
The Health Authorities may inspect any investigation site or the Sponsor in the course of the study 
or after its completion, to verify the conduct of the study and quality of the data. The Investigator 
must provide to the inspectors direct access to study documents. 
15.6. CONFIDENTIALITY 
The present materials (protocol and related documentation, e-CRF, Investigator's Brochure) 
contain confidential information.  
Except if agreed to in writing with the Study Manager, the investigators must hold such 
information confidential, and must not disclose it to others (except where required by Applicable 
Law). 
15.7. CLINICAL STUDY REPORT 
Data analysis, and clinical study report writing are under the Sponsor’s responsibility.  
Upon completion of the data analysis, a final report, including a review of the objectives and 
methods, a presentation and discussion of the results are drawn up according to ICH Guidelines 
(Structure and Content of Clinical Study Reports, ICH-E3, CPMP/ICH/137/95). 
The report is a clinical and statistical integrated report. It must be signed by the Sponsor's 
representative(s) and the Coordinating Investigator. 
15.8. STUDY RESULTS COMMUNICATION 
Upon completion of the study, the global results of the Research are communicated to the 
investigator. According to the Local Regulation, the patient can ask the Investigator for the 
results. 
15.9. STUDY RESULTS PUBLICATION 
The information and data collected during the conduct of this clinical study are considered 
confidential and are used by the Sponsor in connection with the development of the study drug. 
This information may be disclosed if deemed necessary by the Sponsor. 
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To allow use of the information derived from this clinical study and to insure compliance with 
Current Regulations, the Investigator must provide the Sponsor with complete test results and all 
data collected during the study.  
Only the Sponsor may make study information available to physicians and to Regulatory 
Agencies, except as required by Current Regulations. 
All the results of this study including data, reports, discoveries and inventions resulting from the 
study, are the property of the Sponsor. 
In the event the Sponsor chooses to publish study data, the manuscript must be provided to the 
author(s) at least 30 days prior to the expected date of submission to the intended publisher. 
The investigator(s) can reserve the right to publish or present study data; if so, the manuscript or 
abstract must be provided to the Sponsor for review at least 30 days prior to the expected date of 
submission to the intended publisher or of planned presentation. 
In addition, if necessary, (the) investigator(s) shall withhold publication for an additional 60 days, 
to allow the filing of a patent application, or to allow the Sponsor to take any measures he deems 
appropriate to establish and preserve his proprietary rights. 
It is agreed that publication of study results by each site shall be made only as part of a 
publication of the study results obtained by all sites performing the protocol, once the study is 
completed and finalised.  
The authors list is agreed by all investigators prior to publication. The names of the authors are 
provided according to their participation in the design of the protocol as well as their recruitment 
of eligible and analysable patients. 
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16. REFERENCES 
 
[1] 
F373280 INVESTIGATOR'S BROCHURE, version January 2013 
 
[2] 
NODARI S., TRIGGIONAI M., CAMPIA U., MANERBA A., MILESI G., CESANA 
M.B., GHEORGHIADE M., DEI CAS L. 
n-3 Polyunsaturated Fatty Acids in the prevention of atrial Fibrillation Recurrences after 
electrical cardioversion. A prospective, Randomised study 
Circulation, 2011; 124:1100-1106 
 
[3] 
NODARI S., TRIGGIANI M., CAMPIA U., MANERBA A., MILESI G., CESANA 
M B., GHEORGHIADE M., DEI CAS L. 
Effects of n-3 polyunsaturated fatty acids on left ventricular function and functional 
capacity in patients with dilated cardiomyopathy 
J. Am. Coll. Cardiol. 2011;57;870-879 
 
[4] 
MOERTL D., HAMMER A., STEINER S., HUTULEAC R., VONBANK K., 
BERGER R. 
Dose-dependant effects of omega-3-polyunsaturated fatty acids on systolic left ventricular 
function, endothelial function, and markers of inflammation in chronic heart failure of non 
ischemic origin: A double-blind, placebo-controlled, 3-arm study  
American Heart Journal 2011; 161:915.e1-915.e9 - volume 161, number 5 
 
[5] 
GISSI-HF INVESTIGATORS 
Effects of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GSSI-
HF Trial): a randomised, double-blind, placebo-controlled trial 
The lancet on line - August 2008 
 
[6] 
CAMM A.J., KIRCHHOF P., LIP G.Y., SCHOTTEN U., SAVELIEVA I., ERNST S., 
VAN GELDER I.C., AL-ATTAR N., HINDRICKS G., PRENDERGAST B., 
HEIDBUCHEL H., ALFIERI O., ANGELINI A., ATAR D., COLONNA P., DE 
CATERINA R., DE SUTTER J., GOETTE A., GORENEK B., HELDAL M., 
HOHLOSER S.H., KOLH P., LE HEUZEY J.Y., PONIKOWSKI P., RUTTEN F.H. 
Guidelines for the management of atrial fibrillation: the Task Force for the Management of 
Atrial Fibrillation of the European Society of Cardiology (ESC). 
European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery,  
Eur Heart J. 2010 Oct;31(19):2369-429 
 
 
[7] 
KOWEY PR, REIFFEL JA, ELLENBOGEN KA, NACCARELLI GV, PRATT CM. 
Efficacy and safety of prescription omega-3 fatty acids for the prevention of recurrent 
symptomatic atrial fibrillation: a randomised controlled trial. 
JAMA. 2010;304:2363–2372. 
 
 
 
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[8] 
BIANCONI L., CALO L., MENNUNI M., SANTINI L., MOROSETTI P., 
AZZOLINI P., BARBATO G., BISCIONE F., ROMANO P., SANTINI M.  
N-3 polyunsaturated fatty acids for the prevention of arrhythmia recurrence after electrical 
cardioversion of chronic persistent atrial fibrillation: a randomised, double-blind, 
multicentre study  
Europace (2011) 13, 174-181 
 
[9] 
OMACOR® SUMMARY PRODUCT CARACTERISTICS (SPC) dated 17/02/2012 
 
[10] 
BEPANTHENE ® SUMMARY PRODUCT CARACTERISTICS (SPC) 
 
[11] 
TOUBOUL P, BRUGADA J, CAPUCCI A, CRIJNS HJ, EDVARDSSON N, 
 
HOHNLOSER SH.  
Dronedarone for prevention of atrial fibrillation: a dose-ranging study.  
Eur Heart J 2003;24(16):1481-7. 
 
[12] LE HEUZEY JY AND ALL.  
A Short-Term, Randomised, Double-Blind, Parallel-Group Study to Evaluate the Efficacy 
and Safety of Dronedarone versus Amiodarone in Patients with Persistent Atrial 
Fibrillation: The DIONYSOS Study. 
J Cardiovasc Electrophysiol. 
 
[13] METCALF G.R., JAMES J.M., GIBSON A.R., EDWARDS J., STUBBERFIELD J., 
STUKLIS R., YOUNG D.G., ROBERTS-THOMSON K. & CLELAND G.L.M.L. & 
OKEN H. 
Effects of fish-oil supplementation on myocardial fatty acids in humans.  
Am J Clin Nutr (2007); 85 : 1225. 
 
[14] ARTERBURN M.L. & OKEN H. 
Distribution, interconversion and dose response of n-3 fatty acids in humans.  
Am J Clin Nutr (2006);83 : 1469-1473S. 
 
[15] TIELEMAN RG, VAN GELDER IC, CRIJNS HJ, DE KAM PJ, VAN DEN BERG 
MP, HAAKSMA J, VAN DER WOUDE HJ, AND ALLESSIE MA. 
Early recurrences of atrial fibrillation after electrical cardioversion: a result of 
fibrillation-induced electrical remodelling of the atria? 
J. Am. Coll. Cardiol. 1998;31;167-173 
 
[16] 
SALM P, TAYLOR PJ, KOSTNER K 
Simultaneous quantification of total eicosapentaenoic acid, docosahexaenoic acid and 
arachidonic acid in plasma by high-performance liquid chromatography-tandem mass 
spectrometry.  
Biomed Chromatogr 2011 Jun;25(6):652-9. 
 
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[17] LEGRAND P., SCHMITT B., MOUROT J., CATHELINE D., CHESNEAU G., 
MIREAUX M., KERHOAS N., WEILL P. 
The consumption of food products from linseed-fed animals maintains erythrocyte omega-3 
fatty acids in obese human 
Lipids, 2010, 45, 11-19. 
 
[18] HARRIS WS, VON SCHACKY C. 
The Omega-3 Index: a new risk factor for death from coronary heart disease? 
Prev Med. 2004 Jul; 39(1):212-20 
 
[19] ABSTRACT: P5161 . 
NODARI S, MANERBA A., MADURERI A., BERLINGHIERI N., PULCINI E., 
FRATTINI S., METRA M, DEI CAS L. 
Effects of Polyunsaturated Fatty Acids n-3 (PUFA n-3) in the prophylaxis of atrial 
fibrillation relapses after external electric cardioversion 
World Congress of Cardiology 2006, 2-6 September, Barcelona – Spain 
 
[20] 
KIRCHHOF P., AURICCHIO A., BAX J., CRIJNS H., CAMM J., DIENER HC., 
 
GOETTE A., HINDRICKS G., HOHNLOSER S., KAPPENBERGER L., KUCK 
 
KH., LIP HYG., OLSSON B., MEINERTZ T., PRIORI S., RAVENS U., 
 
STEINBECK G., SVERHAGE E., TIJSSEN J., VINCENT A., BREITHARDT G. 
 
Outcome parameters from a consensus conference organized by the German Atrial 
 
Fibrillation Competence NETwork and the European Heart Rhythm Association. 
 
Europace 2007, 9, 1006-1023 
 
[21] 
EUROPEAN MEDICINES AGENCY 
 
Addendum to the guideline on antiarrhythmics on atrial fibrillation and atrial flutter. 
 
EMA/CHMA/EWP/213056/2010 
 
[22] 
OWEN AJ, PETER-PRZYBOROWSKA BA, HOY AJ, MCLENNAN PL. 
Dietary fish oil dose- and time-response effects on cardiac phospholipid fatty acid 
composition. 
Lipids. 2004;39:955–961 
 
[23] 
ROBERTO M. LANG, MICHELLE BIERIG, RICHARD B. DEVEREUX, FRANK 
A. FLACHSKAMPF*, ELYSE FOSTER, PATRICIA A. PELLIKKA, MICHAEL H. 
PICARD, MARY J. ROMAN, JAMES SEWARD, JACK SHANEWISE, SCOTT 
SOLOMON, KIRK T. SPENCER, MARTIN ST. JOHN SUTTON, WILLIAM 
STEWART. 
 
Recommendations for chamber quantification 
 
Eur J Echocardiography (2006) 7, 79-108 
 
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17. APPENDICES 
 
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17.1. DECLARATION OF HELSINKI 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
ETHICAL PRINCIPLES FOR MEDICAL RESEARCH INVOLVING 
HUMAN SUBJECTS 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 29th WMA 
General Assembly, Tokyo, Japan, October 1975 35th WMA General Assembly, Venice, Italy, October 1983 41st 
WMA General Assembly, Hong Kong, September 1989 48th WMA General Assembly, Somerset West, Republic of 
South Africa, October 1996 52nd WMA General Assembly, Edinburgh, Scotland, October 2000 53th WMA General 
Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 55th WMA General Assembly, Tokyo 
2004 (Note of Clarification on Paragraph 30 added) 59th WMA General Assembly, Seoul, October 2008 
 
A. INTRODUCTION  
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of 
ethical principles for medical research involving human subjects, including research on identifiable 
human material and data. The Declaration is intended to be read as a whole and each of its constituent 
paragraphs should not be applied without consideration of all other relevant paragraphs.  
2. Although the Declaration is addressed primarily to physicians, the WMA encourages other participants 
in medical research involving human subjects to adopt these principles.  
3. It is the duty of the physician to promote and safeguard the health of patients, including those who are 
involved in medical research. The physician's knowledge and conscience are dedicated to the fulfilment 
of this duty.   
4. The Declaration of Geneva of the WMA binds the physician with the words, “The health of my patient 
will be my first consideration,” and the International Code of Medical Ethics declares that, “A physician 
shall act in the patient's best interest when providing medical care.”  
5. Medical progress is based on research that ultimately must include studies involving human subjects. 
Populations that are underrepresented in medical research should be provided appropriate access to 
participation in research.  
6. In medical research involving human subjects, the well-being of the individual research subject must 
take precedence over all other interests.  
7. The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic interventions 
(methods, procedures and treatments). Even the best current interventions must be evaluated continually 
through research for their safety, effectiveness, efficiency, accessibility and quality.  
8. In medical practice and in medical research, most interventions involve risks and burdens.  
9. Medical research is subject to ethical standards that promote respect for all human subjects and protect 
their health and rights. Some research populations are particularly vulnerable and need special 
protection. These include those who cannot give or refuse consent for themselves and those who may be 
vulnerable to coercion or undue influence.  
10. Physicians should consider the ethical, legal and regulatory norms and standards for research involving 
human subjects in their own countries as well as applicable international norms and standards. No 
national or international ethical, legal or regulatory requirement should reduce or eliminate any of the 
protections for research subjects set forth in this Declaration.  
 
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B. PRINCIPLES FOR ALL MEDICAL RESEARCH  
11. It is the duty of physicians who participate in medical research to protect the life, health, dignity, 
integrity, right to self-determination, privacy, and confidentiality of personal information of research 
subjects.  
12. Medical research involving human subjects must conform to generally accepted scientific principles, be 
based on a thorough knowledge of the scientific literature, other relevant sources of information, and 
adequate laboratory and, as appropriate, animal experimentation. The welfare of animals used for 
research must be respected.   
13. Appropriate caution must be exercised in the conduct of medical research that may harm the 
environment.  
14. The design and performance of each research study involving human subjects must be clearly described 
in a research protocol. The protocol should contain a statement of the ethical considerations involved 
and should indicate how the principles in this Declaration have been addressed. The protocol should 
include information regarding funding, sponsors, institutional affiliations, other potential conflicts of 
interest, incentives for subjects and provisions for treating and/or compensating subjects who are 
harmed as a consequence of participation in the research study. The protocol should describe 
arrangements for post-study access by study subjects to interventions identified as beneficial in the 
study or access to other appropriate care or benefits.   
15. The research protocol must be submitted for consideration, comment, guidance and approval to a 
research ethics committee before the study begins. This committee must be independent of the 
researcher, the sponsor and any other undue influence. It must take into consideration the laws and 
regulations of the country or countries in which the research is to be performed as well as applicable 
international norms and standards but these must not be allowed to reduce or eliminate any of the 
protections for research subjects set forth in this Declaration. The committee must have the right to 
monitor ongoing studies. The researcher must provide monitoring information to the committee, 
especially information about any serious adverse events. No change to the protocol may be made 
without consideration and approval by the committee.  
16. Medical research involving human subjects must be conducted only by individuals with the appropriate 
scientific training and qualifications. Research on patients or healthy volunteers requires the 
supervision of a competent and appropriately qualified physician or other health care professional. The 
responsibility for the protection of research subjects must always rest with the physician or other health 
care professional and never the research subjects, even though they have given consent.  
17. Medical research involving a disadvantaged or vulnerable population or community is only justified if 
the research is responsive to the health needs and priorities of this population or community and if 
there is a reasonable likelihood that this population or community stands to benefit from the results of 
the research.   
18. Every medical research study involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and communities involved in the research in 
comparison with foreseeable benefits to them and to other individuals or communities affected by the 
condition under investigation.  
19. Every clinical trial must be registered in a publicly accessible database before recruitment of the first 
subject.  
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20. Physicians may not participate in a research study involving human subjects unless they are confident 
that the risks involved have been adequately assessed and can be satisfactorily managed. Physicians 
must immediately stop a study when the risks are found to outweigh the potential benefits or when 
there is conclusive proof of positive and beneficial results.  
21. Medical research involving human subjects may only be conducted if the importance of the objective 
outweighs the inherent risks and burdens to the research subjects.  
22. Participation by competent individuals as subjects in medical research must be voluntary. Although it 
may be appropriate to consult family members or community leaders, no competent individual may be 
enrolled in a research study unless he or she freely agrees.  
23. Every precaution must be taken to protect the privacy of research subjects and the confidentiality of 
their personal information and to minimize the impact of the study on their physical, mental and social 
integrity.   
24. In medical research involving competent human subjects, each potential subject must be adequately 
informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional 
affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort 
it may entail, and any other relevant aspects of the study. The potential subject must be informed of the 
right to refuse to participate in the study or to withdraw consent to participate at any time without 
reprisal. Special attention should be given to the specific information needs of individual potential 
subjects as well as to the methods used to deliver the information. After ensuring that the potential 
subject has understood the information, the physician or another appropriately qualified individual 
must then seek the potential subject’s freely-given informed consent, preferably in writing. If the 
consent cannot be expressed in writing, the non-written consent must be formally documented and 
witnessed.  
25. For medical research using identifiable human material or data, physicians must normally seek consent 
for the collection, analysis, storage and/or reuse. There may be situations where consent would be 
impossible or impractical to obtain for such research or would pose a threat to the validity of the 
research. In such situations the research may be done only after consideration and approval of a 
research ethics committee.   
26. When seeking informed consent for participation in a research study the physician should be 
particularly cautious if the potential subject is in a dependent relationship with the physician or may 
consent under duress. In such situations the informed consent should be sought by an appropriately 
qualified individual who is completely independent of this relationship.  
27. For a potential research subject who is incompetent, the physician must seek informed consent from the 
legally authorized representative. These individuals must not be included in a research study that has 
no likelihood of benefit for them unless it is intended to promote the health of the population 
represented by the potential subject, the research cannot instead be performed with competent persons, 
and the research entails only minimal risk and minimal burden.   
28. When a potential research subject who is deemed incompetent is able to give assent to decisions about 
participation in research, the physician must seek that assent in addition to the consent of the legally 
authorized representative. The potential subject’s dissent should be respected.  
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29. Research involving subjects who are physically or mentally incapable of giving consent, for example, 
unconscious patients, may be done only if the physical or mental condition that prevents giving 
informed consent is a necessary characteristic of the research population. In such circumstances the 
physician should seek informed consent from the legally authorized representative. If no such 
representative is available and if the research cannot be delayed, the study may proceed without 
informed consent provided that the specific reasons for involving subjects with a condition that renders 
them unable to give informed consent have been stated in the research protocol and the study has been 
approved by a research ethics committee. Consent to remain in the research should be obtained as soon 
as possible from the subject or a legally authorized representative.  
30. Authors, editors and publishers all have ethical obligations with regard to the publication of the results 
of research. Authors have a duty to make publicly available the results of their research on human 
subjects and are accountable for the completeness and accuracy of their reports. They should adhere to 
accepted guidelines for ethical reporting. Negative and inconclusive as well as positive results should 
be published or otherwise made publicly available. Sources of funding, institutional affiliations and 
conflicts of interest should be declared in the publication. Reports of research not in accordance with 
the principles of this Declaration should not be accepted for publication.  
 
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE  
31. The physician may combine medical research with medical care only to the extent that the research is 
justified by its potential preventive, diagnostic or therapeutic value and if the physician has good 
reason to believe that participation in the research study will not adversely affect the health of the 
patients who serve as research subjects.   
32. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the 
best current proven intervention, except in the following circumstances:  
• 
The use of placebo, or no treatment, is acceptable in studies where no current proven intervention 
exists; or  
• 
Where for compelling and scientifically sound methodological reasons the use of placebo is 
necessary to determine the efficacy or safety of an intervention and the patients who receive 
placebo or no treatment will not be subject to any risk of serious or irreversible harm.  Extreme 
care must be taken to avoid abuse of this option.  
33. At the conclusion of the study, patients entered into the study are entitled to be informed about the 
outcome of the study and to share any benefits that result from it, for example, access to interventions 
identified as beneficial in the study or to other appropriate care or benefits.  
34. The physician must fully inform the patient which aspects of the care are related to the research. The 
refusal of a patient to participate in a study or the patient’s decision to withdraw from the study must 
never interfere with the patient-physician relationship.  
35. In the treatment of a patient, where proven interventions do not exist or have been ineffective, the 
physician, after seeking expert advice, with informed consent from the patient or a legally authorized 
representative, may use an unproven intervention if in the physician's judgement it offers hope of 
saving life, re-establishing health or alleviating suffering. Where possible, this intervention should be 
made the object of research, designed to evaluate its safety and efficacy. In all cases, new information 
should be recorded and, where appropriate, made publicly available.  
 
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17.2. SAE REPORT FORM 
 
 
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N O T I F I C A T I O N  O F  S E R I O U S  A D V E R S E  E V E N T  ( S A E )  O R  P R E G N A N C Y    
TO PIERRE FABRE PRODUCT SAFETY DEPARTMENT 
 
TO BE TRANSMITTED TO THE MONITOR BY FAX WITHIN 24H : G. ALCARAZ ............... Fax n° +33 5 34 50 65 92 
Transmission date  
 
 
  
 
  
 
 
 
(ddmmyyyy) 
Country :  
........................................
 
 
 
   SAE N° 
 
 
 
                      FIRST NOTIFICATION           FOLLOW-UP   
 
 SUBJECT CHARACTERISTICS  
 
     Surname    
 
 
 
          First name 
 
 
Birth date  
 
 
 
 
 
 
 
 
  
 
 
Gender 
 
1=M,    2=F 
   Height 
 
 
 
cm 
 Weight 
 
 
 
 
 
kg 
 
 
 DESCRIPTION OF THE EVENT 
The serious adverse event resulted in : 
 Death (whatever may be the cause) 
 Hospitalisation (*) or extension thereof 
 Life threatening 
 Invalidity or disability 
 
 Congenital abnormality or abnormal pregnancy outcome 
 Cancer 
 Other  (any other serious clinical or laboratory event 
     according to the investigator or the protocol, overdosage 
      meeting seriousness criteria, suicide attempts) 
Other fact to be notified : 
 Pregnancy exposure 
Nature of the event (if clinical nature, indicate the diagnosis or the major symptom) : 
........................................................................................................................................................................................................... 
........................................................................................................................................................................................................... 
........................................................................................................................................................................................................... 
AE onset date  |__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
 
Seriousness onset date  |__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
 
Summary description (if clinical cause, significant history, progression of event, available laboratory results, etc...) : 
 
 
 
 
 
 
(*) Except hospitalisations with durations and goals planned in the protocol 
 
 THE SAE IN RELATION TO THE TRIAL 
                                                      TREATMENT NUMBER         |___|___|___|___|___|___| 
• Time of occurrence of SAE 
 
 During the selection or run-in period 
 
 During the administration phase of the study treatment 
 
 After the administration phase of the study treatment 
• Date of first study treatment administration 
• Date of last study treatment administration 
   before the occurence of SAE 
|__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
 
|__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
• Was the blind broken ?       Yes         No          Not applicable 
   If yes, or if this is an open study, drug(s) administered : 
 
 
 
 
 
  Conditions of administration (cycles(s), daily dose(s), route(s) of administration, etc..) :  
 
 
 
 
 
 
 
 
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Transmission date 
 
 
  
 
  
 
 
 
  (ddmmyyyy) 
Country : ............................................ 
 
 
 
  SAE N° 
 
 
 
                     FIRST NOTIFICATION           FOLLOW-UP   
 
 CONCOMITANT MEDICATION SINCE TRIAL INITIATION and UP UNTIL THE OCCURRENCE OF THE SAE 
     (EXCEPT THE TREATMENTS GIVEN FOR THE SAE)  
 
INN or trade name 
 
 
Daily dose 
 
Start date 
(ddmmyy) 
Ongoing at 
occurence of the 
event 
 
Stop date 
(ddmmyy) 
Route of 
admin. 
 
Indication 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 MEASURES TAKEN FOLLOWING THE SAE 
• Study treatment 
 
 No change 
 
 Dosage modification, specify :……………………………..….      Modification Date : 
 
 Temporarily discontinued                                                       Readministration date : 
 
 Withdrawn                                                                                                  End date : 
 
 Not applicable 
 
 
 
 
 ____/____/_____ 
 ____/____/_____ 
 ____/____/_____ 
• The event led to : 
 
 Prescription of corrective or symptomatic treatments (specify names and dosages) : 
 
 
 
 Discontinuation of concomitant treatments (specify names) : 
 
 
 
 Others, specify : 
 
 
 OUTCOME 
         Not recovered/Not resolved                  Recovering/Resolving               Recovered/Resolved 
         Recovered/Resolved with sequelae     Fatal                                          Unknown 
 
                In case of death, has an autopsy been conducted ?       Yes         No 
 
 INVESTIGATOR CAUSALITY ASSESSMENT (investigator’s assessment to be done as soon as possible) 
 Not Suspected                          Suspected                    Insufficient data 
comments : ............................................................................................................................................................. 
 
Enclose in the notification the results of carried out examinations, reports of hospitalisation, etc... 
 
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17.3. PREDEFINED LIMITS OF LABORATORY AND VITAL SIGN 
POTENTIALLY CLINICALLY SIGNIFICANT CHANGES AND VALUES  
 
List of Predefined Potentially Clinically Significant Change For Laboratory Values(¤) 
 
 
PARAMETERS 
UNIT 
PSC 
 
 
 
Decrease 
Increase 
MUSCLE 
Creatine  Phosphokinase 
U / l 
- 
236 
KIDNEY 
Creatinine 
Urea 
Uric acid 
Phosphate 
Calcium 
µmol/l 
mmol/l 
µmol/l 
mmol/l 
mmol/l 
- 
- 
- 
0.39 
0.30 
35 
3.2 
119 
0.39 
0.30 
ELECTROLYTES 
Sodium 
Potassium 
Chloride 
Bicarbonate 
mmol/l 
mmol/l 
mmol/l 
mmol/l 
8 
1.1 
8 
7 
8 
1.1 
7 
8 
METABOLISM/ 
NUTRITIONAL 
Glucose (random) 
Albumin 
Protein 
Cholesterol 
HDL cholesterol 
LDL cholesterol 
Triglycerides 
mmol/l 
g/l 
g/l 
mmol/l 
mmol/l 
mmol/l 
mmol/l 
3 
6 
11 
- 
0.91 
2.17 
- 
3.7 
6 
10 
1.97 
0.85 
2.04 
2.91 
ERYTHROCYTES 
Erythrocyte count 
Haemoglobin 
Haematocrit 
MCV  
MCH (Fe) 
MCHC (Fe) 
T/l 
g/l 
1 
fl 
fmol 
mmol/l 
0.7 
20 
0.06 
7 
0.19 
2 
0.7 
- 
0.06 
7 
0.19 
2 
LEUKOCYTES 
Leukocyte count 
G/l 
4.2 
3.8 
DIFFERENTIAL 
COUNT 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
G/l 
G/l 
G/l 
G/l 
G/l 
3.47 
1.76 
- 
- 
- 
3.19 
1.63 
0.49 
0.41 
0.14 
URINE 
Specific gravity 
pH 
- 
- 
0.017 
2 
0.015 
2 
LIVER 
Total bilirubin 
ASAT (SGOT) 
ALAT (SGPT) 
Gamma GT 
Alkaline phosphatase 
µmol/l 
U/l 
U/l 
U/l 
U/l 
- 
- 
- 
- 
-- 
10 
N x (23/36) 
N x (28/45) 
N x (25/38) 
N x (30/95) 
 
N = upper limit of normal range 
 
(¤) Delta-limits from « Routine Laboratory Tests in Clinical Trials » W. Leigh Thompson, Rocco 
L. Brunelle, Gregory G. Enas, Patrick J. Simpson and Randy L. Walker Lilly Research 
Laboratories, Lilly Corporate Centre, Indianapolis, Indiana in « Clinical Trials and Tribulations » 
1988. 
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Definition of Clinically Noteworthy Abnormal Laboratory Values (CNALV) 
 
 
PARAMETERS 
CNALV 
HAEMOGLOBIN 
 
• Decrease of at least 2g/dl and value < 10 g/dl whatever the baseline 
value 
• If missing baseline : value <10g/dl 
NEUTROPHILS 
• < 1 500/mm3 whatever the baseline value 
WBC 
(if missing value for neutrophils) 
• < 3 000/mm3 whatever the baseline value 
PLATELETS 
• < 100 000/mm3 whatever the baseline value 
SERUM CREATININE 
• Increase of at least 30 % as compared to baseline value and 
value > 150 µmol/l whatever the baseline value 
• If missing baseline : value > 150 µmol/l 
LIVER FUNCTION TESTS 
 
 
ALAT 
 
 If normal baseline :  
 
 
•ALAT > 2 N 
 If abnormal baseline : 
→if baseline value ≤ 2.5 N : 
  
• increase of at least 100 % as compared to baseline value 
→ if baseline value > 2.5 N :  
 
 
• value > 5 N 
and/or 
ASAT 
 
  If normal baseline :  
 
 
• ASAT > 2 N 
  If abnormal baseline : 
→ if baseline value ≤ 2.5 N : 
  
• increase of at least 100 % as compared to baseline value 
→ if baseline value > 2.5 N :  
 
 
• value > 5 N 
and/or 
Alkaline phosphatase (AP) 
 
  If normal baseline :  
 
 
• AP > 1.25 N 
  If abnormal baseline :  
 
 
• AP > 2 N 
and/or 
Total bilirubin (TB) 
  If normal baseline :  
 
 
• TB > 1.5 N 
  If abnormal baseline :  
 
 
• TB > 2 N 
N=upper limit of normal range 
International consensus Meeting. International Journal of Clinical Pharmacology, Therapy and Toxicology, 1990;28:317-322 
Standardisation of definitions and criteria of causality assessment of adverse drug reactions: drugs-induced liver disorders: report 
of an Standardisation of definitions and criteria of causality assessment of adverse drug reactions: drugs-induced cytopenia. 
International Journal of Clinical Pharmacology, Therapy and Toxicology, 1991;29:75-81 
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Cardiovascular Safety 
 
Table 1: Predefined Limits for Potentially Clinically Significant Changes (PSC) and PSC 
Leading to Clinically Significant Values (PSCV) 
 
Parameter 
PSC 
PSCV 
SBP 
Increase ≥ 20 mmHg 
Decrease ≥ 20 mmHg 
SBP ≥ 160 mmHg and increase ≥ 20 mmHg 
SBP ≤ 90 mmHg and decrease ≥ 20 mmHg 
DBP 
Increase ≥ 10 mmHg 
Decrease ≥ 10 mmHg 
DBP ≥ 100 mmHg and increase ≥ 10 mmHg 
DBP ≤ 50 mmHg and decrease ≥ 10 mmHg 
HR 
Increase ≥ 10 bpm 
Decrease ≥ 10 bpm 
HR ≥ 110 bpm and increase ≥ 10 bpm 
HR ≤ 50 bpm and decrease ≥ 10 bpm 
 
Table 2: Predefined Classes for changes from Baseline to the Maximum (and/ or Minimum) 
Post-baseline Value 
Classes of Change from Baseline to the Maximum 
Post-baseline Value 
Classes of Change from Baseline to the 
Minimum Post-baseline Value 
SBP  mmHg 
DBP  mmHg 
HR bpm 
SBP  mmHg 
DBP  mmHg 
HR bpm 
All 
All 
All 
All 
All 
All 
≥  0 
≥  0 
≥  0 
≤  0 
≤  0 
≤  0 
>  0 
>  0 
>  0 
<  0 
<  0 
<  0 
≥ 10 
≥  5 
≥ 10 
≤ -10 
≤ - 5 
≤ -10 
≥ 20 
≥ 10 
≥ 20 
≤ -20 
≤ -10 
≤ -20 
≥ 30 
≥ 15 
≥ 30 
≤ -30 
≤ -15 
≤ -30 
≥ 40 
≥ 20 
 
≤ -40 
≤ -20 
 
 
≥ 25 
 
 
≤ -25 
 
 
≥ 30 
 
 
≤ -30 
 
 
Table 3: Classes for Vital Signs Maximum or Minimum Values 
Classes  for  the Maximum Post-baseline Value 
for each parameter 
Classes  for  the Minimum Post-baseline Value 
for each parameter 
SBP  mmHg 
DBP  mmHg 
HR bpm 
SBP  mmHg 
DBP  mmHg 
HR bpm 
< 120 
< 80 
≤ 50 
≤ 90 
≤ 50 
≤ 50 
[120 ;140[ 
[80;90[ 
]50 ;75[ 
[90 ;120[ 
[50;80[ 
]50 ;75[ 
[140;160[ 
 [90;100[ 
[75;100[ 
[120;140[ 
 [80;90[ 
[75;100[ 
≥ 160 
≥ 100 
≥ 100 
≥ 140 
≥ 90 
≥ 100 
 
Table 4: Classes for Maximum or Minimum of BP in its entirety 
Classification of Maximum Values for Blood 
Pressure (mmHg) 
Classification of Minimum Values Blood 
Pressure (mmHg) 
SBP < 140 and DBP < 90 
SBP > 90 and DBP > 50 
SBP [140;160[ and DBP < 100 
or DBP [90;100[ and SBP < 160 
SBP ≤  90 or DBP ≤  50 
SBP ≥ 160 or DBP ≥ 100 
 
 
Table 5: Definition of orthostatic hypotension 
Orthostatic Hypotension * 
SBP Decrease ≥ 20 mmHg or DBP Decrease ≥ 10 mmHg between supine and standing positions 
* Consensus Committee of the American Autonomic Society and the American Academy of Neurolog :Consensus statement on the definition of 
orthostatic hypotension, pure autonomic failure and multiple system atrophy. Neurology 1996;46:1470-3. 
 
 
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16.1.1.5. 
Protocol amendment n° PA03  
General and substantial dated on 23 October 
2013 linked to Protocol and appendices 
(version 5: 23 October 2013) 
 
 
 
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CLINICAL STUDY PROTOCOL AMENDMENT n° PA03 Version 1 
(General – Substantial) 
 
 
 
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Pierre Fabre Médicament 
Represented by: Institut de Recherche Pierre Fabre 
45, Place Abel Gance 
F-92100 Boulogne, France 
 
 
CLINICAL STUDY PROTOCOL AMENDMENT n° PA03 Version 1 
 
(General – Substantial) 
 
 
Efficacy and safety study of F373280 for maintenance of sinus rhythm after electrical 
cardioversion in patients with persistent Atrial Fibrillation and Chronic Heart Failure. 
 
International, multicentric, randomised, double-blind, placebo controlled study 
 
Pierre Fabre Study Code: 
F373280 CA 2 01  
EudraCT Number or equivalent : 2012-003487-48 
Sponsor’s Representative: 
Gaëlle ALCARAZ 
INSTITUT DE RECHERCHE PIERRE FABRE - Centre de R&D Pierre 
Fabre - BP 13562  
3 avenue Hubert Curien  
31035 TOULOUSE Cedex 1 
 
Study Coordinating Investigator: 
Pr Savina NODARI 
Department of Clinical and Surgical Specialities, Radiological 
Science and Public Health 
Section of Cardiovascular Diseases 
University Medical School and Spedali Civili Hospital of Brescia 
c/o Spedali Civili di Brescia 
Piazzale Spedali Civili, 1 
25123 - BRESCIA, ITALY 
 
Date of amendment PA03: 
23 October 2013 
 
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INVESTIGATOR SIGNATURE FORM  
STUDY: Efficacy and safety study of F373280 for maintenance of sinus rhythm after 
electrical cardioversion in patients with persistent Atrial Fibrillation and Chronic Heart 
Failure. 
 
International, multicentric, randomised, double-blind, placebo controlled study 
 
Clinical Study Protocol Amendment n° PA03 Version 1 
(General – Substantial) 
Dated: 23/10/2013 
 
 
By my signature below, I, Dr _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _, hereby confirm that I have read, taken 
note of (and will apply) the modifications brought by the protocol amendment n° PA03 and I will 
conduct the trial according to these new modalities. 
 
 
Date: 
Signature: 
 
 
 
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HISTORY OF AMENDMENTS 
 
N° 
TYPE 
APPLICATION 
AREA 
DATE 
MODIFICATIONS 
NA 
NA 
General 
NA 
Following French CA request (ANSM) and leading to 
protocol version 2: 
- Add of a non inclusion criteria: “Breast-feeding female 
patient” 
- Add of haematology examination at visit 3 and 6 
 
PA01 
Substantial 
Local (Italy) 
01.03.2013 
Corresponding to Protocol Version 3: 
- Integration of the modification included in the protocol 
version 2 
- Harmonisation of the protocol and the Informed 
Consent Form: 
* adjustment of the selection criteria n°10 related to the 
contraception method  
* addition of a letter that is given by the patient to his/her 
general practitioner (GP) 
* precision that the sponsor can not collect a copy of the 
Informed Consent Form  
* precision that the patient card is in Italian language 
only (without any English mention)     
 
PA02 
Non 
Substantial 
General 
28.03.2013 
Corresponding to Protocol Version 4 : 
- change of Sponsor’s Representative (Clinical Study 
Manager),  
- modification of the technical handling of the blood 
samples 
for 
determination 
of 
red 
blood 
cells 
concentration of DHA: the centrifugation is no more 
needed, 
- precision on the function and address of the 
International Study Coordinator Pr Nodari,  
- add of address and contacts details of two CRO newly 
involved 
in 
the 
study: 
Theradis 
(in 
charge 
of 
transportation of blood samples to the Analytical centre 
and material supply) and “Clinact” (in charge of refund 
of patients expenses linked to the study), 
 - adjustment of the wording, in agreement with the 
commitment to the French Ethics Committee. In the 
paragraphe 
8.3.2.1, 
the 
wording 
"hematology 
examination” is replaced by "standard hematologic 
dosage", 
  - precision of the full title in the study synopsis (in 
agreement with the commitment to the Spanish Ethics 
Committee),  
- correction of a mistake in section 8.1.1.3 (related to 
TTEM transmission) and sections 3, 9 and study 
synopsis (related to the definition of INR not stabilized). 
- addition of the changes included in the local italian 
substantial protocol amendment (i.e: contraception 
method, letter to General Practionner, patient card in 
Italian and no collection of the consent form by the 
sponsor in Italy). 
 
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1. AMENDMENT RATIONALE 
 
 
This amendment relates to an adjustment of some criteria in order to improve the feasibility of the study 
and to minor changes as typographical errors or style. Finally a change affects the recipient of the SAEs 
reports. 
 
The clinical study protocol is updated with the following changes:  
- Due to a recruitment rate significantly lower than expected the planned end of study is postponed to 
January 2015. 
 
- The authorized history of the first documented persistent atrial fibrillation passes from less than 1 year to 
less than 3 years. This modification will expand our target population without changing the characteristics 
of the selected patients by enabling the management of patients who experienced a longer period without 
relapse. 
 
- At selection a hyperkalemia or a hypokalemia will be better defined by the standards of the local 
laboratories.  
 
- Regarding previous treatments by amiodarone the non inclusion criteria of the protocol are adapted as 
follow: 
• 
Previous treatment with oral amiodarone within 4 months prior to inclusion 
• 
Intake of oral amiodarone for more than 1 month within 4 to 12 months before inclusion 
• 
Previous treatment with intravenous amiodarone within 4 weeks prior to inclusion 
 
Despite the long half life of amiodarone, these time limits relating to its non-use before inclusion allow to 
ensure the absence of amiodarone at sufficient levels to interfere with the assessment of the product. 
 
- For male with a child-bearing potential partner (in Italy only): 
Taking into account the duration of spermatogenesis the absolute abstention from sexual intercourse or 
the use of double barrier contraception method are extended to 3 months after the end of the study. 
 
- Ranolazine is an antiangina treatment with antiarrhythmic properties. This treatment is added to the 
prohibited treatments in order to exclude a potential association between the study product and a 
treatment having an antiarrhythmic effect. 
 
- Updated Serious Adverse Events (SAEs) form. Main change is the SAE sending: SAEs have to be 
reported to the Corporate Vigilance Department, and not anymore to the clinical study manager. Also 
SAEs can be sent by e-mail and by fax. 
 
- Addition of Alpha Bioresearch as CRO involved for Feasibility, Monitoring and Regulatory issues in Spain. 
 
- Some minor typographic errors are corrected in the protocol. 
 
 
 
 
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2. CHANGES DESCRIPTION 
 
PREVIOUS VERSION 
MODIFIED VERSION 
Sponsor's Representative: 
Gaëlle ALCARAZ 
INSTITUT DE RECHERCHE PIERRE FABRE - Centre de 
R&D Pierre Fabre - BP 13562  
3 avenue Hubert Curien  
31035 TOULOUSE Cédex 1 
Phone: +33 5 34 50 62 16  
Fax:+33 5 34 50 65 92  
E-mail:gaelle.alcaraz@pierre-fabre.com  
 
Medical Director : 
Richard ROCHE, MD 
Institut de Recherche Pierre Fabre 
Centre de R&D Pierre Fabre 
BP 13 562 
3, Avenue Hubert Curien 
31035 TOULOUSE Cedex 1 
Phone: +33 5 34 50 61 94 
Fax: +33 5 34 50 65 92 
E-mail: richard.roche@pierre-fabre.com 
Sponsor's Representative: 
Gaëlle ALCARAZ 
INSTITUT DE RECHERCHE PIERRE FABRE - Centre de 
R&D Pierre Fabre - BP 13562  
3 avenue Hubert Curien  
31035 TOULOUSE Cédex 1 
Phone: +33 5 34 50 62 16  
Fax:+33 5 34 50 69 69 
E-mail:gaelle.alcaraz@pierre-fabre.com  
 
Medical Director : 
Richard ROCHE, MD 
Institut de Recherche Pierre Fabre 
Centre de R&D Pierre Fabre 
BP 13 562 
3, Avenue Hubert Curien 
31035 TOULOUSE Cedex 1 
Phone: +33 5 34 50 61 94 
Fax: +33 5 34 50 69 69 
E-mail: richard.roche@pierre-fabre.com 
CONTRACT RESEARCH 
ORGANISATIONS 
For Feasibility, Monitoring and Regulatory issues: 
Pharmaceutical Service Network (PSN) 
Rufino Gonzalez 
28 037 Madrid - SPAIN 
Phone: +34 91 375 6930 - Fax: +34 91 375 6931 
E-mail: www.psnglobal.org 
 
CONTRACT RESEARCH 
ORGANISATIONS 
For Feasibility, Monitoring and Regulatory issues: 
Pharmaceutical Service Network (PSN) 
Rufino Gonzalez 
28 037 Madrid - SPAIN 
Phone: +34 91 375 6930 - Fax: +34 91 375 6931 
E-mail: www.psnglobal.org 
 
For Feasibility, Monitoring and Regulatory issues (in 
Spain): 
Alpha Bioresearch 
Paseo de la Castellana, 163 - 2º Izquierda 
28 046 Madrid - SPAIN 
Phone: +34 91 745 2520 - Fax: +34 91 745 0653 
E-mail: teresa.bricio@alphabioresearch.com 
SYNOPSIS 
Planned Study Period:  
January 2013 –  April 2014 
SYNOPSIS 
Planned Study Period:  
January 2013 –  January 2015 
Diagnosis and Criteria for Inclusion: 
Inclusion Criteria: 
2. 
Patients with persistent AF between 7 days and 6 
months duration for whom electrical cardioversion is 
Diagnosis and Criteria for Inclusion: 
Inclusion Criteria: 
2.     Patients with current episode of persistent AF between 7 
days and 6 months duration for whom electrical 
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warranted. 
3. 
History of first documented persistent AF less than 1 
year. 
12. 
For male with a child-bearing potential partner (In 
Italy only): 
- 
absolute abstention from sexual intercourse during 
the whole duration of the study and for a month after the 
end of the study or 
- 
use of double barrier contraception method (use of 
condom for male and effective contraception method for 
the partner) from the entire duration of the study to a 
month after the end of the study 
 
Non-Inclusion Criteria: 
Criteria related to pathologies: 
1. 
History of first documented episode of persistent AF 
more than 1 year 
[…] 
9. 
Hyperkalemia or hypokalemia (K>5.5 mEq/L or K < 
3.5 mEq/L) at selection  
 
Criteria related to treatments: 
[…] 
12. Concomitant treatment with any anti-arrhythmic drug 
(within 7 days prior to selection), except stable dose 
of digoxin, betablockers, calcium-blockers 
13. Previous treatment with oral amiodarone within 12 
months prior to inclusion 
14. Previous treatment with intravenous amiodarone 
within 6 months prior to inclusion 
cardioversion is warranted 
3. 
History of first documented persistent AF less than 3 
years 
12. 
For male with a child-bearing potential partner (In 
Italy only): 
- absolute abstention from sexual intercourse during the whole 
duration of the study and for 3 months after the end of the 
study or 
- use of double barrier contraception method (use of condom 
for male and effective contraception method for the partner) 
from the entire duration of the study to 3 months after the 
end of the study 
 
Non-Inclusion Criteria: 
Criteria related to pathologies: 
1. 
History of first documented episode of persistent AF 
more than 3 years 
[…] 
9. 
Hyperkalemia or hypokalemia (according to the 
standards of local laboratories) at selection  
 
Criteria related to treatments: 
[…] 
12. Concomitant treatment with ranolazine or any 
antiarrhythmic drug (within 7 days prior to selection), 
except stable dose of digoxin, betablockers, calcium-
blockers 
13. Oral amiodarone: 
         13a  Previous treatment with oral amiodarone within 
4 months prior to inclusion 
                 13b Intake of oral amiodarone for more than 1 
month within 4 to 12 months before inclusion 
14. Previous treatment with intravenous amiodarone 
within 4 weeks prior to inclusion 
Evaluation Criteria: 
 
Efficacy evaluation variables: 
Other: 
• 
Evolution of echocardiographic parameters (from V4 
to V6 and V9) (Left atrial diameter (mm), Left atrial 
area (cm²), Left atrial volume (mL), Left atrial 
volume/BSA (mL/m2), Left ventricular ejection 
fraction (%),Left ventricular volume (mL), Left 
ventricular volume/BSA(mL/m2), Left ventricular end 
diastolic diameter (mm), Left ventricular end diastolic 
volume (mL) Left ventricular end systolic diameter 
(mm), Left ventricular end systolic volume (mL)) 
 
Safety criteria: 
- Haematology: haematocrit, haemoglobin, RBC, WBC, 
differential count, platelets 
Evaluation Criteria: 
 
Efficacy evaluation variables: 
Other: 
• 
Evolution of echocardiographic parameters (from V4 
to V6 and V9) (Left atrial diameter (mm), Left atrial 
area (cm²), Left atrial volume (mL), Left atrial 
volume/BSA (mL/m2), Left ventricular ejection 
fraction (%), Left ventricular end diastolic 
volume/BSA (mL/ m2), Left ventricular end systolic 
volume/BSA (mL/m2), Left ventricular end diastolic 
diameter (mm), Left ventricular end diastolic volume 
(mL) Left ventricular end systolic diameter (mm), 
Left ventricular end systolic volume (mL)) 
 
Safety criteria: 
- Haematology: haematocrit, haemoglobin, red blood cell 
(RBC) count, white blood cell (WBC) count, differential 
count, reticulocytes, platelets 
STUDY FLOW-CHART 
Please see flow-chart of previous version in appendix 1. 
STUDY FLOW-CHART 
Please see flow-chart of modified version in appendix 2. 
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1. INTRODUCTION AND STUDY 
RATIONALE 
1.2. Information on the test product 
1.2.3. Clinical data 
Part A: Single dose 
Regarding the reported Treatment Emergent Adverse Events 
(TEAEs) that were judged by the Investigator as having a 
causal relationship with the study drug administration in the 
absence of an alternative explanation, 4 were observed in the 
placebo group (palpitation, dizziness in standing position , 2 
symptomatic 
orthostatic 
hypotensions 
without 
loss 
of 
consciousness) and 4 in the group of F373280 at the dosage of 
16g 
(meteorism, 
liquid 
stool, 
symptomatic 
orthostatic 
hypotension and dizziness in standing position).  
1. INTRODUCTION AND STUDY 
RATIONALE 
1.2. Information on the test product 
1.2.3. Clinical data 
Part A: Single dose 
Regarding the reported Treatment Emergent Adverse Events 
(TEAEs) that were judged by the Investigator as having a 
causal relationship with the study drug administration in the 
absence of an alternative explanation, 3 TEAs were observed in 
the placebo group (palpitation, dizziness in standing position , 
symptomatic 
orthostatic 
hypotensions 
without 
loss 
of 
consciousness) and 4 in the group of F373280 at the dosage of 
16g 
(meteorism, 
liquid 
stool, 
symptomatic 
orthostatic 
hypotension and dizziness in standing position).  
3. ETHICAL CONSIDERATIONS RELATING 
TO THE STUDY 
During the study, in case of AF recurrence that would require 
cardioversion or the introduction of an anti-arrhythmic because 
of intolerable and/or uncomfortable clinical symptoms, patients 
will be withdrawn and the tested product stopped. These 
patients will be considered as treatment failure 
3. ETHICAL CONSIDERATIONS RELATING 
TO THE STUDY 
During the study, in case of AF recurrence that would require 
cardioversion or the introduction of an anti-arrhythmic because 
of intolerable and/or uncomfortable clinical symptoms for 
instance, patients will be withdrawn and the tested product 
stopped. These patients will be considered as treatment failure 
4. STUDY DESIGN 
4.1. Overall description 
- 
Visit 4 (V4): W5 (D35 ± 2D): follow-up visit 
(removing of Holter ECG device and installation of 
the TTEM) 
4. STUDY DESIGN 
4.1. Overall description 
- 
Visit 4 (V4): W5 (D35 -2/+7D): follow-up visit 
(removing of Holter ECG device and installation of 
the TTEM) 
4.2. Discussion of the study design 
4.2.1. Choice of the study population 
The study aim is to investigate the product effect in patients 
with: 
Persistent AF history (less than one year) with a duration of the 
current episode from 7 days to 6 months 
[…] 
For the successful rate of electrical cardioversion, patients 
should have a stable medical treatment of heart failure and 
should not have myocardial infarction or unstable angina or 
unstable ischemic coronaropathy (assessed by coronarography 
or cardiac stress test or effort test within 6 months before 
selection).  
4.2. Discussion of the study design 
4.2.1. Choice of the study population 
The study aim is to investigate the product effect in patients 
with: 
Persistent AF history (less than three years) with a duration of 
the current episode from 7 days to 6 months 
[…] 
For the successful rate of electrical cardioversion, patients 
should have a stable medical treatment of heart failure and 
should not have myocardial infarction or unstable angina or 
unstable ischemic coronaropathy assessed by coronarography 
or cardiac stress test (Echo stress, exercise stress test, nuclear 
or MR perfusion evaluation methods) within 6 months before 
selection. 
5. STUDY POPULATION 
5.1.Inclusion criteria 
5. STUDY POPULATION 
5.1.Inclusion criteria 
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Demographic 
Characteristics 
and 
Other 
Baseline 
Characteristics: 
1. 
[…] 
2. 
Patient with persistent AF between 7 days and 6 months 
duration for whomelectrical cardioversion is warranted 
3. 
History of first documented persistent AF less than 1 year 
 
 
[…] 
 
12 For male with a child-bearing potential partner (In Italy 
only): 
- absolute abstention from sexual intercourse during the whole 
duration of the study and for a month after the end of the study 
or 
 -use of double barrier contraception method (use of condom 
for male and effective contraception method for the partner) 
from the entire duration of the study to a month after the end of 
the study 
Demographic 
Characteristics 
and 
Other 
Baseline 
Characteristics: 
1. 
[…] 
2. 
Patient with current episode of persistent AF between 7 
days and 6 months duration for whom electrical 
cardioversion is warranted 
3. 
History of first documented persistent AF less than 3 
years 
[…] 
 
12.For male with a child-bearing potential partner (In Italy 
only): 
- absolute abstention from sexual intercourse during the whole 
duration of the study and for 3 months after the end of the study 
or 
 -use of double barrier contraception method (use of condom 
for male and effective contraception method for the partner) 
from the entire duration of the study to 3 months after the end 
of the study 
5.2.Non Inclusion criteria 
Criteria related to pathologies: 
1. History of first documented episode of persistent AF more 
than 1 year, 
[…] 
9. 
Hyperkalemia or hypokalemia (K > 5.5 mEq/L or K < 
3.5 mEq/L) at selection 
5.2.Non Inclusion criteria 
Criteria related to pathologies: 
1. History of first documented episode of persistent AF more 
than 3 years, 
[…] 
9. 
Hyperkalemia or hypokalemia (according to the 
standards of local laboratories) at selection 
Criteria related to treatments: 
12. Concomitant treatment with any anti-arrhythmic drug 
(within 7 days prior to selection), except stable dose 
of digoxin, betablockers, calcium-blockers 
13. Previous treatment with oral amiodarone within 12 
months prior to inclusion 
14. Previous treatment with intravenous amiodarone 
within 6 months prior to inclusion 
 
Criteria related to treatments: 
12. Concomitant treatment with ranolazine or any anti-
arrhythmic drug (within 7 days prior to selection), 
except stable dose of digoxin, betablockers, calcium-
blockers 
13. Oral amiodarone: 
         13a  Previous treatment with oral amiodarone within 
4 months prior to inclusion 
                 13b Intake of oral amiodarone for more than 1 
month within 4 to 12 months before inclusion 
14. Previous treatment with intravenous amiodarone 
within 4 weeks prior to inclusion 
5.6. Withdrawal criteria 
 
• 
Patients who will not revert to sinus rhythm or with early 
relapse within the observation period after ECV (i.e. 
unsuccessful ECV) will be considered to have finished follow-
up. 
• 
An occurrence of AF recurrence that would require, at the 
investigator’s judgement, a cardioversion or an introduction of 
an anti-arrhythmic because of intolerable and uncomfortable 
clinical symptoms. 
5.6. Withdrawal criteria 
• 
Patients who will not revert to sinus rhythm (i.e. 
unsuccessful ECV) or with early relapse within the observation 
period after ECV will be considered to have finished follow-up. 
• 
Occurrence of AF recurrence that would require, at the 
investigator’s judgement, a cardioversion or an introduction of 
an anti-arrhythmic because of intolerable and/or uncomfortable 
clinical symptoms for instance. 
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6. STUDY TREATMENT 
6.3. Distribution to centre and storage 
As soon as the Pharmacist or the Investigator receives the trial 
medication, he/she will check the contents and immediately 
acknowledges the receipt in the IVRS/IWRS. The copy of the 
acknowledgement will be kept in the Investigator’s file.  
6. STUDY TREATMENT 
6.3. Distribution to centre and storage 
As soon as the Pharmacist or the Investigator receives the trial 
medication, he/she will check the contents and immediately 
acknowledges the receipt in the IVRS/IWRS. The copy of the 
acknowledgement will be kept in the Investigator’s or the 
Pharmacist’s file.  
6.4. Allocation of treatments and dispensation to 
patient 
Practically, once the patient’s eligibility is confirmed, at 
selection visit:  
• 
The Investigator: 
− Calls the vocal server  
− Answers the questions relating to the patient  
− In return, the treatment number to be allocated for the 
first 12-week period to the patient is given by the 
vocal server.  
[…] 
At visit 5, the Investigator will contact again the IVRS/IWRS to 
obtain for visit 6 the treatment number for the last 12-week 
period of treatment according to the same process as described 
above. 
6.4. Allocation of treatments and dispensation to 
patient 
Practically, once the patient’s eligibility is confirmed, at 
selection visit:  
• 
The Investigator: 
− Contacts the IVRS/IWRS 
− Answers the questions relating to the patient  
− In return, the treatment number to be allocated for the 
first 12-week period to the patient is given by the 
IVRS/IWRS.  
[…] 
At visit 6, the Investigator will contact again the IVRS/IWRS to 
obtain the treatment number for the last 12-week period of 
treatment according to the same process as described above. 
 
7. CONCOMITANT TREATMENTS 
7.2. Prohibited treatments  
[…] 
7. CONCOMITANT TREATMENTS 
7.2. Prohibited treatments  
[…] 
- 
Ranolazine 
8. EVALUATION CRITERIA 
8.1.2.5. Evolution of echocardiographic parameters 
8.1.2.5.1. Definition 
The following echocardiographic parameters will be assessed: 
Left atrial diameter (mm), Left atrial area (cm2), Left atrial 
volume (mL), Left atrial volume/BSA (mL/m2), Left ventricular 
ejection fraction (%),Left ventricular volume (mL), Left 
ventricular volume/BSA(mL/m2, Left ventricular end diastolic 
diameter (mm) Left ventricular end diastolic volume (mL), Left 
ventricular end systolic diameter (mm) and Left ventricular end 
systolic volume (mL), 
8. EVALUATION CRITERIA 
8.1.2.5. Evolution of echocardiographic parameters 
8.1.2.5.1. Definition 
The following echocardiographic parameters will be assessed: 
Left atrial diameter (mm), LAA (cm2), Left atrial volume (mL), 
Left atrial volume/BSA (mL/m2), LVEF (%), Left ventricular 
end diastolic volume/BSA (mL/m2), Left ventricular end 
systolic volume/BSA (mL/m2), Left ventricular end diastolic 
diameter (mm), Left ventricular end diastolic volume (mL), 
Left ventricular end systolic diameter (mm) and Left ventricular 
end systolic volume (mL). 
9. STUDY PROCEDURES 
Visit 1 - Selection Visit (Week -4 to Week -1) 
• 
The patient will enter the selection period in which 
anticoagulant (anti-vitamin K) will be adjusted to achieve an 
9. STUDY PROCEDURES 
Visit 1 - Selection Visit (Week -4 to Week -1) 
• 
The patient will enter the selection period in which 
anticoagulant (AVK) will be adjusted to achieve an 
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International Normalized Ratio (INR) of 2 to 3 before electrical 
cardioversion.  
International Normalized Ratio of 2 to 3 before ECV.  
Visit 4 (Week 5: D35 ± 2 days) 
 
Visit 4 (Week 5: D35 -2/+7 days) 
• 
Body weight (body weight measured at V3 to be 
used) 
Visit 5 (Week 8: D56 ± 7 days) – Visit 6 (Week 12: D84 ± 7 
days) - Visit 7 (Week 16: D112 ± 7 days) - Visit 8 (Week 20: 
D140 ± 7 days) 
 
In addition: 
- at visit 5, the investigator will contact the IVRS/IWRS to 
obtain another treatment unit to be dispensed at visit 6 for the 
last 12-week period. 
 
- at visit 6, an echocardiography will be performed, an 
haematology examination will be done and the red blood cell 
concentration of DHA will be measured.  
Visit 5 (Week 8: D56 ± 7 days) – Visit 6 (Week 12: D84 ± 7 
days) - Visit 7 (Week 16: D112 ± 7 days) - Visit 8 (Week 20: 
D140 ± 7 days) 
 
In addition: 
- at visit 6: 
 
• 
the investigator will contact the IVRS/IWRS to 
obtain the treatment unit number to be dispensed at 
visit 6 for the last 12-week period. 
• 
an 
echocardiography 
will 
be 
performed, 
an 
haematology examination will be done and the RBC 
concentration of DHA will be measured.  
10.2.2. Reporting of SAE 
All serious adverse events, according to the above-mentioned 
definitions and regardless of treatment or relationship to study 
drug, must be reported by the Investigator as soon as he/she is 
informed of the event. 
The Investigator must notify the Sponsor of this event by 
sending, within 24 hours, the "Notification of serious adverse 
event" form ("first notification") (see appendix 17.2) with all 
the available information about the event, to the Sponsor's 
representative: 
Gaëlle ALCARAZ 
INSTITUT DE RECHERCHE PIERRE FABRE,  
Centre de R&D Pierre Fabre – BP 13562 
3 Avenue Hubert Curien 
31035 TOULOUSE Cedex 1 
Phone: +33 5 35 50 62 16 
Fax: + 33 5 34 50 65 92 
Email: gaelle.alcaraz@pierre-fabre.com 
In case of non-inclusion the reporting period ends when the 
non-inclusion is documented. 
10.2.2. Reporting of SAE 
All Serious Adverse Events, according to the above-mentioned 
definitions and regardless of treatment or relationship to study 
drug, and occurring once the informed consent form has 
been signed, must be reported by the Investigator as soon as 
he/she is informed of the event. 
The Investigator must notify the Sponsor of this event by 
sending, within 24 hours, the "Notification of serious adverse 
event" form ("first notification") with all the available 
information about the event (see appendix 17.2), to the 
Sponsor's Corporate Vigilances e-mail dedicated box: 
HQ.pharmacovigilance@pierre-fabre.com 
In case it is not possible to send the report by e-mail it 
can be sent by FAX at the following number: 
+ 33 1 49 10 80 90 
In case of non-inclusion, the reporting period ends when the 
non-inclusion is documented. 
13. STATISTICAL ANALYSIS 
13.4. Data sets analysed   
The following 2 data sets will be analysed (as defined by the 
Validation Committee):   […]  
• 
The Per Protocol Set (PP) which is the subset of the Full 
Analysis Set composed of all patients with a primary efficacy 
13. STATISTICAL ANALYSIS 
13.4. Data sets analysed   
The following 3 data sets will be analysed (as defined by the 
Validation Committee):   […]  
• 
The Per Protocol Set (PP) which is the subset of the Full 
Analysis Set composed of all patients with a primary efficacy 
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criteria available and without any major protocol deviation or 
other source of bias for primary criteria analyses.  
criteria available and without any major protocol deviation or 
other source of bias for primary criteria analyses. This data set 
will be used to perform the supportive analysis of the 
primary efficacy criterion. 
16. REFERENCES 
[1] 
F373280 
INVESTIGATOR'S 
BROCHURE, 
version 
January 2013 
16. REFERENCES 
[1] 
F373280 
INVESTIGATOR'S 
BROCHURE, 
version 
October 2013 
 
 
 
 
 
 
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APPENDIX 1 
 
STUDY FLOW-CHART FROM PROTOCOL VERSION 4
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F373280 CA 201
V1
V2
V3
V4
V5
V6
V7
V8
V9
Weeks
W-4 to W-1
D1
W4
 (28 -2D/+7 D) 
W5
 (35 +/-2 D)
W8 
(56+/-7D)
W12 
(84+/-7D)
W16 
(112+/-7D)
W20 
(140+/-7D) 
W24 
(168+/-7D)
Outpatient or Hospitalization (1)
X
Informed consent
X
Demographic characteristics
X
Medico-surgical history
X
Concomitant disease
X
Concomitant treatment
X
X
X
X
X
X
X
X
X
Habits
X
Global physical examination (body weight)
X
X
X
X
X
X
X
X
Echocardiography
X
X
X
X
X
Eligibility criteria check
X
X
Blood pressure, heart rate 
X
X
X
X
X
X
X
X
X
12-Lead  ECG Recording
X
X
X
X
X
X
X
X
INR 
 
 
 (2)
X
X
X
X
X
aPTT, TCT 
X
X
X
X
X
X
X
X
Biochemistry
X
X
Hematology
X
X
X
X
Urinary pregnancy test
X
X
Red Blood Cell concentrations of DHA 
X
X
X
X
Treatment allocation
X
X
IVRS
X
X
X
X
ECV (3)
X
Drug administration 
 
 
 
 
 
 
 
 
Adverse events recording
X
X
X
X
X
X
X
X
Holter ECG 
 (4)
 
 (5)
TTEM (6)
 
 
 
 
(3) In patients with AF
(1) Outpatient or hospitalization according to clinical practice of the centre (less or more than 24 hours)
(6) TTEM everyday from week 6 to week 8. Then every 2 days from week 9 to week 24. In case of AF symptoms. In case of AF recurrence for at least 10 minutes and the patient does not 
stop  the study treatment then TTEM every 4 weeks
(2) In case of AVK introduction: INR 2 to 3 times a week, then weekly untill the ECV, then every 4 weeks after ECV.
(5) 7-day Holter ECG
(4) 24-hour Holter ECG
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APPENDIX 2 
 
 
STUDY FLOW-CHART FROM PROTOCOL VERSION 5 (modified version) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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F373280 CA 201 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
Weeks 
W-4 to W-1 
D1 
W4 
(28 -2D/+7 D) 
W5 
(35 -2D/+7 D) 
W8 
(56+/-7D) 
W12 
(84+/-7D) 
W16 
(112+/-7D) 
W20 
(140+/-7D)  
W24 
(168+/-7D) 
  
  
  
  
  
  
  
  
  
  
Outpatient or Hospitalization (1) 
  
  
X 
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
  
  
  
  
  
  
  
  
Demographic characteristics 
X 
  
  
  
  
  
  
  
  
Medico-surgical history 
X 
  
  
  
  
  
  
  
  
Concomitant disease 
X 
  
  
  
  
  
  
  
  
Concomitant treatment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Habits 
X 
  
  
  
  
  
  
  
  
Global physical examination (body weight) 
X 
X 
X 
 
X 
X 
X 
X 
X 
Echocardiography 
X 
X 
  
X 
  
X 
  
  
X 
Eligibility criteria check 
X 
X 
  
  
  
  
  
  
  
Blood pressure, heart rate  
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead  ECG Recording 
X 
X 
X 
  
X 
X 
X 
X 
X 
INR  
 
 
                     (2) 
  
X 
X 
X 
X 
X 
aPTT, TCT  
X 
X 
X 
  
X 
X 
X 
X 
X 
Biochemistry 
X 
  
  
  
  
  
  
  
X 
Hematology 
X 
  
X 
  
  
X 
  
  
X 
Urinary pregnancy test 
  
X 
  
  
  
  
  
  
X 
Red Blood Cell concentrations of DHA  
  
X 
X 
  
  
X 
  
  
X 
Treatment allocation 
  
X 
  
  
  
X 
  
  
  
IVRS/IWRS 
X 
X 
  
  
 
X 
  
  
  
ECV (3) 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Drug administration  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Adverse events recording 
  
X 
X 
X 
X 
X 
X 
X 
X 
Holter ECG 
                (4) 
  
 
                (5) 
 
 
 
 
 
TTEM (6) 
  
  
 
 
 
  
  
  
  
(1) Outpatient or hospitalization according to clinical practice of the centre (less or more than 24 hours) 
(2) In case of AVK introduction: INR 2 to 3 times a week, then weekly untill the ECV, then every 4 weeks after ECV. 
(3) In patients with AF 
(4) 24-hour Holter ECG 
(5) 7-day Holter ECG 
(6) TTEM: everyday from week 6 to week 8;. then every 2 days from week 9 to week 24; at any time in case of AF symptoms. 
In case of AF recurrence for at least 10 minutes and if the patient does not stop  the study treatment then TTEM once a week 
 
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F 373280 CA 2 01 
 
 
 
 
 
 
 
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Pierre Fabre Médicament 
Represented by: Institut de Recherche Pierre Fabre 
45, Place Abel Gance 
F-92100 Boulogne 
CLINICAL STUDY PROTOCOL 
 
Efficacy and safety study of F373280 for maintenance of sinus rhythm after 
electrical cardioversion in patients with persistent Atrial Fibrillation and 
Chronic Heart Failure. 
International, multicentric, randomised, double-blind, placebo controlled study 
F373280 / Soft Capsules / 1g  
Pierre Fabre Study Code: 
EudraCT Number: 
 
Sponsor's Representative: 
 
 
 
 
 
 
 
 
Study Coordinating Investigator 
F 373280 CA 2 01  
2012 – 003487 - 48 
 
Gaëlle ALCARAZ 
INSTITUT DE RECHERCHE PIERRE FABRE - Centre de 
R&D Pierre Fabre - BP 13562  
3 avenue Hubert Curien  
31035 TOULOUSE Cédex 1, FRANCE 
Phone: +33 5 34 50 62 16  
Fax:+33 5 34 50 69 69  
E-mail:gaelle.alcaraz@pierre-fabre.com  
 
Pr Savina NODARI 
Associate Professor of Cardiology 
Department of Clinical and Surgical Specialities, 
Radiological Science and Public Health 
Section of Cardiovascular Diseases 
University Medical School and Spedali Civili Hospital of 
Brescia 
c/o Spedali Civili di Brescia 
Piazzale Spedali Civili, 1 
25123 - BRESCIA, ITALY 
Phone: +39 030 3996 587 – +39 030 393849 
Fax: +39 030 3700 359 
E-mail: savinanodari@gmail.com; nodari@med.unibs.it 
 
Version 5 –23OCT2013 
 
The information contained in this document is confidential and is the property of the Sponsor, Pierre Fabre 
Medicament. This information is given for the needs of the study and must not be disclosed without prior written 
consent of the Sponsor Pierre Fabre Medicament. Persons to whom this information is given for the needs of the 
study must be informed that it is confidential and must not be disclosed. 
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SPONSOR PERSONNEL 
PIERRE FABRE MEDICAMENT 
represented by 
Institut de Recherche Pierre Fabre 
 
Clinical Study Manager (Monitor) 
Gaëlle ALCARAZ 
Phone: +33 5 34 50 62 16  
Fax: + 33 5 34 50 69 69 
E-mail: gaelle.alcaraz@pierre-
fabre.com 
Institut de Recherche Pierre Fabre 
Centre de R&D Pierre Fabre 
BP 13 562 
3, Avenue Hubert Curien 
31035 TOULOUSE Cedex 1, FRANCE 
 
 
Medical Director 
Richard ROCHE, MD 
Phone: +33 5 34 50 61 94 
Fax: +33 5 34 50 69 69 
E-mail: richard.roche@pierre-
fabre.com 
Institut de Recherche Pierre Fabre 
Centre de R&D Pierre Fabre 
BP 13 562 
3, Avenue Hubert Curien 
31035 TOULOUSE Cedex 1, FRANCE 
 
 
 
 
 
 
 
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CONTRACT RESEARCH ORGANISATIONS 
 
For Feasibility, Monitoring and Regulatory issues: 
Pharmaceutical Service Network (PSN) 
Rufino Gonzalez 
28 037 Madrid - SPAIN 
Phone: +34 91 375 6930 - Fax: +34 91 375 6931 
E-mail: www.psnglobal.org 
 
For Feasibility, Monitoring and Regulatory issues (in Spain): 
Alpha Bioresearch 
Paseo de la Castellana, 163 - 2º Izquierda 
28 046 Madrid - SPAIN 
Phone: +34 91 745 2520 - Fax: +34 91 745 0653 
E-mail: teresa.bricio@alphabioresearch.com 
 
For Centralised Randomisation and Electronic Case Report Form 
S-Clinica 
6, Chaussée de Boondael 
B-1050 Brussels - BELGIUM 
Phone: +32 2 645 0567 - Fax: +32 2 645 0569 
E-mail: irena.seredina@s-clinica.com 
 
For Centralised Reading of Holder ECG and TTEM and equipment supply: 
Biomedical System 
1945 Chaussée de Wavre 
B-1160 Brussels - BELGIUM 
Phone: +32 2 661 20 70 - Fax: +32 2 661 20 71 
E-mail: sjacobs@biomedsys.com 
 
For intra erythrocyte DHA dosage: 
Agrocampus Ouest 
Laboratoire de Biochimie 
65 rue de Saint Brieuc – CS 84215 
35042 RENNES Cedex - FRANCE 
Phone: +33 2 23 48 55 49 - Fax: +33 2 23 48 55 50 
E-mail: daniel.catheline@agrocampus-ouest.fr 
 
For transportation of blood sample to the Analytical centre (Agrocampus) and material 
supply: 
Theradis Pharma 
41, chemin des Presses 
06800 CAGNES-SUR-MER – FRANCE 
Phone: +33 (0)4 97 02 07 07 - Fax: +33 (0)4 97 10 08 78 
E-mail: chantal.raffy@theradis.pharma.com 
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For refund of patients expenses linked to the study (in France): 
CLINACT 
6-10 rue TROYON 
92310 SEVRES – FRANCE 
Phone: +33 1 46 90 27 27 - Fax: +33 1 46 23 01 56 
Email: sebastien.beaumont@clinact.com 
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Protocol F 373280 CA 2 01 
COUNTRY COORDINATING INVESTIGATOR  
SIGNATURE FORM 
Protocol Version 5 – 23 OCT 2013 
 
 
Country: …………………….. 
 
Country Coordinating Investigator:  
"Name"  
Date:   
 
 
 
 
 
 
Signature:  
 
 
 
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Protocol F 373280 CA 2 01 
INVESTIGATOR SIGNATURE FORM 
Protocol Version 5 – 23 OCT 2013 
 
 
 
By my signature below, I, Dr / Pr "                                         ", hereby confirm that I agree: 
♦ to conduct the trial described in the protocol F 373280 CA 2 01, dated 23 October 2013 in 
compliance with GCP, with applicable regulatory requirements and with the protocol 
agreed upon by the Sponsor Pierre Fabre Médicament and given approval / favourable* 
opinion by the Ethics Committee; 
♦ to document the delegation of significant study-related tasks and to notify the Sponsor of 
changes in site personnel involved in the study; 
♦ to comply with the procedure for data recording and reporting; 
♦ to allow monitoring, auditing and inspection; 
♦ to retain the trial-related essential documents until the Sponsor informs that these documents 
are no longer needed. 
Furthermore, I hereby confirm that I will have and will use the available adequate resources, 
personnel and facilities for conduct this trial. 
 
I have been informed that certain regulatory authorities require the Sponsor Pierre Fabre 
Médicament to obtain and supply details about the investigator’s ownership interest in the 
Sponsor or the study drug, and more generally about his/her financial relationships with the 
Sponsor. The Sponsor will use and disclose the information solely for the purpose of complying 
with regulatory requirements. 
Hence I agree: 
♦ to supply the Sponsor with any information regarding ownership interest and financial 
relationships with the Sponsor (including those of my spouse and dependent children); 
♦ to promptly update this information if any relevant changes occur during the course of the 
study and for 1 year following completion of the study; 
♦ that the Sponsor may disclose this information about such ownership interests and financial 
relationships to regulatory authorities. 
* To be adapted  
 
Date:  
Signature:  
 
 
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TABLE OF CONTENTS OF CLINICAL STUDY PROTOCOL 
 
1. 
INTRODUCTION AND STUDY RATIONALE ................................................................ 22 
1.1. 
TARGET PATHOLOGY AND THERAPY ........................................................................ 22 
1.2. 
INFORMATION ON THE TEST PRODUCT .................................................................... 24 
1.2.1. 
Chemical and pharmaceutical characteristics .................................................................... 25 
1.2.1.1. 
Nomenclature and structure ............................................................................................ 25 
1.2.1.2. 
Physical and chemical general properties ...................................................................... 25 
1.2.2. 
Non-clinical Data .............................................................................................................. 26 
1.2.2.1. 
Pharmacological profile ................................................................................................. 26 
1.2.2.2. 
Safety pharmacology ...................................................................................................... 27 
1.2.2.3. 
Toxicology profile .......................................................................................................... 27 
1.2.2.4. 
Pharmacokinetic data ..................................................................................................... 27 
1.2.3. 
Clinical data ....................................................................................................................... 27 
1.3. 
STUDY RATIONALE ......................................................................................................... 30 
1.4. 
OVERALL RISK AND BENEFIT ASSESSMENT ............................................................ 30 
2. 
STUDY OBJECTIVES ......................................................................................................... 33 
2.1. 
PRIMARY OBJECTIVE ..................................................................................................... 33 
2.2. 
SECONDARY OBJECTIVES ............................................................................................. 33 
3. 
ETHICAL CONSIDERATIONS RELATING TO THE STUDY .................................... 33 
4. 
STUDY DESIGN ................................................................................................................... 35 
4.1. 
OVERALL DESCRIPTION ................................................................................................ 35 
4.2. 
DISCUSSION OF THE STUDY DESIGN .......................................................................... 35 
4.2.1. 
Choice of the Study Population ......................................................................................... 35 
4.2.2. 
Choice of the Study Design ............................................................................................... 36 
4.2.3. 
Choice of the Dose ............................................................................................................ 38 
4.2.4. 
Choice of the Sample Size ................................................................................................. 38 
5. 
STUDY POPULATION ........................................................................................................ 38 
5.1. 
INCLUSION CRITERIA ..................................................................................................... 38 
5.2. 
NON INCLUSION CRITERIA ........................................................................................... 39 
5.3. 
NUMBER OF PATIENTS ................................................................................................... 40 
5.4. 
RECRUITMENT MODALITIES ........................................................................................ 41 
5.5. 
PATIENT IDENTIFICATION ............................................................................................ 41 
5.6. 
WITHDRAWAL CRITERIA ............................................................................................... 41 
5.7. 
REPLACEMENT OF PATIENTS ....................................................................................... 42 
5.8. 
POST-STUDY EXCLUSION PERIOD .............................................................................. 42 
5.9. 
STUDY CARD AND LETTER FOR GENERAL PRACTITIONER(S) ............................ 42 
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6. 
STUDY TREATMENT ......................................................................................................... 43 
6.1. 
SOURCE, PRESENTATION AND COMPOSITION OF  INVESTIGATIONAL 
PRODUCT ........................................................................................................................... 43 
6.2. 
PACKAGING AND LABELLING ..................................................................................... 43 
6.2.1. 
Packaging .......................................................................................................................... 44 
6.2.2. 
Labelling ............................................................................................................................ 44 
6.3. 
DISTRIBUTION TO CENTRE AND STORAGE .............................................................. 45 
6.4. 
ALLOCATION OF TREATMENTS AND DISPENSATION TO PATIENT ................... 46 
6.5. 
DRUG ADMINISTRATION ............................................................................................... 47 
6.5.1. 
Duration of Treatment ....................................................................................................... 47 
6.5.2. 
Dose Schedule ................................................................................................................... 47 
6.5.3. 
Route and Conditions of Administration ........................................................................... 47 
6.6. 
ACCOUNTABILITY ON SITE AND RETURN/DESTRUCTION OF  
INVESTIGATIONAL PRODUCT ...................................................................................... 47 
6.7. 
RECALL OF INVESTIGATIONAL PRODUCTS ............................................................. 48 
7. 
CONCOMITANT TREATMENTS ..................................................................................... 48 
7.1. 
ANTI-VITAMIN K TREATMENT ..................................................................................... 49 
7.2. 
PROHIBITED TREATMENTS ........................................................................................... 49 
7.3. 
AUTHORISED TREATMENTS ......................................................................................... 49 
8. 
EVALUATION CRITERIA ................................................................................................. 50 
8.1. 
PRIMARY EFFICACY CRITERION ................................................................................. 50 
8.1.1. 
Time to the first Atrial Fibrillation Recurrence ................................................................. 50 
8.1.1.1. 
Definition ........................................................................................................................ 50 
8.1.1.2. 
Schedule ......................................................................................................................... 50 
8.1.1.3. 
Evaluation Methods ........................................................................................................ 50 
8.1.2. 
Secondary Efficacy Criteria .............................................................................................. 51 
8.1.2.1. 
Numbers of AF episodes in the first week following visit 3 (ECV visit) ...................... 51 
8.1.2.2. 
Duration of AF episodes in the first week following visit 3 (ECV visit) ....................... 52 
8.1.2.3. 
Clinical parameters evaluation ....................................................................................... 52 
8.1.2.4. 
Cardioversion assessment ............................................................................................... 53 
8.1.2.5. 
Evolution of echocardiographic parameters ................................................................... 53 
8.2. 
BIOMARKER ASSESSMENT: RED BLOOD CELL  CONCENTRATIONS OF 
DHA ..................................................................................................................................... 54 
8.2.1. 
Definition ........................................................................................................................... 54 
8.2.2. 
Blood samples ................................................................................................................... 54 
8.2.2.1. 
Collection schedule ........................................................................................................ 54 
8.2.2.2. 
Technical handling ......................................................................................................... 55 
8.2.3. 
DHA concentration measurement ..................................................................................... 55 
8.3. 
SAFETY ASSESSMENT .................................................................................................... 55 
8.3.1. 
Adverse Events .................................................................................................................. 55 
8.3.2. 
Laboratory Investigations .................................................................................................. 56 
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8.3.2.1. 
Schedule ......................................................................................................................... 56 
8.3.2.2. 
Technical Procedures and Parameters ............................................................................ 56 
8.3.3. 
Global Physical Examination ............................................................................................ 57 
8.3.4. 
Vital Signs ......................................................................................................................... 57 
8.3.4.1. 
Schedule ......................................................................................................................... 57 
8.3.4.2. 
Technical Procedure and Parameters.............................................................................. 57 
8.3.5. 
Electrocardiogram (ECG) .................................................................................................. 58 
8.3.5.1. 
Schedule ......................................................................................................................... 58 
8.3.5.2. 
Technical Procedure and Parameters.............................................................................. 58 
8.3.6. 
Coagulation parameters ..................................................................................................... 58 
8.3.7. 
Concomitant Treatments ................................................................................................... 59 
8.4. 
COMPLIANCE .................................................................................................................... 59 
9. 
STUDY PROCEDURES ....................................................................................................... 59 
10. ADVERSE EVENTS: DEFINITION AND REPORTING ............................................... 65 
10.1. ADVERSE EVENTS ........................................................................................................... 65 
10.1.1. Definition of Adverse Events ............................................................................................ 65 
10.1.2. Grading of Adverse Events ............................................................................................... 66 
10.1.3. Reporting of Adverse Events ............................................................................................ 66 
10.2. SERIOUS ADVERSE EVENTS (SAE) .............................................................................. 66 
10.2.1. Definition ........................................................................................................................... 66 
10.2.2. Reporting of SAE .............................................................................................................. 67 
10.2.3. Follow-up of SAE ............................................................................................................. 67 
10.2.4. SAE Occurring After the Study ......................................................................................... 68 
10.3. REPORTING OF OVERDOSAGE TO THE SPONSOR ................................................... 68 
10.4. REPORTING OF PREGNANCY TO THE SPONSOR ...................................................... 68 
10.5. SPONSOR'S RESPONSIBILITIES FOR SAFETY REPORTING  PURPOSES ............... 69 
11. DATA COLLECTION AND STUDY MONITORING ..................................................... 69 
11.1. DATA COLLECTION ......................................................................................................... 69 
11.1.1. Case Report Form .............................................................................................................. 69 
11.1.2. Source Documents ............................................................................................................. 70 
11.2. STUDY MONITORING ...................................................................................................... 70 
11.2.1. Monitoring visits ............................................................................................................... 70 
11.2.1.1. Site Preselection Visit .................................................................................................... 71 
11.2.1.2. Initiation Visit ................................................................................................................. 71 
11.2.1.3. Follow-up Visits ............................................................................................................. 71 
11.2.1.4. Closing Visit ................................................................................................................... 72 
11.2.2. Direct Access to Source Documents ................................................................................. 72 
11.3. INDEPENDENT DATA MONITORING COMMITTEE ................................................... 72 
12. DATA MANAGEMENT ...................................................................................................... 73 
12.1. DATA ENTRY ..................................................................................................................... 73 
12.2. DATA CLEANING ............................................................................................................. 73 
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12.3. DATA CODING .................................................................................................................. 73 
12.4. DATA STORAGE ............................................................................................................... 74 
12.5. DATABASE LOCK ............................................................................................................. 74 
13. STATISTICAL ANALYSIS ................................................................................................. 74 
13.1. GENERAL CONSIDERATIONS ........................................................................................ 74 
13.2. SAMPLE SIZE ..................................................................................................................... 75 
13.3. PROTOCOL DEVIATIONS ................................................................................................ 75 
13.4. DATA SETS ANALYSED .................................................................................................. 75 
13.5. HANDLING OF DROPOUTS AND MISSING DATA ..................................................... 76 
13.5.1. Dropouts ............................................................................................................................ 76 
13.5.2. Repositioning of Visits ...................................................................................................... 76 
13.5.3. Missing Data ...................................................................................................................... 76 
13.6. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ............................... 76 
13.7. EFFICACY ANALYSIS ...................................................................................................... 77 
13.7.1. Primary Criterion ............................................................................................................... 77 
13.7.1.1. Primary Analysis ............................................................................................................ 77 
13.7.1.2. Supportive Analysis ....................................................................................................... 77 
13.7.2. Secondary Criteria ............................................................................................................. 77 
13.7.2.1. Numbers of Atrial Fibrillation Episodes ........................................................................ 77 
13.7.2.2. Duration of Atrial Fibrillation Episodes ......................................................................... 78 
13.7.2.3. Time to first AF recurrence less than 10 minutes or symtomatic .................................. 78 
13.7.2.4. Clinical parameters evaluation ....................................................................................... 78 
13.7.2.5. Biomarker analysis: red blood cell concentrations of DHA ........................................... 78 
13.8. SAFETY ANALYSIS .......................................................................................................... 79 
13.8.1. Adverse Events .................................................................................................................. 79 
13.8.2. Clinical Laboratory Evaluation ......................................................................................... 80 
13.8.3. Global Physical Examination ............................................................................................ 82 
13.8.4. Vital Signs, Physical Findings and Other Observations Related to Safety ....................... 82 
13.8.4.1. Vital Sign Measurements Over Time ............................................................................. 82 
13.8.4.2. Body weight ................................................................................................................... 82 
13.8.4.3. Individual Patient Changes ............................................................................................. 82 
13.8.5. ECG ................................................................................................................................... 83 
13.8.6. Coagulation parameters ..................................................................................................... 83 
13.9. CONCOMITANT TREATMENTS ..................................................................................... 83 
13.10. COMPLIANCE .................................................................................................................... 83 
13.11. INTERIM ANALYSIS AND DATA MONITORING ........................................................ 84 
14. GENERAL ETHICAL CONSIDERATIONS .................................................................... 84 
14.1. ETHICAL CONDITIONS ................................................................................................... 84 
14.2. ETHICS COMMITTEE AND LEGAL REQUIREMENTS ................................................ 84 
14.3. PATIENT'S INFORMATION LEAFLET AND INFORMED CONSENT  FORM ........... 85 
14.4. PERSONAL DATA PROTECTION ................................................................................... 85 
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14.5. INSURANCE POLICY ........................................................................................................ 86 
15. ADMINISTRATIVE PROCEDURES ................................................................................ 86 
15.1. PROTOCOL AMENDMENT .............................................................................................. 86 
15.2. SOURCE DOCUMENTS, INVESTIGATOR'S FILE STORAGE ..................................... 86 
15.3. END OF THE STUDY ......................................................................................................... 87 
15.3.1. Definition of the End of Study .......................................................................................... 87 
15.3.2. Early Study Termination ................................................................................................... 87 
15.3.2.1. Early Study Termination Decided by the Sponsor ......................................................... 87 
15.3.2.2. Early Study Termination Decided by the Competent Authorities.................................. 88 
15.4. AUDIT .................................................................................................................................. 88 
15.5. INSPECTION ....................................................................................................................... 88 
15.6. CONFIDENTIALITY .......................................................................................................... 88 
15.7. CLINICAL STUDY REPORT ............................................................................................. 89 
15.8. STUDY RESULTS COMMUNICATION .......................................................................... 89 
15.9. STUDY RESULTS PUBLICATION ................................................................................... 89 
16. REFERENCES ...................................................................................................................... 91 
17. APPENDICES ....................................................................................................................... 94 
17.1. DECLARATION OF HELSINKI ........................................................................................ 95 
17.2. SAE REPORT FORM .......................................................................................................... 99 
17.3. PREDEFINED LIMITS OF LABORATORY AND VITAL SIGN POTENTIALLY 
CLINICALLY SIGNIFICANT CHANGES AND VALUES ............................................ 103 
 
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SYNOPSIS 
 
Name of Sponsor: 
Pierre Fabre Médicament represented by the Institut de Recherche Pierre Fabre (IRPF) 
Name of Finished Product: 
Not applicable 
Name of Active Substance:  
F373280 (Panthenyl-Ester of DHA) 
Title of the Study: 
Efficacy and safety study of F373280 for maintenance of sinus rhythm after electrical 
cardioversion in patients with persistent Atrial Fibrillation and Chronic Heart Failure. 
International, multicentric, randomised, double-blind, placebo controlled study 
Abbreviated Title: 
Not applicable 
Study Coordinating Investigator: 
Pr Savina NODARI 
 
Study Centres: 
International, multicentric 
Publication / Rationale: 
F373280 is a new therapy based on DHA delivery (pro-drug) developed for the maintenance 
of sinus rhythm after electrical cardioversion in persistent atrial fibrillation (AF) patients with 
chronic heart failure. 
The results of a pharmacological study performed in animals evidenced that DHA reduces the 
duration of AF induced by burst pacing.[1] 
Moreover, the effectiveness of PolyUnsaturated Fatty Acid (PUFA) has been proven in the 
following conditions: 
− 
prevention of AF recurrence in patients with persistent AF, in co-administration 
with amiodarone (add on therapy) [2]  
− 
Improvement of ventricular functional parameters, morbi-mortality and duration of 
hospitalisation in patients with heart failure [3, 4, 5] 
Taking into account these studies, it seems that DHA might be of therapeutic interest in the 
treatment of patients with both persistent atrial fibrillation and chronic heart failure. 
This phase IIa study is designed to assess the efficacy and the safety of the investigational 
product (F373280) for maintenance of sinus rhythm after electrical cardioversion (ECV) in 
patients with persistent atrial fibrillation and chronic heart failure. 
Planned Study Period: 
January 2013 –  January 2015 
Clinical Phase: IIa 
 
Objectives: 
Primary: 
- Efficacy of F373280 on the maintenance of sinus rhythm after direct electrical 
cardioversion in patients with persistent atrial fibrillation and chronic heart failure 
Secondary: 
- Efficacy of F373280 on the efficiency of direct electrical  cardioversion 
- Effect of F373280 on echocardiographic parameters 
- Safety and tolerability of F373280 
Methodology: 
- International, multicentre, randomised, double-blind, placebo-controlled 
- Selection period 
- Start of treatment 4 weeks before ECV 
• 
Condition to ECV:  
− 
INR 2-3 anti-vitamin K should be given at least 3 weeks before ECV) 
− 
No spontaneous cardioversion before ECV 
- Follow-up 20 weeks after visit 3 (ECV visit) 
• 
Condition: successful ECV or spontaneous CV 
- Cardiac monitoring: 
• 
7-days continuous ECG ambulatory recording (Holter ECG) between visit 3 (ECV 
visit) and visit 4 (week 5) in patients with sinusal rhythm 
• 
TTEM: daily transmission from week 6 to week 8; then every two days from week 
9 to week 24, and in case of AF symptoms 
- Treatment duration: 24 weeks 
Study Schedule 
9 visits will be scheduled: 
- V1/ W-4 to W-1: selection visit (7 to 28 days before the inclusion visit)  
- V2/ D1: Inclusion visit (start of treatment) 
- V3/ W4 (D28 -2/+7 days): cardioversion visit (outpatient or hospitalization according to 
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clinical practice of the centre) (installation of the Holter device) 
- V4/ W5 (D35± 2 days): follow-up visit (removing of the Holter device and installation of 
the TTEM) 
- V5/ W8 (D56± 7 days): follow-up visit 
- V6/ W12 (D84 ± 7 days): follow-up visit 
- V7/ W16 (D112 ± 7 days): follow-up visit 
- V8/ W20 (D140 ± 7 days): follow-up visit 
- V9/ W24 (D168 ± 7 days): final study visit 
 
Number of  Patients: 
76 x 2 patients  
Diagnosis and Criteria for Inclusion: 
Inclusion Criteria: 
Demographic Characteristics and Other Baseline Characteristics: 
1. 
Men or women aged more than 18 years (inclusive) 
2. 
Patients with current episode of persistent AF between 7 days and 6 months duration for 
whom electrical cardioversion is warranted 
3. 
History of first documented persistent AF less than 3 years. 
4. 
History of ischemic or non ischemic heart failure  
5. 
NYHA class I or II chronic heart failure at selection and at inclusion 
6. 
Reduced left ventricular ejection fraction between 30% and 45% inclusive (using the 
two-dimensional echocardiography biplane Simpson’s rule) at selection and at inclusion 
7. 
On appropriate, stable medical treatments for heart failure, including a diuretic and/or 
angiotensin-converting enzyme, and/or angiotensin-receptor blocker and/or 
mineralocorticoid receptor (MR) antagonists, and/or betablockers 
8. 
Left atrial area ≤ 40 cm² at selection and at inclusion 
9. 
Patients treated or having to be treated by anti-vitamin K 
10. For female patient of child-bearing potential:  
• 
in all the countries except Italy:  
- 
use of an effective method of contraception (hormonal contraception or intra-
uterine device) assessed by the investigator, for at least 2 months before the 
selection in the study, and agreement to go on using it during the whole duration of 
the study and up to 1 month after the last dose of the study treatment 
- 
documented as surgically sterilized 
 
• 
in Italy only:  
- 
absolute abstention from sexual intercourse during the whole duration of the study 
and for a month after the end of the study or 
- 
use of double barrier contraception method (use of effective medical contraception 
method) from at least 2 months before the start of the study to the entire duration of 
the study and for a month after the end of the study or 
- 
documented as surgically sterilized 
 
11. For female patient of child-bearing potential: negative urine pregnancy test at inclusion 
12. For male with a child-bearing potential partner (In Italy only): 
- 
Absolute abstention from sexual intercourse during the whole duration of the study 
and for 3 months after the end of the study or 
- 
 use of double barrier contraception method (use of condom for male and effective 
contraception method for the partner) from the entire duration of the study to 3 
months after the end of the study. 
 
 
Ethical /legal considerations: 
13. Having signed his/her written informed consent, 
14. Affiliated to a social security system, or is beneficiary (if applicable in the national 
regulation) 
 
Non-Inclusion Criteria: 
Criteria related to pathologies: 
1. 
History of first documented episode of persistent AF more than 3 years 
2. 
More than two successful cardioversions (electrical or pharmacological) in the last 6 
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months 
3. 
Secondary Atrial Fibrillation due to alcohol or severe valvular heart disease (grade III to 
IV) 
4. 
NYHA class III or IV heart failure at selection or at inclusion 
5. 
Thyroid disease uncontrolled by treatment: TSH ± T4L ± T3L to be checked in case of 
treatment for thyroid disease 
6. 
Myocardial infarction or unstable angina or presence of unstable ischemic 
coronaropathy assessed by coronarography or cardiac stress test (Echo stress, exercise 
stress test, nuclear or MR perfusion evaluation methods) within 6 months before 
selection 
7. 
Severe chronic kidney disease (creatinine ≥ 25 mg/L or estimated glomerular filtration 
rate < 30 mL/min) at selection 
8. 
Bradycardia (HR ≤ 50 bpm) 
9. 
Hyperkalemia or hypokalemia (according to the standards of local laboratories) at 
selection  
10. Cardiac surgery within 3 months before selection or planned during the study duration 
 
 
Criteria related to treatments: 
11. Previously ineffective pharmacological or electrical cardioversion 
12. Concomitant treatment with ranolazine or any antiarrhythmic drug (within 7 days prior 
to selection), except stable dose of digoxin, betablockers, calcium-blockers 
13. Oral amiodarone: 
              13a  Previous treatment with oral amiodarone within 4 months prior to inclusion 
              13b  Intake of oral amiodarone for more than 1 month within 4 to 12 months before 
inclusion 
14. Previous treatment with intravenous amiodarone within 4 weeks prior to inclusion 
15. Patient requiring a cardiac resynchronization therapy (CRT) or having undergone CRT 
implantation within the last 6 months  
16. Treatment with any Polyunsaturated Fatty Acid (PUFA) within the last 3 months 
17. Dietary supplement with ω 3 or ω 6 according to investigator’s judgement 
18. Having undergone any form of ablation therapy for AF 
19. Patient treated with other anticoagulant treatment than antivitamin K: thrombin inhibitor 
such as Dabigatran or treated with antiaggregant P2Y12 inhibitors such as Clopidogrel 
or Prasugrel 
 
Other criteria: 
20. Patient liable not to comply with protocol instructions and/or with treatment, in the 
investigator’s opinion 
21. Patient having taken part in a clinical trial in the preceding 2 months or taking part 
in a trial at the time of selection 
22. Patient linguistically or mentally unable to understand the nature, objectives and 
possible consequences of the trial, or refusing to patient himself/herself to its 
constraints 
23. Patient family member or work associate (secretary, nurse, technician,..) of the 
Investigator 
24. Patient having forfeited his / her freedom by administrative or legal award or being 
under guardianship 
25. Breastfeeding female patient 
 
Exclusion criteria before V3: 
Patients not stabilized for INR (i.e. values not between 2 and 3) on at least 3 consecutive 
weekly tests performed before ECV will be excluded from the study, unless the presence of 
atrial thrombosis may be excluded with ECHO –TE (trans-esophageal echocardiograph) 
performed  in the same day (before ECV) 
ECV will be performed in patients without dyskalemia 
If necessary for obtaining stabilized INR between 2 and 3, the ECV (and following visits) 
could be postponed by 7 days. 
Test Product:  
F373280  
Soft Capsules  
Dose: 
Arm with 1g of F373280 
Mode of Administration: 
Oral, one capsule each evening with dinner. 
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Duration of Treatment: 
24 weeks of treatment exposure with F373280 (25 weeks if ECV postponed by 1 week) 
Reference Therapy 
Placebo soft capsules 
Placebo will be administered in the same conditions as the tested product. 
Mode of Administration: 
Oral, one capsule each evening with dinner 
Evaluation Criteria: 
Efficacy evaluation variables: 
 
Primary evaluation variable: 
- Time to first Atrial Fibrillation recurrence defined by the first episode of AF lasting for at 
least 10 minutes (Follow up of 20 weeks after visit 3 (ECV visit). 
Handling of AF recurrences: 7-day continuous ECG (5-leads/2 or 3 channels) ambulatory 
recording (holter ECG) between visit 3 (ECV visit) and visit 4 (week 5). Then, the follow 
up will be documented using the TTEM: daily transmission from week 6 to week 8. Then, 
every two days from week 9 to week 24. 
For randomised patients with spontaneous cardioversion before ECV, the recurrence of AF 
will be assessed after visit 3 (week 5).  
Moreover, during this TTEM period, if patient experiences any AF symptoms, it should be 
recorded and documented using the TTEM.  
All ECG traces will be evaluated by a Central Reading Laboratory. 
 
Secondary evaluation variables: 
During the 7-day continuous ECG monitoring, 
• 
Numbers of AF episodes 
• 
Duration of AF episodes 
 
Clinical parameters: 
During the whole study: 
• 
Number of recurrence of symptomatic AF episodes 
• 
EHRA score 
• 
Hospitalization for cardiovascular events 
• 
Hospitalization for thromboembolic stroke 
• 
All causes of hospitalization 
 
Cardioversion: 
• 
Assessment of spontaneous cardioversion 
• 
Assessment of successful cardioversion 
• 
Number of patients needing an other cardioversion after the initial ECV 
 
Other: 
• 
Evolution of echocardiographic parameters (from V4 to V6 and V9) (Left atrial 
diameter (mm), Left atrial area (cm²), Left atrial volume (mL), Left atrial 
volume/BSA (mL/m2), Left ventricular ejection fraction (%), Left ventricular end 
diastolic volume/BSA (mL/m2), Left ventricular end systolic volume/BSA(mL/m2), 
Left ventricular end diastolic diameter (mm), Left ventricular end diastolic volume 
(mL) Left ventricular end systolic diameter (mm), Left ventricular end systolic 
volume (mL)) 
• 
Evolution of omega 3 index and intra erythrocyte DHA (For this assessment 
samples will be centralized). 
 
Safety criteria: 
- Adverse events (observed and / or spontaneously reported) 
- Vital signs (Blood pressure (supine and standing), heart rate 
- Physical examination (body weight)  
- Standard 12-lead ECG: heart rate (bpm), PR (ms), QRS (ms), QT (ms), repolarisation 
patterns (ECG not centralized) 
- Haematology: haematocrit, haemoglobin, red blood cell (RBC) count, white blood cell 
(WBC) count, WBC differential count, reticulocytes, platelets 
- Biochemistry: sodium, potassium, bicarbonate, chloride, alkaline phosphatase, gamma 
GT, albumin, total bilirubin, conjugated bilirubin, creatinin, aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), fasting glucose, total cholesterol, cholesterol 
(HDL, LDL), triglycerides, creatin phosphokinase (CPK) fibrinogen (local laboratory) 
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- Coagulation parameters: Activated partial thromboplastin time (aPTT), thrombin clotting 
time (TCT), INR (local laboratory), Prothrombine Time (PT) 
Statistical Methods: 
Sample Size: 
Assuming an AF recurrence rate under placebo of 85%, a power of 80%, an alpha risk of 5% 
and a rate of not assessable patients of 15%, 76 randomised patients per group will be 
necessary, using a log-rank test of survival curves, a difference between groups of 20%.  
Primary Efficacy Analysis 
The primary analysis, performed on the Full Analysis Set (FAS: all randomised patients with 
at least one dose of treatment and with a successful cardioversion observed at visit 3), will be 
a survival analysis using the Kaplan Meier method and Cox regression model. 
Secondary Analyses  
All secondary efficacy criteria will be described and compared using appropriate tests on the 
FAS. 
Safety Analyses 
Descriptive statistics will be performed on the Safety Set (all randomised patients with at 
least one dose of treatment).  
 
 
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STUDY FLOW-CHART 
F373280 CA 201 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
Weeks 
W-4 to W-1 
D1 
W4 
(28 -2D/+7 D) 
W5 
(35 -2D/+7 D) 
W8 
(56+/-7D) 
W12 
(84+/-7D) 
W16 
(112+/-7D) 
W20 
(140+/-7D)  
W24 
(168+/-7D) 
  
  
  
  
  
  
  
  
  
  
Outpatient or Hospitalization (1) 
  
  
X 
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
  
  
  
  
  
  
  
  
Demographic characteristics 
X 
  
  
  
  
  
  
  
  
Medico-surgical history 
X 
  
  
  
  
  
  
  
  
Concomitant disease 
X 
  
  
  
  
  
  
  
  
Concomitant treatment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Habits 
X 
  
  
  
  
  
  
  
  
Global physical examination (body weight) 
X 
X 
X 
 
X 
X 
X 
X 
X 
Echocardiography 
X 
X 
  
X 
  
X 
  
  
X 
Eligibility criteria check 
X 
X 
  
  
  
  
  
  
  
Blood pressure, heart rate  
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead  ECG Recording 
X 
X 
X 
  
X 
X 
X 
X 
X 
INR  
 
 
                     (2) 
  
X 
X 
X 
X 
X 
aPTT, TCT  
X 
X 
X 
  
X 
X 
X 
X 
X 
Biochemistry 
X 
  
  
  
  
  
  
  
X 
Hematology 
X 
  
X 
  
  
X 
  
  
X 
Urinary pregnancy test 
  
X 
  
  
  
  
  
  
X 
Red Blood Cell concentrations of DHA  
  
X 
X 
  
  
X 
  
  
X 
Treatment allocation 
  
X 
  
  
  
X 
  
  
  
IVRS/IWRS 
X 
X 
  
  
 
X 
  
  
  
ECV (3) 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Drug administration  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Adverse events recording 
  
X 
X 
X 
X 
X 
X 
X 
X 
Holter ECG 
                (4) 
  
 
                (5) 
 
 
 
 
 
TTEM (6) 
  
  
 
 
 
  
  
  
  
(1) Outpatient or hospitalization according to clinical practice of the centre (less or more than 24 hours) 
(2) In case of AVK introduction: INR 2 to 3 times a week, then weekly until the ECV, then every 4 weeks after ECV 
(3) In patients with AF 
(4) 24-hour Holter ECG 
(5) 7-day Holter ECG 
(6) TTEM: everyday from week 6 to week 8;. then every 2 days from week 9 to week 24; at any time in case of AF symptoms. 
In case of AF recurrence for at least 10 minutes and if the patient does not stop the study treatment, then TTEM once a week 
 
 
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LIST OF ABBREVIATIONS 
 
aPTT 
: 
Activated partial thromboplastin time 
AE 
: 
Adverse event 
AF 
: 
Atrial fibrillation 
ALA 
: 
Alpha-linoleic acid 
ALT 
: 
Alanine aminotransferase 
AST 
: 
Aspartate aminotransferase 
AUC 
: 
Area under the plasma concentration versus time curve 
AUCinf 
: 
Total area under the curve extrapolated to infinity 
AVK 
: 
Anti-vitamin K 
βHCG 
: 
beta human chorionic gonadotrophin 
BLQ 
: 
Below the limit of quantification 
BMI 
: 
Body mass index 
BP 
: 
Blood pressure 
BSA 
: 
Body Surface Area 
CEP 
: 
Protocol evaluation committee 
CHMP 
: 
Committee for medicinal products for human use 
Cmax 
: 
Maximum concentration 
Cmin 
: 
Minimum concentration 
CNALV 
: 
Clinically noteworthy abnormal laboratory value 
CPK 
: 
Creatin phosphokinase 
CPP 
: 
Comité de protection des personnes  
CRA 
: 
Clinical research associate 
CRT 
: 
Cardiac resynchronization therapy 
CSC 
: 
“Clinically Significant Change”, i.e., Predefined potentially clinically significant 
change leading to a potentially clinically significant value (vital signs) 
CV 
: 
Coefficient of variation 
DBP 
: 
Diastolic blood pressure 
DHA 
: 
Docosahexaenoic acid 
EC 
: 
Ethics committee 
ECG 
: 
Electrocardiogram 
ECHO –TE : 
Trans-esophageal echocardiograph 
ECV 
: 
Electrical cardioversion 
EHRA 
: 
European heart rhythm association 
EPA 
: 
Eicosapentaenoic acid 
e-CRF 
: 
Electronic case report form 
FAS 
: 
Full analysis set 
Fe 
: 
Fraction of the administered drug excreted in urine 
GCP 
: 
Good clinical practice 
GFR 
:  Glomerular Filtration Rate 
HBs 
: 
Hepatitis B antigen 
HCV 
: 
Hepatitis C virus 
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HDL 
: 
High density lipoprotein 
HF 
: 
Heart failure 
HIV 
: 
Human immunodeficiency virus 
HR 
: 
Heart rate 
ICH 
: 
International conference on harmonisation of technical requirements for 
registration of pharmaceuticals for human use 
IDMC 
: 
Independent data monitoring committee 
INR 
: 
International normalized ratio 
IRPF 
: 
Institut de Recherche Pierre Fabre 
IVRS 
: 
Interactive voice response system 
LAA 
: 
Left atrial area 
LC/MS-MS : 
Liquid chromatography with tandem mass spectrometry 
LDL 
: 
Low density lipoprotein 
LOQ 
: 
Limit of quantification 
LVEF 
: 
Left ventricular ejection fraction 
MedDRA 
: 
Medical dictionary for regulatory activities 
MR 
: 
Mineralocorticoid receptor 
MR perfusion : 
Magnetic Resonance perfusion 
MTD 
: 
Maximum tolerated dose 
N 
: 
Number of determinations or replicates 
NOAEL 
: 
No observed adverse effect level 
NYHA 
: 
New York heart association 
od 
: 
Once a day 
PC 
: 
“Predefined Change”, i.e., Predefined potentially clinically significant change (lab 
or vital signs) 
PCA 
: 
PC leading to an out-of-range value (lab values) 
PFB 
: 
Pierre Fabre Biométrie 
PSC 
: 
Potentially Clinically Significant Change 
PSCV 
: 
Potentially Clinically Significant Value 
PUFA 
: 
PolyUnsaturated fatty acid 
p.o. 
: 
Per os 
PP 
: 
Per protocol data set 
RBC 
: 
Red blood cells 
SAE 
: 
Serious adverse event 
SBP 
: 
Systolic blood pressure 
SD 
: 
Standard deviation 
T1/2 
: 
Terminal half-life 
T0 
: 
Time of drug administration 
Tmax 
: 
Time to reach the maximal concentration 
TCT 
: 
Thrombin clotting time 
TEAEs 
: 
Treatment emergent adverse events 
TTEM 
: 
TransTelephonic ECG monitoring 
WBC 
: 
White blood cells 
WHO-DRUG : 
World health organization drug reference list 
 
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1. INTRODUCTION AND STUDY RATIONALE 
1.1. 
TARGET PATHOLOGY AND THERAPY 
Atrial Fibrillation (AF) is a supraventricular arrhythmia characterized by uncoordinated atrial 
electric activity with consequent deterioration of atrial mechanical function. It is the most 
common sustained cardiac rhythm disorder, increasing in prevalence with age. Haemodynamic 
impairment and thromboembolic events related to AF result in significant morbidity and mortality 
[7]. 
In 2009, Decision Resources estimated that there were 7.8 million diagnosed prevalent cases of 
AF in US, Europe and Japan. This age-related pathology should increase to 9.4 million cases in 
2019.  
Except for the conventional class I and class III anti-arrhythmic agents, the Polyunsaturated Fatty 
Acids (PUFAs) constitute one emerging antiarrhythmic therapy. These compounds potently 
address the AF substrate by directly targeting both the electrical and the structural remodelling of 
the deficient atria. The n-3 PUFAs, essential for human, are alpha-linoleic acid (ALA), 
eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). First, PUFAs specifically 
modulate ionic channels by fastening their inactivating mode which renders these compounds 
selective for pathological situations (such as AF) without any major effect in normal conditions. 
PUFAs are “open Kv1.5 channel blockers” leading to a lengthening of atrial action potential 
duration and are “persistent Nav1.5 channel blockers” leading to hyperpolarization of diastolic 
resting potential. Second, PUFAs influence structural remodelling through their anti-inflammatory 
effects as they directly compete with arachidonic acid in the production of inflammatory 
eicosanoids. In summary, PUFAs share unique, well-tolerated antiarrhythmic potential by 
interacting with the electrical and structural remodelling during sustained AF. In animal studies, it 
was recently demonstrated that DHA is particularly effective in pathologic conditions such as 
ischemia and/or AF. 
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The potential anti-arrythmic effects of a PUFA were previously developed in AF: nicotinyl ester 
of DHA (pro-drug based on DHA delivery) was assessed in a two-week ventricular tachypaced 
canine model. Dogs were subjected to 4 weeks of medication prior to undergoing an 
electrophysiology study, and received either placebo or nicotinyl ester of DHA. Dogs were 
tachypaced at 240 beats per min for the final two weeks of the treatment plan. The results showed 
that the tested PUFA reduced the duration of AF induced by burst pacing, and the incidence of 
sustained AF, compared to dogs treated with the placebo [1]. 
In clinical practice, Nodari and coll [2] assessed n-3 PUFAs in the prevention of AF recurrences 
after electrical cardioversion (ECV). All included patients were treated with amiodarone and a 
renin-angiotensin-aldosterone system inhibitor. The 199 patients were assigned either to placebo 
or n-3 PUFAs 2 g/d and then underwent direct ECV 4 weeks later. The primary end point was the 
maintenance of sinus rhythm at 1 year after cardioversion. At the 1-year follow up, the 
maintenance of sinus rhythm was significantly higher in the n-3 PUFAs treated patients compared 
with the placebo group (hazard ratio, 0.62 [95% confidence interval, 0.52 to 0.72] and 0.36 [95% 
confidence interval, 0.26 to 0.46], respectively; p = 0.0001). The study concludes that in patients 
with persistent AF on amiodarone and a renin-angiotensin-aldosterone system inhibitor, the 
addition of n-3 PUFAs 2 g/d improves the probability of the maintenance of sinus rhythm after 
direct current cardioversion. Previously, during the World Congress of Cardiology in 2006, an 
abstract reported the effectiveness of PUFAs on top of traditional treatment (amiodarone, beta 
blockers, renin-angiotensin-aldosterone system inhibitor) in the prevention of AF relapses in 
patients having undergone ECV. In the PUFA group, AF relapses were significantly lower than in 
the placebo group at 1 month (3.3% vs 10%; p = 0.043), at 3 months (10% vs 25%; p = 0.004) and 
at 6 months (13.3% vs 40%; p < 0.0001) [19]. 
In contrast, in the general AF population (paroxystic atrial fibrillation and persistent atrial 
fibrillation), PUFAs failed to prove their efficacy [7] because of the absence of cardiac 
remodelling or because of a short pre-treatment duration before ECV (1 week) [8]. The effects of 
PUFAs were only observed in patients with persistent AF on add on therapy and after a sufficient 
pre-treatment before ECV. Persistent AF is commonly associated to heart failure. Previous studies 
performed in heart failure population demonstrated the benefit of PUFAs on the improvement of 
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functional ventricular parameters and morbi-mortality, and on the reduction of hospitalisation [3, 
4, 5]. 
Nodari and coll [3] performed a trial in patients with chronic heart failure (NYHA I to III and 
LVEF< 45%). After a treatment of 133 patients with PUFAs (n=67) or placebo (n=66) at a dosage 
of 5 g/day for 1 month, then 2 g/day for 11 months, the n-3 PUFAs group and the placebo group 
differed significantly (p <0.001) in regard to:  
− LVEF (increased by 10.4% and decreased by 5.0%, respectively) 
− peak VO2 (increased by 6.2% and decreased by 4.5%, respectively) 
− exercise duration (increased by 7.5% and decreased by 4.8%, respectively) 
− mean New York Heart Association functional class (decreased from 1.88+/- 0.33 to 1.61 
+/- 0.49 and increased from 1.83+/- 0.38 to 2.14 +/- 0.65, respectively).  
The hospitalization rates for patients with HF were 6% in the n-3 PUFAs and 30% in the placebo 
group (p <0.0002). 
Moertl and coll [4] performed a dose-ranging study in patients with a more severe chronic heart 
failure (NYHA III and IV and LVEF < 35%). It was a double-blind, randomised, controlled pilot 
trial in 43 patients treated with PUFAs or placebo for 3 months (1 g/d n3-PUFA (n = 14), 4 g/d 
n3-PUFA (n = 13), or placebo (n = 16)). After treatment, left ventricular ejection fraction 
increased in a dose-dependent manner (p = 0.01 for linear trend) in the 4 g/d (baseline vs 3 
months [mean ± SD]: 24% ± 7% vs 29% ± 8%, p = 0.005) and 1 g/d treatment groups (24% ± 8% 
vs 27% ± 8%, p = 0.02). 
No changes in any investigated parameters were noted with placebo. 
Taking into account these studies performed with PUFAs, it seems that the best target for DHA is 
persistent AF in patients with heart failure. The aim of this proof of concept study is to assess in 
stand alone therapy (without association of other anti-arrhythmic treatments), the effect of 
F373280 in patients with persistent AF and heart failure in the maintenance of sinus rhythm after 
ECV. 
1.2. 
INFORMATION ON THE TEST PRODUCT 
F373280 or panthenyl ester of DHA is the mono-ester of panthotenic alcohol and DHA, selected 
to be developed for the management of AF.  
F373280 is a prodrug of DHA. 
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A brief summary of F373280 known characteristics is presented in this section. For further details, 
please refer to the F373280 Investigator’s Brochure. [1] 
1.2.1. 
Chemical and pharmaceutical characteristics 
1.2.1.1. 
Nomenclature and structure 
Chemical name (IUPAC):  
(4Z,7Z,10Z,13Z,16Z,19Z)-3-((R)-2,4-dihydroxy-3,3-diméthylbutanamido) 
propyl 
docosa-
4,7,10,13,16,19-hexaenoate 
Structural formula: 
O
O
O
O
NNHH
O
O
OHH
O
OHH
 
Laboratory code: F373280 
Molecular formula: C31H49NO5 
Molecular mass: 515.7 
1.2.1.2. 
Physical and chemical general properties 
Appearance: Clear oily viscous liquid 
Solubilities:  
− Water: Practically insoluble 
− Alcohol: Very soluble  
− Trimethylpentane: Slightly soluble  
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1.2.2. 
Non-clinical Data 
Non-clinical data are exhaustively detailed in the Investigator’s brochure [1]. A brief summary is 
provided below. 
1.2.2.1. 
Pharmacological profile 
F373280 (mono-ester of panthotenic alcohol and DHA) is a novel pro-drug of DHA which exerts 
antiarrhythmic properties by interacting with the electrical and structural remodelling of the atria.  
Experimental investigations were conducted in HEK293 cell line transfected with human Kv1.5 
channel using the whole cell patch clamp technique to evaluate whether F373280 could block the 
sustained component of IKv1.5. F373280 concentration-dependently reduced Kv1.5 channel activity 
with an IC50 value of 13.7 µM. 
The effects of F373280 on atrial effective refractory period were investigated in anesthetized pig 
using a conventional pacing protocol through epicardial electrodes placed on the left atrium. 
F373280 administered as a bolus and an infusion (10 mg/kg) significantly increased atrial 
effective refractory period (23.8 ± 2.2 ms versus -7.3 ± 11.5 ms in the presence of vehicle, p < 
0.05). In addition, F373280 was devoid of significant effect on the hemodynamic and the 
electrocardiogram (ECG) intervals.  
Proof of the pharmacological concept was performed with a different DHA derivative named: 
Nicotinyl ester of DHA (pro-drug based on DHA delivery). Ventricular tachypacing-induced 
congestive heart failure provides a clinically-relevant animal model of AF associated with 
structural remodelling, as is often seen clinically. It has been shown that sustained oral PUFA 
administration suppresses congestive heart failure-induced AF-promotion and fibrosis in the 
ventricular tachypacing canine model. Nicotinyl ester of DHA was tested in this model, at 1 g/day 
and 5 g/day, during 4 weeks, to prevent congestive heart failure-related atrial structural 
remodelling and AF promotion in dogs. Nicotinyl ester of DHA dose dependently reduced heart 
failure-induced increases in AF duration (989 ± 111 sec, n=5 in the presence of placebo versus 
637 ± 196 sec, n=5 in the presence of 1 g/kg/d Nicotinyl ester of DHA and 79 ± 51 sec, n=5, in 
the presence of 5 g/kg/d Nicotinyl ester of DHA). The protective effect of Nicotinyl ester of DHA 
was associated with a marked increase of plasma level of DHA and important incorporation of 
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DHA in the left atrial tissue. Because F373280 similarly to Nicotinyl ester of DHA increases 
plasma level of DHA, it could be estimated that the compound may exert a similar protective 
effect [1]. 
1.2.2.2. 
Safety pharmacology 
A battery of safety pharmacology studies was performed to evaluate the effects of F373280 on the 
central nervous, cardiovascular and respiratory systems. Data of these studies are exhaustively 
detailed in the Investigator’s brochure [1]. 
No particular alerts were evidenced with F373280. 
1.2.2.3. 
Toxicology profile 
 
Concerning the toxicological data, 4-week and 26-week repeat-dose studies in rat and dog were 
performed. Compared to the high administered doses of F373280 (500 to 2000 mg/kg/day), low 
circulating concentrations of F373280 were measured.  
During these toxicity studies, no toxicity was observed in rat after 4 and 26 weeks of dosing and 
in dog after 4 weeks of dosing. A NOAEL of 2000 mg/kg/day was established in these repeat 
toxicity studies.  
During the 26-week toxicity study in dogs, the NOAEL was set at 1000 mg/kg/day based on 
changes observed on red blood cell parameters. 
Based on toxicological profiles, F373280 is considered to support the proposed clinical trial. 
 
1.2.2.4. 
Pharmacokinetic data  
According to animal studies described in the Investigator’s brochure [1], the non-clinical 
pharmacokinetic profile of F373280 is not associated with particular alerts concerning the 
proposed clinical phase IIa study. 
1.2.3. 
Clinical data 
Part A: single dose 
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Six consecutive single ascending doses were tested (0.5 g, 1 g, 2 g, 4 g, 8 g and 16 g) on 6 
independent cohorts of 8 subjects (6 verum + 2 placebo). 49 subjects were treated and 48 
completed the study. 
No Serious Adverse Events (SAE) occurred in the course of the study. 
Regarding the reported Treatment Emergent Adverse Events (TEAEs) that were judged by the 
Investigator as having a causal relationship with the study drug administration in the absence of 
an alternative explanation, 3 TEAEs were observed in the placebo group (palpitation, dizziness in 
standing position, symptomatic orthostatic hypotension without loss of consciousness) and 4 in 
the group of F373280 at the dosage of 16 g (meteorism, liquid stool, symptomatic orthostatic 
hypotension and dizziness in standing position). None of these adverse events (AE) were reported 
in the groups of F373280 at the dosages of 0.5 g, 1 g, 2 g, 4 g and 8 g. 
After a single administration of the different tested doses no difference between the tested product 
and placebo has been reported, regarding vital signs (heart rate, systolic blood pressure and 
diastolic blood pressure), biological parameters (related to coagulation: platelets and fibrinogen) 
and coagulation parameters (bleeding time, prothrombin time/INR, activated partial 
thromboplastin time, thrombin clotting time). Variations of these parameters were within the 
physiological ranges. 
After single oral administration of F373280 from 0.5 g to 16 g in 36 young healthy male subjects 
(6 per dose level), the following was observed: 
 
- F373280: Whatever the tested dose there is no circulating F373280 in plasma: only few, 
sparse and non consecutive samples with quantifiable level of F373280 close to LOQ were 
observed. This confirms that F373280 is a prodrug. 
- Panthenol: Cmax and AUC increased with the administered dose between 0.5 and 16 g. 
Panthenol concentrations were rapidly cleared from plasma with a mean terminal half-life 
around 2 hours. 
- DHA: after 0.5 and 1 g, low increased in DHA plasma concentrations compared to the 
baseline levels led to a high inter-individual variability of the corresponding 
Pharmacokinetics parameters. Plasma exposure in DHA increased with the administered dose 
between 2 and 16 g with no departure from proportionality (baseline corrected parameters). 
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Part B: Multiple doses  
Three consecutive repeated ascending doses (1, 2 and 4 g) were tested on 3 independent cohorts of 
12 subjects (9 verum + 3 placebo, double blind). 36 subjects completed the study. Each treatment 
was administered over a period of 28 days. Pharmacokinetic parameters were assessed over a 
period of 14 days.  
Among the TEAE judged by the investigator as suspected to F373280, 5/9 TEAEs were classified 
according the System Organ Class in vascular system disorder with orthostatic hypotension (2 in 
the 1 g group, 1 in the 2 g group and 2 in the 4 g group) and 4/9 were classified in nervous system 
disorder with 3 dizziness (2 in the 2 g group and 1 in the 4 g group) and 1 migraine (in the 1 g 
group). These TEAEs have already been reported with PUFAs and are commonly observed in 
phase I studies. 
After a repeated administration of the different tested doses, no difference between the tested 
products and placebo was reported regarding vital signs (heart rate, systolic blood pressure and 
diastolic blood pressure), biological parameters. The assessment of coagulation parameters and 
platelet function after administration of repeated dose of F373280 did not report any bleeding 
issue. The reported changes in coagulation parameters and platelet function were within 
physiological ranges. 
After a 14-day repeated oral administration of F373280 from 1 g to 4 g, the following was 
observed: 
 Panthenol: Cmax and AUC increased with the administered dose between 1 and 4 g. No 
accumulation of panthenol in plasma was observed. 
 
 DHA: Plasma exposure increased with dose. A 2-fold accumulation in total plasma exposure 
of DHA was observed after 14 days of administration, whatever the administered dose. 
 
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1.3. 
STUDY RATIONALE 
F373280 is a new therapy based on DHA delivery (pro-drug) developed for the maintenance of 
sinus rhythm after ECV in persistent AF patients with chronic heart failure. 
The results of a pharmacological study performed in animals evidenced that DHA reduces the 
duration of AF induced by burst pacing [1]. 
Moreover, the effectiveness of PUFAs has been proven in the following conditions: 
- 
Prevention of AF recurrence in patients with persistent AF in co-administration with 
amiodarone (add on therapy) [2], 
- 
Improvement of ventricular functional parameters, morbi-mortality and duration of 
hospitalisation in patients with heart failure [3, 4, 5]. 
Taking into account these studies, it seems that DHA might be of therapeutic interest in the 
treatment of patients with both persistent AF and chronic heart failure. 
This phase IIa study is designed to assess the efficacy and the safety of the investigational product 
(F373280) for maintenance of sinus rhythm after ECV in patients with persistent AF and chronic 
heart failure. 
1.4. 
OVERALL RISK AND BENEFIT ASSESSMENT 
F373280 is a new pro-drug of DHA.  
DHA is a well-known long chain PUFAs with a long-term clinical experience in cardiovascular 
diseases. DHA is contained in several medicinal products such as Omacor, (1 g of Omacor 
contains about 320 mg of DHA acid) marketed by Laboratoires Pierre Fabre for 
hypertriglyceridemia and as an adjuvant treatment for secondary prevention after myocardial 
infarction. According to the summary product characteristics of Omacor [9]: 
 
- The frequencies of adverse reactions are ranked according to the following: common 
(>1/100, <1/10); uncommon (>1/1000, <1/100); rare (>1/10000, <1/1000); very rare (<1/10000), 
not known (cannot be estimated from the available data). 
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- The reported adverse events are: 
• Infection and infestations: 
Uncommon: gastroenteritis 
• Immune system disorders: 
Uncommon: hypersensitivity 
• Metabolism and nutrition disorders: 
Rare: hyperglycaemia 
• Nervous system disorders: 
Uncommon: dizziness, dysgeusia 
Rare: headache 
• Vascular disorders: 
Very rare: hypotension 
• Respiratory thoracic and mediastinal disorders:  
Very rare: nasal dryness 
• Gastrointestinal disorders: 
Common: dyspepsia, nausea 
Uncommon: abdominal pain, gastrointestinal disorders, gastritis, abdominal pain upper 
Rare: gastrointestinal pain 
Very rare: lower gastrointestinal haemorrhage 
• Hepatobiliary disorders:  
Rare: hepatic disorders  
• Skin and subcutaneous tissue disorders:  
Rare: acne, rash pruritic 
Very rare: urticaria 
• General disorders and administration site conditions: 
Rare: malaise sensation 
• Investigations: 
Very rare: white blood count increased, blood lactate dehydrogenase increased 
Moderate elevation of transaminases has been reported in patients with hypertriglyceridaemia. 
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Panthenol is a well-known substance with a long-term experience in medical, nutraceutic and 
cosmetic uses. According to the summary product characteristics of a product such as 
Bépanthene (tablet indicated in alopecia) which contains panthenol (100 mg), adverse event 
observed are rare cases of urticaria and erythema [10]. Panthenol is metabolised in panthotenic 
acid, i.e. B5 vitamin. 
Concerning toxicological studies performed results can support the administration of F373280 in 
the proposed clinical phase II study without particular alert [1]. 
Any safety warning was reported during a phase I study performed with F373280 administered to 
84 healthy volunteers in single dose in a range between 500 mg and 16 g or in repeated dose 
during 28 days in a range between 1 g and 4 g. Adverse events reported and related to study 
treatment were minor to moderate. The adverse events were palpitations, orthostatic hypotension, 
dizziness, meteorism and liquid stool. Most were reported in both groups (placebo and F373280) 
without a dose relationship. The assessment of coagulation parameters and platelet function after 
administration of repeated dose of F373280 did not report any bleeding concern: the reported 
changes in coagulation parameters and platelet function were within physiological ranges. 
Moreover, DHA has been associated with anticoagulant products in AF studies [2, 8]. The range 
of PUFAs doses tested was between 2 g to 3 g (640 mg to 960 mg of DHA) and the range of study 
durations between 6 to 12 months. This association did not report a significant side effect of 
bleeding. 
DHA has already been used in HF patients in several studies without safety concern [3, 4, 5]. The 
range of PUFAs doses tested was between 1 g to 5 g (1 g of the tested PUFAs contains about 320 
mg of DHA acid) and the range of study durations was between 3 months to 3.9 years. 
Thus, inclusion of patients with no specific antiarrhythmic treatment is acceptable. They will 
receive an anticoagulant treatment to prevent the thrombo-embolic complications of AF 
(particularly stroke) and the adequate treatments to control the heart rate and heart failure.   
In conclusion, the overall available data allow in safe conditions the treatment of patients with 
persistent AF and chronic heart failure with F373280 in safe conditions. 
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2. STUDY OBJECTIVES 
2.1. 
PRIMARY OBJECTIVE 
The primary objective of the study is to assess the efficacy of F373280 on the maintenance of 
sinus rhythm after direct ECV in patients with persistent AF and chronic heart failure. 
2.2. 
SECONDARY OBJECTIVES 
The secondary objectives of the study are to assess: 
• the efficacy of F373280 on the efficiency of direct ECV 
• the effect of F373280 on echocardiographic parameters 
• the safety and tolerability of F373280 
3. ETHICAL CONSIDERATIONS RELATING TO THE STUDY 
The trial is conducted according to Good Clinical Practices (CPMP/ICH/135/95), the National 
regulations and the Declaration of Helsinki and its subsequent amendments (see Appendix 17.1). 
This protocol and the informed consent form will be submitted for approval to independent local 
or national Institutional Review Boards/Ethics Committees before the study set up, according to 
national regulation. 
All the protocol amendments or critical events liable to increase the risks incurred by the patients 
or to compromise the validity of the study or patients' rights will be submitted to the coordinator 
and to the Ethics Committees. 
After being informed orally and in writing of all potential risks and constraints of the trial, as well 
as their freedom to withdraw their participation at any time, patients will then sign a consent form.  
A time of reflection will be given to the patients, before giving a written consent and starting the 
study procedures. 
The use of a placebo is in accordance with EMA Addendum to the guideline on antiarrhythmics 
on AF and atrial flutter (EMA/CHMP/EWP/213056/2010) [21] and is acceptable because the 
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included patients will remain under the standard treatment of AF and chronic heart failure. Except 
antiarrythmics, they will receive anticoagulant (anti-vitamin K), rate control treatment, chronic 
heart failure treatment. During the study, in case of AF recurrence that would require 
cardioversion or the introduction of an anti-arrhythmic because of intolerable and/or 
uncomfortable clinical symptoms for instance, patients will be withdrawn and the tested product 
stopped. These patients will be considered as treatment failure. 
In this study, patients will be carefully screened, particularly for their cardiac condition, with 
ECG, 24-hour holter monitor and echocardiographic data, and their biologic and coagulation 
condition. 
The study will be addressed only to patients requiring an ECV due to their persistent AF, in the 
following conditions: 
- 
ECV in patients not presenting a contra-indication 
- 
Anticoagulation with anti-vitamin K (AVK) for at least 3 weeks before ECV 
- 
ECV in patients with stabilized INR (i.e. values between 2 and 3;sp to ) on at least 3 
consecutive weekly tests performed. Patients not stabilized for INR (i.e. values not 
between 2 and 3) on at least 3 consecutive weekly tests performed before ECV will be 
excluded from the study, unless the presence of atrial thrombosis may be excluded 
with ECHO –TE (trans-esophageal echocardiograph) performed in the same day 
(before ECV). Patients who do not revert to sinus rhythm or present an early relapse 
within the observation period after ECV will be withdrawn and the tested product 
stopped. 
During the whole study, patients will remain under medical control: visits in cardiology units will 
be scheduled at least every month. This follow up will include clinical signs, ECG, biological and 
coagulation parameters. Moreover, patient’s cardiac rhythm will be monitored between visits 
using daily, then every 2 days Trans Telephonic ECG Monitoring (TTEM) reviewed by a Central 
Reading Laboratory. 
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Patients may withdraw from the study at any time without having to give a reason and can expect 
to receive regular conventional therapy. 
4. STUDY DESIGN 
4.1. 
OVERALL DESCRIPTION 
This phase IIa trial will be conducted as an international, multicentric, 24 weeks, double-blind, 
placebo-controlled, randomised, parallel group design, trial in 152 patients suffering from 
persistent AF and chronic heart failure. 
After a 1 to 4-week of run-in period without treatment, patients will be randomised into one of the 
following treatment groups: F373280 1 g or placebo for 24 weeks.  
Nine visits are planned for the study: 
- 
Visit 1 (V1): W-4 to W-1: Selection visit (7 to 28 days before the Inclusion Visit) 
- 
Visit 2 (V2): D1: Inclusion visit (start of treatment)  
- 
Visit 3 (V3): W4 (D28 -2/+7D): cardioversion visit (outpatient or hospitalization 
according to clinical practice of the centre) (installation of the Holter ECG device) 
- 
Visit 4 (V4): W5 (D35 -2/+7D): follow-up visit (removing of Holter ECG device and 
installation of the TTEM) 
- 
Visit 5 (V5): W8 (D56 ± 7D): follow-up visit 
- 
Visit 6 (V6): W12 (D84 ± 7D): follow-up visit 
- 
Visit 7 (V7): W16 (D112 ± 7D) : follow-up visit 
- 
Visit 8 (V8): W20 (D140 ± 7D): follow-up visit 
- 
Visit 9 (V9): W24 (D168 ± 7D): final study visit 
4.2. 
DISCUSSION OF THE STUDY DESIGN 
4.2.1. 
Choice of the Study Population 
The target indication of F373280 will be the maintenance of sinus rhythm after cardioversion of 
patients with persistent AF and chronic heart failure. In the present proof of concept study, the 
evaluation will focus on patients within this indication. This target population is justified by: 
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− The proved efficacy of PUFAs in patients with persistent AF with or without heart failure 
in co-administration with amiodarone (add on therapy) [2] 
− The proved efficacy of PUFAs on the improvement of ventricular functional parameters, 
morbi-mortality and duration of hospitalisation in patients with heart failure [3, 4, 5] 
The study aim is to investigate the product effect in patients with: 
− Persistent AF history (less than three years) with a duration of the current episode from 7 
days to 6 months. 
− a moderately abnormal systolic heart failure (Left Ventricular Ejection Fraction (LVEF) 
between 30 to 45% as defined in the report from the American Society of 
Echocardiography’s Guideline). According to a sub-group analysis performed in patients 
with persistent AF associated to heart failure (Nodari S. personnal data), PUFAs would 
be effective to prevent recurrence of AF after cardioversion in patients with moderately 
abnormal LVEF. 
 
− a Left Atrial Area (LAA) not severely abnormal (less than 40 cm2 as defined in the report 
from the American Society of Echocardiography’s Guideline). According to a sub-group 
analysis performed in patients with persistent AF associated to heart failure (Nodari S. 
personnal data), PUFAs would not be effective to prevent recurrence of AF after 
cardioversion of patients with severely abnormal LAA. 
For the successful rate of ECV, patients should have a stable medical treatment of heart failure 
and should not have any myocardial infarction or unstable angina or unstable ischemic 
coronaropathy assessed by coronarography or cardiac stress test (Echo stress, exercise stress 
test, nuclear or MR perfusion evaluation methods) within 6 months before selection.  
4.2.2. 
Choice of the Study Design 
As the target indication would be the prevention of AF recurrence after ECV, the study design 
meets 
the 
requirements 
of 
EMA 
guideline 
on 
antiarrhythmics 
in 
AF 
(EMA/CHMP/EWP/213056/2010) [21]. 
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As F373280 aims to be a safe treatment for the prevention of AF recurrence, it will not be tested 
as an add-on therapy during the study. To avoid any interaction with the tested product, 
antiarrhythmic class I and III will be forbidden during the study. 
The study design is defined in order to avoid methodological bias. A double blind study is 
appropriate to assess the efficacy and safety of the use of F373280 to prevent recurrence of AF 
episodes. Moreover, this study design is similar to the design of almost all trials that have assessed 
intervention for rhythm control [2, 8, 11, 12].  
According to the target indication, only patients with persistent AF and requiring an ECV will be 
included in order to assess the time to first documented recurrence of AF since cardioversion. 
To confirm the persistent nature of AF, a 24-hour holter monitoring will be performed during the 
selection visit.  
Eligible participants will enter a selection phase in which anticoagulant treatment (AVK) will be 
adjusted to achieve an International Normalized Ratio (INR) of 2.0 to 3.0 before ECV. According 
to guidelines for the management of AF [6], AVK should be given at least 3 weeks before 
cardioversion because of risk of thrombo-embolism due to post-cardioversion.  
Experimental data suggest that the maximal incorporation of n-3 PUFAs in the myocardial cell 
membrane takes up to 28 days to occur [22]. In addition, as shown in Nodari’s study [2], the 
duration of pre-treatment with PUFAs before cardioversion appears to be a contributing factor in 
success. Therefore, before starting follow up for the assessment of AF recurrence, treatment with 
F373280 should be started 28 days before ECV.  
Detection of AF recurrence will be performed using systematic (scheduled) ECG recording, thus 
allowing detection of asymptomatic (about 50% of episodes) as well as symptomatic AF episodes. 
According to previous studies, most of AF recurrences occurred during the first days after 
cardioversion [11, 15]. So that, the heart rhythm will be closely monitored during the first week 
after successful cardioversion using an ambulatory continuous 7-day holter ECG recording in 
order to increase sensibility to detect asymptomatic AF episodes. Thereafter, to improve patient 
compliance, this follow up will be continued using an easier device  to carry and to use, i.e. a 
TTEM.  
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Finally, during the study, patients will be scheduled for a clinical visit every month (with an 
additional visit 7 days after visit 3 (ECV visit)) in order to ensure a close medical monitoring and 
to assess efficacy and safety parameters. 
4.2.3. 
Choice of the Dose  
According to a previous study in patients with AF [2], the tested PUFA product (Omacor) at the 
dose of 2 g (i.e. 640 mg of DHA acid) was effective in the prevention of AF after cardioversion. 
Moreover, PUFAs at dosage of 1 g and 2 g were also effective on the improvement of ventricular 
functional parameters, morbi-mortality and duration of hospitalisation in patients with heart 
failure [3, 4, 5].  
From the F373280 phase I study, after a 14-day repeated administration of F373280 (1 g/day), 
observed plasma concentrations of DHA measured before treatment (Cmin) were similar to that of 
an effective dose of Omacor at 2 g/day (60 to 95 mg/mL and 60 to 90 mg/mL, respectively) 
(phase I study of F373280 and [16]). With regard to the rhythm of administration, mean 
peak/trough fluctuation (baseline corrected) was around 0.3. This value supports an once-daily 
administration allowing a 24-hour plasma exposure in DHA. Therefore, a 1 g daily dose of 
F373280 is considered to be appropriate for this proof of concept study. 
4.2.4. 
Choice of the Sample Size 
See chapter 13. 
5. STUDY POPULATION 
Each patient fulfilling all the inclusion criteria and none of the non inclusion criteria will be 
eligible. 
5.1. 
INCLUSION CRITERIA 
Demographic Characteristics and Other Baseline Characteristics: 
1. Men or women aged more than 18 years (inclusive) 
2. Patient with current episode of persistent AF between 7 days and 6 months duration for 
whomelectrical cardioversion is warranted 
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3. History of first documented persistent AF less than 3 years 
4. History of ischemic or non ischemic heart failure 
5.  NYHA class I or II chronic heart failure at selection and at inclusion 
6. Reduced left ventricular ejection fraction between 30% and 45% inclusive (using the two-
dimensional echocardiography biplane Simpson’s rule) at selection and at inclusion 
7. On appropriate, stable medical treatments for heart failure, including a diuretic and/or 
angiotensin-converting enzyme, and/or angiotensin-receptor blocker and/or mineralocorticoid 
receptor (MR) antagonists, and/or betablockers 
8. Left atrial area ≤ 40 cm² at selection and at inclusion 
9. Patient treated or having to be treated by anti-vitamin K 
10. For female patient of child-bearing potential:  
• in all the countries except Italy: 
 
- 
use of an effective method of contraception (hormonal contraception or intra-uterine 
device) assessed by the investigator for at least 2 months before the selection in the 
study and agreement to go on using it during the whole duration of the study and up to 
1 month after the last dose of the study treatment or 
- 
documented as surgically sterilized 
 
• in Italy only: 
- 
absolute abstention from sexual intercourse during the whole duration of the study and 
for a month after the end of the study or 
- 
use of double barrier contraception method (use of effective medical contraception 
method) from at least 2 months before the start of the study to the entire duration of the 
study and for a month after the end of the study or 
- 
documented as surgically sterilized  
 
11. For female patient of child-bearing potential: negative urine pregnancy test at inclusion 
12. For male with a child-bearing potential partner (In Italy only): 
- 
absolute abstention from sexual intercourse during the whole duration of the study and 
for 3 months after the end of the study or 
- 
use of double barrier contraception method (use of condom for male and effective 
contraception method for the partner) from the entire duration of the study to 3 months 
after the end of the study. 
 
Ethical /legal considerations: 
13. Having signed his/her written informed consent, 
14. Affiliated to a social security system, or is a beneficiary (if applicable in the national 
regulation) 
5.2. 
NON INCLUSION CRITERIA 
Criteria related to pathologies: 
1. History of first documented episode of persistent AF more than 3 years, 
2. More than two successful cardioversions (electrical or pharmacological) in the last 6 months, 
3. Secondary Atrial Fibrillation due to alcohol or severe valvular heart disease (grade III to IV), 
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4. NYHA class III or IV heart failure at selection or at inclusion 
5. Thyroid disease uncontrolled by treatment: TSH ± T4L ± T3L to be checked in case of 
treatment for thyroid disease  
6. Myocardial infarction or unstable angina or presence of unstable ischemic coronaropathy 
assessed by coronarography or cardiac stress test (Echo stress, exercise stress test, nuclear or 
MR perfusion evaluation methods) within 6 months before selection 
7. Severe chronic kidney disease (creatinine ≥ 25 mg/L or estimated glomerular filtration rate < 
30 mL/min) at selection 
8. Bradycardia (HR ≤ 50 bpm) 
9. Hyperkalemia or hypokalemia (according to the standards of local laboratories) at selection 
10. Cardiac surgery within 3 months before selection or planned during the study duration 
Criteria related to treatments: 
11. Previously ineffective pharmacological or electrical cardioversion 
12. Concomitant treatment with ranolazine or any anti-arrhythmic drug (within 7 days prior to 
selection), except stable dose of digoxin, beta-blockers, calcium-blockers. 
13. Oral amiodarone: 
13a   Previous treatment with oral amiodarone within 4 months prior to inclusion 
      13b   Intake of oral amiodarone for more than 1 month within 4 to 12 months before inclusion 
14. Previous treatment with intravenous amiodarone within 4 weeks prior to inclusion 
15. Patient requiring a cardiac resynchronization therapy (CRT) or having undergone CRT 
implantation within the last 6 months 
16. Treatment with any Polyunsaturated Fatted Acid within the last 3 months 
Dietary supplement with ω3 or ω6 according to investigator’s judgment 
18. Having undergone any form of ablation therapy for AF 
19. Patient treated with other anticoagulant treatment than antivitamin K: thrombin inhibitor such 
as Dabigatran or treated with antiaggregant P2Y12 inhibitors such as Clopidogrel or Prasugrel 
Others criteria:  
20. Patient liable not to comply with protocol instructions and/or with treatment, in the 
investigator’s opinion, 
21. Patient having taken part in a clinical trial in the preceding 2 months or taking part in a trial at 
the time of selection, 
22. Patient linguistically or mentally unable to understand the nature, objectives and possible 
consequences of the trial, or refusing to patient himself / herself to its constraints, 
23. Patient family member or work associate (secretary, nurse, technician…) of the Investigator, 
24. Patient having forfeited his / her freedom by administrative or legal award or being under 
guardianship, 
25. Breastfeeding female patient. 
5.3. 
NUMBER OF PATIENTS 
76 x 2 patients (taking into account 15 % of non evaluable patients). 
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5.4. 
RECRUITMENT MODALITIES 
Patients will be recruited within the medical consultation of each centre involved in the study. If 
necessary and when authorized by local and national regulation, some specific supports or tools 
will be used to improve the recruitment (announcement, mailing to general practitioners, leaflet, 
website including ClinicalTrials.gov, CRO…). 
Before implementation, the documents will be submitted to and approved by the Ethics 
Committee. 
5.5. 
 PATIENT IDENTIFICATION 
Patient's code will contain 7 digits: the 2 first digits corresponding to the country number, the 
following 2 digits corresponding to the centre number and the last 3 digits corresponding to the 
patient's chronological order once having signed the written informed consent. 
5.6. 
WITHDRAWAL CRITERIA 
Reasons for a patient's premature withdrawal from the study may be the following: 
• Patient's decision. A patient who wishes to withdraw from the study for any reason may 
do so at any time but must inform the investigator. In all cases, the Investigator should 
attempt to contact the patient as soon as possible for a final assessment in order to: 
− have the patient's decision written on the consent form 
− obtain the reason(s) for withdrawal and report it/them in the case report form 
− evaluate the patient's clinical condition 
− if necessary, take appropriate therapeutic measures: management of an adverse effect or 
concomitant disease, prescription of another treatment. 
• Investigator's decision in the patient's interest, particularly if a serious adverse event 
occurs and is considered by the Investigator liable to threaten the health of the patient. The 
monitor will be informed by phone or fax and a letter or report explaining the withdrawal 
will be forwarded to the monitor as soon as possible. 
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• Erroneous inclusion according to the study protocol. Any inclusion not respecting 
inclusion/non inclusion criteria will immediately be withdrawn and an appropriate 
treatment will be given by the investigator under his/her responsibility. Erroneous 
inclusions will not be paid to the investigator. 
• Patients who could not be treated with AVK for at least 3 weeks before ECV. 
• Patients who will not have a stabilized INR between 2 and 3 on at least 3 consecutive 
weekly tests. 
• Patients with only 2 consecutives INR tests between 2 and 3 in the last 3 weeks for whom 
a trans-oesophagoal echocardiography can not be performed before ECV or for whom a 
trans-oesophagoal echocardiography shows a thrombus in the atria.  
• Patients who will not revert to sinus rhythm (i.e. unsuccessful ECV) or with early relapse 
within the observation period after ECV will be considered to have finished follow-up. 
• Occurrence of AF recurrence that would require, at the investigator’s judgement, a 
cardioversion or an introduction of an anti-arrhythmic because of intolerable and/or 
uncomfortable clinical symptoms for instance. 
5.7. 
REPLACEMENT OF PATIENTS 
Withdrawn patients will not be replaced. 
5.8. 
POST-STUDY EXCLUSION PERIOD  
Patients will not be allowed to participate to another clinical trial during 3 months following the 
study termination. 
5.9. 
STUDY CARD AND LETTER FOR GENERAL PRACTITIONER(S) 
The patient will receive from the Investigating Centre at Visit 1 - Selection Visit:  
- a personal card to be kept all along the study duration and providing the following information: 
patient's name, sponsor's name, study code, EUDRACT number, start date and expected end date 
of the study, complete address of the Investigating Centre with the name and phone number of the 
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Investigator and a sponsor 24H/24 phone contact number in case of emergency (French and 
English languages): 33 (0)5 63 35 25 83. For Italy, this card will be in Italian only, without any 
English mention. 
- in Italy, a letter to be given to his/her general practitioner. This letter intends to inform the 
general practitioner(s) (and any other doctors who take care of the patient) that the patient 
participates to the clinical study. It describes the study treatment and includes some information 
on the forbidden treatment during the study.  
 
6. STUDY TREATMENT 
The Clinical Pharmacy Department of the Institut de Recherche Pierre Fabre (IRPF) will supply 
the investigational centres with the treatment necessary for the conduct of the trial.  
6.1. 
SOURCE, PRESENTATION AND COMPOSITION OF 
 
INVESTIGATIONAL PRODUCT 
F373280 and placebo will be prepared in Soft Capsules similar presentation.  
• F373280 
Formulation of F373280, 1 g, Soft Capsules: oral administration, oblong size 20, off-white, Soft 
Capsules containing: Panthenyl ester of DHA, gelatine, glycerol, titanium, dioxide, purified water. 
• Placebo 
Formulation of placebo matching tested product, Soft Capsules: oral administration, oblong size 
20, off-white, Soft Capsules containing: paraffin liquid, fish flavour, gelatine, glycerol, titanium, 
dioxide, purified water. 
 
Placebo and F373280 capsules will be packaged in opaque blisters. 
6.2. 
PACKAGING AND LABELLING 
The treatment units will be packed and labelled by the Clinical Pharmacy Department of the IRPF 
according to European Directive and local requirements. 
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6.2.1. 
Packaging 
Each treatment unit will be composed of 3 cases for a 12-week treatment period. 
The Investigator will provide the patient with the treatment according to the following schedule: 
At Inclusion Visit (V2): a 12-week treatment unit will contain 3 cases, each case containing: 
− 10 blister packs of four 1 g F373280 soft capsules or placebo soft capsules each. 
At Visit 6 (V6): a 12-week treatment unit will contain 3 cases, each case containing: 
− 10 blister packs of four 1 g F373280 soft capsules or placebo soft capsules each. 
6.2.2. 
Labelling 
Investigational Products will be labelled according to the following rules: 
Labelling should comply with the local requirements for Investigational Medicinal Products. 
On the treatment units and cases, the labels will bear the following indications:  
a) name and address of the sponsor 
b) protocol number 
c) packaging batch number 
d) treatment number 
e) storage conditions 
f) expiry date 
g) pharmaceutical dose form 
h) route of administration 
i) quantity of dosage units 
j) direction for use 
k) legal statements:  
    -“for clinical trial only”, “keep out of the reach and the sight of children”, “please return to 
your doctor any unused product”, respect the prescribed dose” 
On the treatment unit, another label will be affixed with the mention of the Investigator’s name 
and patient’s code (completed by the Investigator). 
In addition, on each case will be mentioned the case number, and a detachable label will bear the 
following indications: 
− Protocol number 
− Packaging batch number 
− Expiry date 
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− Case number 
− Treatment number 
On the blister pack, the label will mention the protocol number, the packaging batch number, the 
case number and the treatment number. 
6.3. 
DISTRIBUTION TO CENTRE AND STORAGE 
The Clinical Pharmacy Department of the IRPF will supply the Investigational Centre with the 
treatment units along the study according to the need, upon request triggered by the patient’s 
selection.  
As soon as the Pharmacist or the Investigator receives the trial medication, he/she will check the 
contents and immediately acknowledges the receipt in the IVRS/IWRS. The copy of the 
acknowledgement will be kept in the Investigator’s or the Pharmacist’s file. The same procedure 
will be applied to all further supplies during the course of the trial. 
At the time of the delivery to the Centre, the following information will be provided: 
• Details of storage conditions that should be respected 
• And, upon request and for the 1st delivery only, a letter of release for the Investigational 
Medicinal Product from the Sponsor's Qualified Person 
The CRA will ensure during the monitoring visits that trial medications have been received in 
good conditions and the acknowledgment of receipt has been performed adequately. 
Treatment units should remain intact until dispensation to the patients. They should be kept at 
temperature below 30°C in an appropriate lockable room only accessible to the person authorised 
to dispense them, under the responsibility of the Pharmacist or the Investigator. 
In the case of undue delay in study execution, the Pharmacist or the Investigator should ensure 
that the expiry date has not been exceeded.  
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6.4. 
ALLOCATION OF TREATMENTS AND DISPENSATION TO PATIENT 
A randomisation list will be established by the Clinical Pharmacy Department of the IRPF. This 
list will be computer-generated with internal software. The randomisation methodology is 
validated by the Biometry Department before generation. 
Treatments F373280 or placebo will be balanced in a 1:1 ratio. 
As the treatment units are prepared for 12-week treatment periods, the Investigator will have to 
allocate a treatment number at inclusion visit (V2) and another one at visit 6.  
For each patient, the treatment number given at visit 6 will not be the same that the one given at 
inclusion visit (V2). 
The treatment numbers will be given through the IVRS/IWRS. 
Practically, once patient’s eligibility is confirmed at selection visit (V1):  
• The Investigator: 
− Contacts the IVRS/IWRS 
− Answers the questions relating to the patient  
− In return, the treatment number to be allocated for the first 12-week period to the patient is 
given by the IVRS/IWRS.  
• The IVRS/IWRS company: 
− Confirms this information by fax/email to the Investigator 
− Fills the “Request for Delivery of Investigational Product” form and sends it by email 
and/or fax to the Clinical Pharmacy Department of the IRPF.  
• The Clinical Pharmacy Department of the IRPF sends the corresponding treatment unit to 
the Investigator within 5 days from reception of the email request form. 
The Investigator will dispense to the patient the case which label indicates the treatment number 
and the administration period. 
At visit 6, the Investigator will contact again the IVRS/IWRS to obtain the treatment number for 
the last 12-week period of treatment according to the same process as described above. 
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6.5. 
DRUG ADMINISTRATION 
6.5.1. 
Duration of Treatment 
For a patient completing the study, the theoretical study treatment exposure to F373280 or 
placebo will be 24 weeks. 
If the ECV is postponed by 1 week to allow INR stabilization, the treatment duration will be 25 
weeks. 
6.5.2. 
Dose Schedule 
One soft capsule of 1g of F373280 or placebo to be taken each day during 24 weeks. 
6.5.3. 
Route and Conditions of Administration 
The soft capsules are to be taken orally. One soft capsule is to be taken each evening with the 
dinner during 24 weeks.  
6.6. 
ACCOUNTABILITY ON SITE AND RETURN/DESTRUCTION OF 
 
INVESTIGATIONAL PRODUCT 
The Investigator should maintain accurate written records of drug received, dispensed, returned 
and any remaining treatment units, on the drug accountability form. These records should be made 
available for Clinical Research Associate (CRA) monitoring. The packaging of the medication 
should remain intact until just before the dispensation. 
At each visit, the Investigator will record the number of soft capsules returned by each patient 
using the appropriate page of the e-CRF. 
At the end of the study, all used and unused treatments including packaging should be noted, and 
return is organised by the CRA to the Clinical Pharmacy Department of the IRPF for destruction. 
A copy of the drug accountability form should be provided by the Investigator to the CRA. 
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6.7. 
RECALL OF INVESTIGATIONAL PRODUCTS  
In case of recall of investigational products (decided by the Competent Authorities or the 
Sponsor), the Investigator will immediately be informed by the Sponsor. 
The Investigator in collaboration with the Sponsor’s representatives (Study Manager, CRA) must 
urgently: 
• Stop the delivery of the concerned investigational products to the patients. 
• Inform the concerned patients that they must immediately stop taking these investigational 
products and bring them back. 
The Study Manager/CRA organises the return of the recalled products to the Clinical Pharmacy 
Department of the IRPF according to the Sponsor’s procedures. 
7. CONCOMITANT TREATMENTS 
Any existing concomitant treatment (at selection visit), any new concomitant treatment or change 
in the dosage of an existing concomitant treatment during the course of the study must be noted 
on the electronic Case Report Forms (e-CRF). All treatments should be evaluated by the 
Investigator at patient’s selection, and treatment prolongation or stop during the study should be 
considered. 
For all concomitant treatments taken during the study, the following information must be noted in 
the relevant section(s) of the e-CRF: 
• The name of the treatment and its form 
• The reason for prescription 
• The route of administration 
• The daily dose 
• The duration of treatment. 
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7.1. 
ANTI-VITAMIN K TREATMENT 
AVK should be given for at least 3 weeks before ECV and continued for the whole study 
duration. The AVK used will be left to the decision of the each Investigator according to his/her 
local practice. 
7.2. 
PROHIBITED TREATMENTS 
- 
Class I and class III antiarrhythmic treatments: 
− Class I 
- 
Class IA: Disopyramide, Procainamide, Quinidine 
- 
Class IB: Lidocaine, Mexiletine 
- 
Class IC: Flecainide, Propafenone 
 
− Class III: Dofetilide, Ibutilide, Sotalol, Amiodarone, Dronedarone. 
 
- 
Ranolazine 
- 
Any PUFA 
- 
Any anticoagulant treatment other than AVK: thrombin inhibitor such as Dabigatran or 
antiaggregant P2Y12 inhibitors such as Clopidogrel or Prasugrel 
- 
Dietary supplement with Omega 3 or Omega 6 
Prohibited treatments at selection must not be prescribed for the duration of the study except in 
case of occurrence of an adverse event or AF episode that requires a corrective treatment in the 
interest of the patient’s health. 
7.3. 
AUTHORISED TREATMENTS 
Other treatments will be authorised during the study duration. 
However, if medication other than study drugs is administered at any time from the start of the 
study, details must be recorded in the e-CRF. During the study, patients must be asked whether 
they have been on a course of prescribed drug treatment or have taken any OTC or herbal drugs 
since the visit. 
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8. EVALUATION CRITERIA 
8.1. 
PRIMARY EFFICACY CRITERION  
8.1.1. 
Time to the first Atrial Fibrillation Recurrence 
8.1.1.1. 
Definition 
Time to first AF recurrence is defined by the first episode of AF (symptomatic or not) lasting for 
at least 10 minutes. 
8.1.1.2. 
Schedule 
The heart rhythm follow up will be performed from the end of ECV visit (visit 3) to the final 
study visit (visit 9).  
For randomised patients with spontaneous cardioversion before ECV, the recurrence of AF will be 
assessed after visit 3 (week 5). 
8.1.1.3. 
Evaluation Methods 
• 7-day holter monitor: 
The heart rhythm monitoring will be carried out from visit 3 to visit 4 using a 7-day continuous 
ECG (5-leads/2 or 3 channels) ambulatory recording (holter ECG) fixed after ECV visit. 
Following holter monitoring, the heart rhythm will be documented using Trans Telephonic ECG 
Monitoring (TTEM). 
• Trans Telephonic ECG Monitoring: 
The ECG follow up will be documented using the TTEM: daily transmission from visit 4 (week 5) 
to visit 5 (week 8). Then every two days from visit 5 (week 8) to visit 9 (week 24 – End of study). 
Moreover, if patient experiences AF symptoms during this TTEM period, it should be 
documented using the TTEM. 
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In case of AF recurrence and provided that the patient does not required a cardioversion or an 
introduction of an anti-arrhythmic at Investigator’s judgement, the patient could be maintained in 
the study with the treatment in order to assess a spontaneous cardioversion. For that purpose the 
patient will continue to transmit a TTEM once a week. 
The TTEM will be centralized by the Central Reading Laboratory. The patient will be requested 
to contact the Central Reading Laboratory for transmission of each stored TTEM. The TTEM will 
be validated by a trained technician, then analysed by a cardiologist. The cardiologist 
interpretation will be faxed to the site. The investigator will be asked to review and sign this 
document. 
The TTEM process will be fully described in a separate document. 
8.1.2. 
Secondary Efficacy Criteria 
8.1.2.1. 
Numbers of AF episodes in the first week following visit 3 (ECV visit) 
8.1.2.1.1. 
Definition 
Number of AF episodes will consist in the assessment of AF episodes with duration at least 10 
minutes (NSup10) and of less than 10 minutes (NInf10), respectively. 
8.1.2.1.2. 
Schedule 
The heart rhythm follow up will be performed from the end of successful ECV visit (visit 3) to the 
study visit 4.  
8.1.2.1.3. 
Evaluation Methods 
• 7-day holter monitor: 
The heart rhythm monitoring will start using a 7-day continuous ECG (5-leads/2 or 3 channels) 
ambulatory recording (holter ECG) after ECV visit from visit 3 to visit 4. 
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8.1.2.2. 
Duration of AF episodes in the first week following visit 3 (ECV visit) 
8.1.2.2.1. 
Definition 
Duration of AF episodes will consist in the sum of duration of each AF episode. 
8.1.2.2.2. 
Schedule 
The heart rhythm follow up will be performed from the end of successful ECV visit (visit 3) to the 
follow up study visit (visit 4).  
8.1.2.2.3. 
Evaluation Methods 
Duration of AF episodes will be assessed using the 7-day continuous ECG (5-leads/2 or 3 
channels) ambulatory recording. 
8.1.2.3. 
Clinical parameters evaluation 
8.1.2.3.1. 
EHRA score assessment 
8.1.2.3.1.1. Definition 
AF related symptoms will be evaluated by the EHRA (European Heart Rhythm Association) score 
[20]. The following items “during presumed arrhythmia episodes" are checked to determine the 
score: palpitation, fatigue, dizziness, dyspnea, chest pain and anxiety. 
Classification of AF-related symptoms (EHRA score) are as follows: 
• EHRA I          - ‘No symptoms’ 
• EHRA II         - ‘Mild symptoms’; normal daily activity not affected 
• EHRA III       - ‘Severe symptoms’; normal daily activity affected 
• EHRA IV       - ‘Disabling symptoms’; normal daily activity discontinued  
This classification relates exclusively to the patient-reported symptoms. 
In addition to this score, the frequency will be classified in three groups, namely occasionally 
(less than once per month), intermediate (1/month to almost daily) and frequent at least daily. 
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8.1.2.3.1.2. Schedule 
EHRA evaluation will be performed in case of evocative symptoms of arrhythmia. 
8.1.2.3.1.3. Evaluation Methods 
EHRA evaluation will be collected by Central Reading Laboratory during all the study period. 
8.1.2.3.2. 
Number of recurrence of symptomatic AF  
It consists of the number of AF recurrences associated with a symptom (palpitation, fatigue, 
dizziness, dyspnea, chest pain and anxiety) and confirmed by an ECG. 
8.1.2.3.3. 
Number and duration of hospitalizations 
• Number and duration of hospitalizations for cardiovascular events 
− Hospitalization for AF treatment 
− Hospitalization for worsening of heart failure 
− Hospitalization for myocardial infarction 
− All cause of hospitalization 
• Number and duration of hospitalizations for thromboembolic stroke  
8.1.2.4. 
Cardioversion assessment 
• Assessment of spontaneous cardioversion before visit 3 
• Assessment of successful cardioversion at visit 3 (i.e. return to sinus rhythm) 
• Shock distribution (1, 2 or 3 shocks) 
• Number of patients needing another cardioversion after initial ECV 
8.1.2.5. 
Evolution of echocardiographic parameters 
8.1.2.5.1. 
Definition 
The following echocardiographic parameters will be assessed: Left atrial diameter (mm), LAA 
(cm2), Left atrial volume (mL), Left atrial volume/BSA (mL/m2), LVEF (%), Left ventricular end 
diastolic volume/BSA (mL/m2), Left ventricular end systolic volume/BSA (mL/m2), Left 
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ventricular end diastolic diameter (mm), Left ventricular end diastolic volume (mL), Left 
ventricular end systolic diameter (mm) and Left ventricular end systolic volume (mL). 
8.1.2.5.2. 
 Schedule 
Measurements will be performed at visit 1 and visit 2 to check the eligibility of the patient.  
Measurements performed at visit 4, visit 6 and visit 9 are done to follow the echocardiographic 
evolution of the patients in sinus rhythm. 
8.1.2.5.3. 
Evaluation method 
The echography evaluations will be carried out according to the recommendations for chamber 
quantification drawn up by the American Society of Echocardiography and the European 
Association of Echocardiography [23]. So, the recommended method for volume measurements is 
to use the biplane method of discs (modified Simpson’s rule) from 2-D measurement. 
8.2. 
BIOMARKER ASSESSMENT: RED BLOOD CELL 
 
CONCENTRATIONS OF DHA 
8.2.1. 
Definition 
Because of the limited human tissue accessibility for biopsy, red blood cell DHA contents is a 
marker of tissue DHA concentration [13], [14]. 
8.2.2. 
Blood samples 
8.2.2.1. 
Collection schedule 
Blood samples will be collected to determine the red blood cells (RBC) concentrations of DHA.  
Blood samples will be performed at visit 2 before treatment, visit 3, visit 6 and visit 9. 
Actual sampling times will be individually reported in the e-CRFs. 
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8.2.2.2. 
Technical handling 
Two blood samples (4 ml) will be collected in EDTA tubes. They will be gently shaken, stored at 
+4°C (no freezing will be allowed) and sent to Analytical Centre in refrigerated conditions 
(between +2°C and +8°C). Analysis will be performed within 2 weeks following reception at the 
Analytical Centre. 
8.2.3. 
DHA concentration measurement 
Analytical determination of RBC concentrations of DHA will be carried out by the Analytical 
Centre. 
Lipids will be extracted from red blood cells samples with a mixture of hexane/isopropanol after 
acidification [17]. Total lipid extracts will be saponified and methylated. The fatty acid methyl 
esters (FAME) will be extracted and analyzed by Gas Chromatography. 
Identification of FAME will be based on retention times obtained for FAME prepared from fatty 
acid standards. The area under peaks will be determined using ChemStation Software (Agilent) 
and results will be expressed as % of total fatty acids. DHA concentration will be calculated using 
the internal standard and expressed as µg/g for red blood cells samples. Thus, omega-3 index will 
be assessed. The omega-3 index represents the content of EPA plus DHA in red blood cells 
(expressed as a percent of total fatty acids). It is a biomarker considered as a new marker of risk 
for death from coronary disease [18]. 
Results of this analytical determination will be kept confidential by the dosing centre until the end 
of the study, and will be provided only at the end of the study (after database lock) in a separate 
file. 
8.3. 
SAFETY ASSESSMENT 
8.3.1. 
Adverse Events 
At selection, any concomitant disease will be reported on the e-CRF. At each further visit, the 
occurrence of AEs since the last visit will be based on the patient's spontaneous reporting, the 
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Investigator's non-leading questioning and his/her clinical evaluation. All AEs will be reported on 
the e-CRF (see section 10). 
8.3.2. 
Laboratory Investigations 
8.3.2.1. 
Schedule 
Laboratory investigations will be performed at visit 1 (before treatment) and visit 9 (end of 
treatment) or End of Treatment visit. 
At visit 3 and 6, only a standard haematologic dosage will be performed.  
Furthermore the kaliemia will be checked before electrical cardioversion at visit 3. 
The total volume of blood samples taken for haematology and biochemistry analysis should not 
exceed 30 mL. 
8.3.2.2. 
Technical Procedures and Parameters 
The following tests will be performed: 
 
Haematology: 
hematocrit, haemoglobin, RBC count, white blood cells (WBC) count, WBC 
differential counts (% and absolute), reticulocytes, platelets.  
 
Chemistry: 
sodium, potassium, bicarbonate, chloride, alkaline phosphatase, gamma GT, 
albumin, total bilirubin, conjugated bilirubin, creatinin, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), fasting glucose, 
total cholesterol, cholesterol (HDL, LDL), triglycerides, creatine 
phosphokinase (CPK), fibrinogen. 
Blood samples will be taken in the morning in fasting conditions.  
The estimation of GFR at selection relies on the measurement of serum creatinine and the 
Cockcroft- Gault formula: 
Cockcroft-Gault formula 
- with serum creatinine expressed as mg/L:  
in men: 
GFR (mL/min) = [(140-age)] x weight / 7.2 x serum creatinine in mg/L] 
 
in women: 
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GFR (mL/min) = [(140-age)] x weight / 7.2 x serum creatinine in mg/L] x 0.85 
 
- with serum creatinine expressed as μmol/l: 
GFR (mL/min) = [(140-age) x weight / serum creatinine in μmol/l] x k,where k = 1.23 for men, 
1.04 for women. 
 
(weight in kg, age in years) 
Additional tests may be done at the Investigator’s discretion, in the patient’s interest. In case of 
any abnormal or clinically significant results, the Investigator will order laboratory control tests. 
8.3.3. 
Global Physical Examination 
A global physical examination including the measurement of body weight will be carried out on 
each body system at visit 1, visit 2, visit 3, visit 5, visit 6, visit 7, visit 8 and visit 9. 
The physical examination will be globally evaluated as “normal/abnormal”. Further target 
inspection will be undertaken for any abnormal finding. 
8.3.4. 
Vital Signs 
Vital signs will consist in blood pressure and heart rate at rest.  
8.3.4.1. 
Schedule 
Vital signs will be measured at each visit. 
8.3.4.2. 
Technical Procedure and Parameters 
Systolic blood pressure (SBP) and diastolic blood pressure (DBP), expressed in mmHg, will be 
measured after at least 5 minutes in supine position and after 2 minutes in standing position.  
The heart rate (HR), expressed in beats per minute (bpm), will be measured by auscultation by 
counting the beats for at least 30 seconds, after at least 5 minutes in supine position and after 2 
minutes in standing position. 
Bodyweight will be measured with patient in underwear and with the same balance at each visit.  
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8.3.5. 
Electrocardiogram (ECG)  
8.3.5.1. 
Schedule 
An ECG will be recorded at visit 1, visit 2, visit 3, visit 5, visit 6, visit 7, visit 8 and visit 9 using 
an usual standardised 12-lead cardiograph. 
8.3.5.2. 
Technical Procedure and Parameters 
• Electrocardiogram: 
The global interpretation from manual reading (normality, clinical relevance) and HR (bpm), PR 
(ms), QRS (ms), QT (ms), repolarisation patterns will be reported in the e-CRF. Each print-out 
will include the patient’s code, date, time, technician's initials and investigator's signature. 
In case of thermic paper ECG print out, a photocopy will be made by the centre to ensure safe 
filing. 
• 24 hour-Holter - ECG 
An ambulatory continuous 24-hour ECG (5-leads/2 or 3 channels) will be recorded at selection 
visit using a holter ECG, in order to confirm persistent AF.  
8.3.6. 
Coagulation parameters 
Coagulation assessment will be evaluated by the following parameters: 
− Prothrombin Time/INR (PT/INR) 
− Activated Partial Thromboplastin Time (aPTT) 
− Thrombin Clotting Time (TCT) 
During the pre-cardioversion period, if the anticoagulation by AVK should be initiated, then the 
INR monitoring will be as follow:  
− INR 2-3 times a week for the first week of treatment 
− INR weekly up to ECV 
− INR every 4 weeks after ECV 
For patients already treated with AVK, INR monitoring will be as follow: 
− INR weekly up to ECV 
− INR every 4 weeks after ECV 
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aPTT and TCT will be performed at visit 1, visit 2, visit 3, visit 5, visit 6, visit 7, visit 8 and visit 
9. 
Anti-coagulation by AVK should be given at least 3 weeks before ECV and continued for the 
whole study duration. 
The quantity of blood samples collected at each time for coagulation parameters will be 2 mL. 
8.3.7. 
Concomitant Treatments 
Concomitant treatments will be evaluated at each study visit. 
Requirements relating to patient's concomitant treatments started before screening visit and 
continued throughout the trial, or started during the trial, can be found in section 7.  
8.4. 
COMPLIANCE 
The patient will be reminded at each visit to bring back at the following visit any used or unused 
remaining soft capsule, blister and case. 
At each visit, the Investigator will record the number of supplied and remaining soft capsules in 
the e-CRF. 
9. STUDY PROCEDURES 
Visit 1 - Selection Visit (Week -4 to Week -1) 
The patient considered eligible for selection by the Investigator will be informed of the 
characteristics and the consequences of the trial both verbally and by reviewing the patient's 
information sheet and consent form (see section 14.3). If the patient accepts to participate in the 
study, he/she will sign the informed consent form and will keep a copy. 
The patient will be assessed for the following: 
• Demographic characteristics (gender, age, height, body surface area) 
• Personal and medico-surgical history 
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• Habits (Tobacco, alcohol consumption, dietary habits including fish consumption…) 
• Cardiovascular diseases, mainly detailed history of Heart Failure and AF characteristics  
• Echocardiography using a two-dimensional echocardiography 
• 12-lead ECG 
• Concomitant diseases, adverse signs or symptoms (able to be used for treatment emergent 
AE determination) 
• Concomitant treatments (authorised, disallowed) 
• Global physical examination/bodyweight 
• Vital signs 
• Biology: haematology, biochemistry, assessment of coagulation parameters: Prothrombin 
Time/INR (PT/INR), Activated Partial Thromboplastin Time (aPTT), Thrombin Clotting 
Time (TCT) 
• Biology assessment of renal function: creatinine or estimated glomerular filtration rate 
If the results of the above assessments are compatible with the selection criteria 
• A 24-hour continuous ECG ambulatory recording (Holter ECG) device will be installed 
on the patient to monitor the patient heart rhythm. The patient will be requested to bring 
back the device after the termination of 24 hours recording. The recording will be 
transmitted from the Investigational site to the Central Reading Laboratory. The Central 
Reading Laboratory will send his/her assessment regarding the confirmation of persistent 
AF within 2 working days to the Investigator. 
• The patient will enter the selection period in which anticoagulant (AVK) will be adjusted 
to achieve an International Normalized Ratio (INR) of 2 to 3 before ECV.  
At the end of the visit, the Investigator will contact the IVRS/IWRS to confirm the patient 
selection (which will automatically order the treatment delivery) and organise the appointment for 
the next visit.  
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The patient will receive from the investigational centre the study card to be kept for the duration 
of the study. 
Visit 2 - Inclusion Visit (Day 1)  
If the patient's behaviour during the selection period and/or the result of complementary 
examinations particularly the confirmation of the presence of persistent AF by the Central 
Reading Laboratory during this period, the INR and laboratory tests, are compatible with the 
inclusion criteria, the patient will be assessed for the following: 
• Adverse events 
• Concomitant treatments (authorised, disallowed) 
• Laboratory examination: red blood cell concentrations of DHA and coagulation 
parameters Prothrombin Time/INR (PT/INR), Activated Partial Thromboplastin Time 
(aPTT), Thrombin Clotting Time (TCT) 
• Global Physical examination/bodyweight 
• Vital signs 
• Echocardiography using a two-dimensional echocardiography 
• 12-lead ECG 
• Urine pregnancy test for women of child bearing potential 
If the results of the above assessments are compatible with the inclusion criteria, the patient will 
be included and allocated a treatment number using the IVRS/IWRS.  
Between this Inclusion visit and the next visit (V3), the INR will be closely monitored (refer to 
paragraph 8.3.6) in order to ensure that the INR is stable (between 2 to 3 before electrical 
cardioversion). 
At the end of the visit, the Investigator will organise the appointment for the next visit and will 
give the treatment for the next 4-week period. 
Visit 3 (Week 4: D28 -2/+7 days) cardioversion 
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Patient will be assessed for the following criteria: 
• Adverse events 
• Concomitant treatments (authorised, disallowed) 
• Laboratory examination: Haematology, RBC concentrations of DHA, Prothrombin 
Time/INR (PT/INR), Activated Partial Thromboplastin Time (aPTT), Thrombin Clotting 
Time (TCT) 
• Global Physical examination /bodyweight 
• Vital signs  
• 12-lead ECG 
• Electrocardioversion (ECV): ECV has to be scheduled 4 weeks after randomization and 
after target international normalized ratio levels will be stabilized (between 2 and 3) on at 
least 3 consecutive weekly tests in patients with AF. Patients not stabilized for INR (i.e. 
values not between 2 and 3) on at least 3 consecutive weekly tests before ECV will be 
excluded from the study, unless the presence of atrial thrombosis may be excluded with 
ECHO –TE performed in the same day (and before ECV). ECV will be performed in the 
morning, with the patient in the fasting state and without dyskalemia. Anesthesia will be 
induced and patients will be cardioverted with administration of a synchronized, biphasic 
current. The initial shock will be set at 100 J if the body weight is less than 70 kg and at 
150 J for higher body weights. Successful cardioversion will be defined as recovery of 
sinus rhythm lasting at least 1 minute after the shock. If unsuccessful, a second 200-J 
shock, and eventually a third 200-J shock, will be administered. Failure of ECV is defined 
as the persistence of AF after the third attempt at cardioversion. After the procedure, 
patients will be monitored on telemetry for at least 6 hours before discharge. Patients who 
will not revert to sinus rhythm or with early relapse within the observation period after 
ECV will be withdrawn from the study and will be considered to have finished their 
follow-up. 
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At the end of the visit, a 7-day continuous ECG (5-leads/2 or 3 channels) ambulatory recording 
(holter ECG) will be installed on the patient in order to monitor the patient heart rhythm after 
ECV.  
At the end of the visit, the Investigator will organise the appointment for the next visit and give 
the treatment to be taken during the next 4-week period. 
Visit 4 (Week 5: D35 -2/+7 days) 
After removal of the continuous ECG ambulatory device, the patient will be assessed for the 
following criteria: 
• Assessment of AE 
• Concomitant treatments (authorised, disallowed) 
• Body weight (body weight measured at V3 to be used) 
• Vitals Signs 
• Echocardiography using a two-dimensional echocardiography 
At the end of the visit, the patient will be given the TTEM device for cardiac monitoring. The 
patient will be clearly instructed on the frequency and modalities of transmission. The patient will 
be requested to performed daily transmission from week 6 to week 8, then every 2 days from 
week 9 to week 24. Moreover, in case of AF symptoms, additional transmissions may be 
performed. 
Visit 5 (Week 8: D56 ± 7 days) – Visit 6 (Week 12: D84 ± 7 days) - Visit 7 (Week 16: D112 ± 
7 days) - Visit 8 (Week 20: D140 ± 7 days) 
Patient will be assessed for the following criteria: 
• Adverse events 
• Concomitant treatments (authorised, disallowed) 
• Laboratory 
examination: 
Prothrombin 
Time/INR 
(PT/INR), 
Activated 
Partial 
Thromboplastin Time (aPTT), Thrombin Clotting Time (TCT). However, in case of 
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discontinuation of anticoagulation after ECV, the monitoring of INR, aPTT and TCT 
should be stopped. 
• Global Physical examination/bodyweight  
• Vital signs  
• 12-lead ECG 
• The cardiac monitoring will be continued using a TTEM device. The device will be given 
to the patient who will be requested to perform daily transmission from week 6 to week 8, 
then every 2 days from week 9 to week 24. Moreover, in case of AF symptoms, additional 
transmissions may be performed. 
The Investigator will collect all unused cases, blisters and soft capsules, and will count the unused 
capsules for each 4-week treatment period. 
At the end of the visit, the Investigator will organise the appointment for the next visit and give 
the treatment to be taken during the next 4-week treatment period. 
In addition: 
- at visit 6: 
• the investigator will contact the IVRS/IWRS to obtain the treatment unit number to 
be dispensed at visit 6 for the last 12-week period. 
• an echocardiography will be performed, an haematology examination will be done 
and the RBC concentration of DHA will be measured.  
 
End-of-Study Visit - Visit 9 (Week 24: D168 ± 7 days) 
Patient will be assessed for the following: 
• Adverse events 
• Concomitant treatments (authorised, disallowed) 
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• Global Physical examination/bodyweight 
• Vital signs 
• 12-lead ECG 
• Laboratory examination: haematology, biochemistry, assessment of coagulation 
parameters: Prothrombin Time/INR (PT/INR), Activated Partial Thromboplastin Time 
(aPTT), Thrombin Clotting Time (TCT), Red blood cell concentration of DHA. 
• Urine pregnancy test for women of childbearing potential 
• Echocardiography using a two-dimensional echocardiography 
The Investigator will collect all unused cases, blisters and soft capsules, and will count the unused 
soft capsules. 
10. ADVERSE EVENTS: DEFINITION AND REPORTING 
10.1. 
ADVERSE EVENTS 
10.1.1. Definition of Adverse Events 
An AE is any adverse change from the patient's baseline condition, i.e. any subjective signs and 
symptoms or change in a concomitant disease present at the Selection Visit considered or not 
related to the treatment. 
AE includes intercurrent signs, symptoms, illnesses and significant deviations from baseline for 
vital signs and laboratory values which may occur during the course of the clinical study. 
All laboratory tests for which abnormal results are collected after study treatment initiation should 
be repeated until the values return to normal or to a stable status. Abnormal results are defined as 
those falling out of the laboratory normal ranges and that are clinically significant. The frequency 
of such checks should be defined by the Investigator according to the degree of abnormality. 
In all cases, the aetiology should, as much as possible, be identified and Pierre Fabre Médicament 
notified. 
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10.1.2. Grading of Adverse Events 
Adverse or intercurrent events are graded as follows: 
• Mild: awareness of signs or symptoms, but easily tolerated 
• Moderate: uncomfortable enough to cause interference with usual activity 
• Severe: incapacity with inability to work or do usual activity 
10.1.3. Reporting of Adverse Events 
The records of AE in the e-CRF describe the nature (diagnosis, signs and symptoms), severity, 
onset date, stop date, outcome and actions taken, and relationship to study treatment (in the 
Investigator's opinion). It must be specified whether the event is serious or not. 
10.2. 
SERIOUS ADVERSE EVENTS (SAE) 
10.2.1. Definition 
A SAE includes, but is not necessarily restricted to, any event which: 
• Results in death (whatever may be the cause) 
• Is life-threatening 
• Results in persistent or significant disability/incapacity 
• Requires the patient's hospitalisation or prolongation of current hospitalisation * 
• Is a congenital anomaly or birth defect 
Other events such as cancer and any additional adverse experience or abnormal laboratory values 
occurring during the study period, defined by the protocol as serious or which the Investigator 
considers significant enough or that suggest a significant hazard, contra-indications, side effect or 
precaution, must be handled as serious adverse events. 
Any overdosage meeting a seriousness criteria should be reported as a SAE (see section 10.3). 
Any pregnancy occurring during/after exposure to the study drug(s) should be reported on the 
SAE notification form (see section 10.4). 
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* any hospitalisation, or prolongation of hospitalisation due to the circumstances listed below: 
− planned (as per protocol) medical/surgical procedure 
− preparation for routine health assessment/procedure (e.g. routine colonoscopy) 
− planned medical/surgical admission (planned prior to entry into study trial, appropriate 
documentation required) 
− administrative or social reasons (e.g. lack of housing, economic inadequacy, care-giver 
respite, family circumstances) 
will not be reported as a SAE. 
10.2.2. Reporting of SAE 
All Serious Adverse Events, according to the above-mentioned definitions and regardless of 
treatment or relationship to study drug, and occurring once the informed consent form has been 
signed, must be reported by the Investigator as soon as he/she is informed of the event. 
The Investigator must notify the Sponsor of this event by sending, within 24 hours, the 
"Notification of serious adverse event" form ("first notification") with all the available 
information about the event (see appendix 17.2), to the Sponsor's Corporate Vigilances e-mail 
dedicated box: 
HQ.pharmacovigilance@pierre-fabre.com 
 
 In case it is not possible to send the report by e-mail it can be sent by FAX at the 
following number: 
+ 33 1 49 10 80 90 
In case of non-inclusion, the reporting period ends when the non-inclusion is documented. 
10.2.3. Follow-up of SAE 
The Investigator must draw-up a specific clinical report and use the "Notification of serious 
adverse event" form ("follow-up") (see appendix 17.2) and collect the results of the carried out 
examinations and the reports of hospitalisation. 
The serious adverse events must be followed up until resolution or stabilisation. 
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10.2.4. SAE Occurring After the Study 
Any SAE occurring during 30 days following the end of the study for the patient should be 
notified to the Sponsor. 
Must also be notified to the Sponsor any event occurring at any time after the end of the study for 
the patient which may be related to the study treatment in the Investigator's opinion. 
10.3. 
REPORTING OF OVERDOSAGE TO THE SPONSOR 
For the purpose of this trial, an overdosage will be defined as any dose exceeding the planned 
prescribed dose of the study drug or the administration of any dose of an associated product that is 
considered both excessive and medically important. 
In the absence of seriousness criteria, the overdosage and associated adverse event if any, are 
reported only on the Adverse Event page of the e-CRF. If the definition of seriousness criteria is 
met, the SAE notification form must also be transmitted to the Sponsor. 
10.4. 
REPORTING OF PREGNANCY TO THE SPONSOR 
Pregnancies discovered in the period in between the informed consent form signed but before any 
study drug exposure are not to be reported to the Sponsor unless associated to a seriousness 
criteria (e.g. serious adverse event study-protocol related procedure). If pregnancy is confirmed, 
the women must not be administered the study drug and must be withdrawn immediately from the 
study.  
If pregnancy is suspected while the patient is receiving study treatment, the study drug should be 
discontinued immediately until the result of the pregnancy testing is known. If pregnancy is 
confirmed, then the study treatment is permanently discontinued in an appropriate manner and the 
patient is withdrawn from the study.  
The Investigator must report to the Sponsor any pregnancy which occurs during or after the 
patient has been exposed to the study drug and until 30 days after the last study drug 
administration. The Investigator must immediately notify the Sponsor using the SAE notification 
form and also report the pregnancy on the AE page of the e-CRF. 
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Women who become pregnant after exposure to the study drug must be followed by the 
Investigator until the completion/termination of the pregnancy. If the pregnancy goes to term, the 
outcome will have to be reported to the Sponsor (baby's healthy status). 
10.5. 
SPONSOR'S RESPONSIBILITIES FOR SAFETY REPORTING 
 
PURPOSES 
Sponsor will submit expedited and periodic reports to both Competent Authorities and Ethics 
Committees per corporate standard operating procedures as regards to the EU directive 
2001/20/EC taking into account local specific requirements. 
11. DATA COLLECTION AND STUDY MONITORING 
11.1. 
DATA COLLECTION 
11.1.1. Case Report Form 
An e-CRF will be used to record all patient data required by the protocol except the central ECG 
(Holter ECG, TTEM) and DHA data which will be transferred from vendors to the subcontractor 
as electronic data files that will be loaded into the study database.  
The e-CRF should be fully validated, compliant with ICH-GCP requirements and European 
regulations and should include a traceability system for data corrections and deletions (audit trail). 
Prior to the start of the study, the Investigator will complete a "Delegation of significant study-
related duties" form. The signature and initials of all personal in charge of e-CRF completion 
should be recorded on this form. Each person involved in e-CRF completion, review, correction 
and / or validation will be trained and will have an individual login and access code to the e-CRF. 
Training sessions will be held by the subcontractor for all participants using this tool. An e-CRF 
user manual will be available for investigators and CRAs.  
All the information included into the e-CRF will be recorded from source documents onto the e-
CRF by an authorised person. 
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The Investigator is responsible for the management and accuracy of the information on the e-
CRF. At each monitoring visit, the e-CRF(s) should be at the CRA's disposition for review and 
validation.  
At the end of the study, a CD-ROM containing the pdf version of all e-CRFs (including audit-
trail) will be sent by the subcontractor to the Sponsor and to the investigational sites for archiving. 
The subcontractor must store all study data for at least 15 years after the end of the study and 
ensure their legibility and accessibility during all the storage period. 
11.1.2. Source Documents 
A source document is an original record or certified copy of an original record of clinical findings, 
observations or any other medical or paramedical activities performed during the clinical trial, 
necessary for the transcription and the verification of the collected data. 
Source documents along with all other trial-related documents (copies of all "informed consent" 
forms, e-CRFs CD-ROM, drug inventories and any correspondence related to the study) must be 
kept in the investigator's file throughout the study, and then, must be stored in the study centre's 
archives for a period of at least 15 years or as per local legal requirements, whatever is the 
longest.  
For further details see section 15.2. 
11.2. 
STUDY MONITORING 
11.2.1. Monitoring visits 
On-site visits will be carried out by a representative of the Sponsor's staff (Study Manager or 
CRA) prior to study initiation and at regular intervals (every 4 to 6 weeks) throughout the study. 
Additional visits and communication by telephone fax or meeting may be performed if necessary. 
Any site visit performed by the Sponsor's representatives will be recorded in the Investigator's 
study file. 
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11.2.1.1. 
Site Preselection Visit 
Before selecting a centre for the study, a visit will be carried out by the CRA and/or the Study 
Manager to ensure that the Investigator has the necessary capacities (availability, patient's 
recruitment, environment), technical means and staff to carry out the study. 
11.2.1.2. 
Initiation Visit 
Before the start of the study at all investigational sites, an initiation visit will be carried out by the 
CRA to check at the latest that: 
• The Investigator: 
− has received the technical protocol, administrative and financial agreement signed by all 
parties 
− has received the written statement of the Ethics Committee approval and the list of its 
members and their functions 
• The original dated and signed curriculum vitae of the investigator(s) has been collected 
• Laboratory normal ranges have been collected  
• All study materials are available on the study site 
• All participants agree with the monitoring procedures and know the study procedures 
• All participants are aware of a possible audit or inspection 
The CRA has also to provide training on the study protocol requirements and study specific 
procedures. 
11.2.1.3. 
Follow-up Visits 
Throughout the study, regular follow-up visits will be carried out by the CRA to check 
compliance with GCP, patient’s informed consents, strict application of the protocol, conformity 
of the data entered on the e-CRF with the source documents and ensure its correct completion, 
adverse events reporting, proper retention, storage and management of the study medication, as 
well as the source and other trial-related documents. 
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11.2.1.4. 
Closing Visit 
At the end of the study, a final visit will be carried out by the CRA to: 
• Verify that the e-CRFs CD-ROM with pdf files are correctly stored 
• Control the accountability of intact and used treatment units and return them to the 
Clinical Pharmacy Department of the IRPF for destruction 
• Obtain the last data clarifications and/or solutions if any 
• Collect the patient's consent forms in sealed envelopes (except in case of specific country 
requirements),  
• Make an on-site review of all study documentation and complete it if necessary 
• And finally, remind the Investigator of his regulatory obligations, study document 
archiving process and duration. 
11.2.2. Direct Access to Source Documents 
In accordance to the requirements of the GCP, all Sponsor representatives (Study Manager, CRA 
and Auditors) have to be given a direct access to all source and study data to perform quality 
monitoring/audit, thus ensuring accuracy and completeness of data).  
Investigators are reminded that all Sponsor representatives keep professional confidentiality with 
regards to the patient data. 
11.3. 
INDEPENDENT DATA MONITORING COMMITTEE 
An Independent Data Monitoring Committee (IDMC) will be established to assess at intervals the 
progress of the clinical trial, the compliance with the inclusion criteria, the quality of follow up, 
the quality of primary end point measures, the safety data. The IDMC will thereafter recommend 
to the Sponsor whether to continue, modify, or stop the study.  
The IDMC operating procedures will be described in an independent document.  
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12. DATA MANAGEMENT  
All clinical data related to the study will be collected and saved in a computerised database by the 
Data Management Department of the subcontractor and under the supervision of the Data 
Manager of Pierre Fabre Biometry (PFB) according to the following procedures.  
12.1. DATA ENTRY 
All required data will be collected by the Investigator or authorised designee (duly identified into 
the delegation task list) on the e-CRFs.  
The e-CRFs used for this study will be developed and maintained by the Data Management 
Department of the subcontractor and approved by the Sponsor.  
Electronic data (Holter ECG, TTEM and DHA) will be transferred by the 3rd party vendor 
according to the specifications given by the Data Manager of the subcontractor. These data will be 
captured and handled in accordance with the European GCP ICH E6 guideline. 
12.2. 
DATA CLEANING 
The subcontractor will define in the Data Validation Plan for reviewing and querying data, 
descriptions of both manual and electronic edit checks. Upon Sponsor approval, the subcontractor 
will program the checks.  
The subcontractor will review the data over the course of the study, working with the Sponsor to 
identify data inconsistencies. The Investigator will be asked to resolve queries by making changes 
directly into the e-CRF.  
12.3. 
DATA CODING 
Adverse events, concomitant diseases, medical/surgical histories will be coded by the 
subcontractor using the MedDRA dictionary (latest version in use). 
Concomitant medication will be coded by the subcontractor using the WHO-DRUG dictionary 
(latest version in use).  
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The Sponsor Clinical Development Physician will validate the coding. 
12.4. 
DATA STORAGE 
Computer data files as well as their modifications will be archived by the subcontractor and kept 
available upon request of the Sponsor. 
12.5. 
DATABASE LOCK 
The validated database will be locked by the subcontractor upon request of the Data Manager of 
PFB following the completion of all steps required, i.e. data entry and check of all data, resolution 
of all queries, validation of the coding, Clinical and Products Safety databases reconciliation and 
validation committee.  
Then, the subcontractor will transfer the locked database in SAS format to the Data Manager of 
PFB who assume storage on the PFB secured server. 
13. STATISTICAL ANALYSIS 
After the database lock and the randomisation code release, the statistical analysis will be 
performed by PFB or under the supervision of the statistician of PFB using SAS® software, 
according to the Statistical Analysis Plan approved by the Validation Committee. 
13.1. 
GENERAL CONSIDERATIONS 
The main objective of the study is to assess the efficacy of F373280 versus placebo on the 
maintenance of sinus rhythm after direct ECV in patients with persistent AF and chronic heart 
failure. 
Only the primary analysis of the primary efficacy criterion, on which is based the sample size 
justification, may lead to a causal interpretation. All other statistical results are to be regarded 
within a descriptive perspective. 
The statistical significance level of the various two sided tests of all analyses will be 5 %. 
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13.2. 
SAMPLE SIZE 
Assuming an AF recurrence rate of 85% under placebo and 65% under active group, i.e. a 
clinically relevant difference ∆ of 20%, a sample size of 64 assessable patients per group is 
required, using a log-rank test of survival curves with a 80 % power and a 5 % two-sided 
significance level. 
According to the previous assumptions and assuming a rate of not assessable patients of 15%, a 
minimum of 76 patients will have to be randomised per group. 
13.3. PROTOCOL DEVIATIONS 
Prior to the database lock and the randomisation code release, the Validation Committee members 
will review the protocol deviations and will classify them as either minor or major. A protocol 
deviation will be considered major when it is likely to bias significantly the treatment effect 
estimate based on the primary efficacy criterion. 
Patients with major deviation(s) will be excluded from the Per Protocol data set (see section 13.4). 
A listing of all protocol deviations will be provided for all randomised patients, including the type 
(major/minor) of protocol deviations according to the decisions made by the members of the 
Validation Committee. 
The number and percentage of patients with major protocol deviations will be tabulated by 
treatment group and type of major protocol deviations on the Full Analysis Set defined in section 
13.4. 
13.4. DATA SETS ANALYSED 
The following 3 data sets will be analysed (as defined by the Validation Committee):  
 
• The Safety Set composed of all randomised patients having received at least one dose of 
the study treatment. This data set will be used to perform analyses of Safety. 
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• The Full Analysis Set (FAS) composed of all randomised patients having received at least 
one dose of the study treatment and with a successful cardioversion observed at visit 3. 
This data set will be used to perform analyses of Efficacy.  
• The Per Protocol Set (PP) which is the subset of the Full Analysis Set composed of all 
patients with a primary efficacy criteria available and without any major protocol 
deviation or other source of bias for primary criteria analyses. This data set will be used to 
perform the supportive analysis of the primary efficacy criterion. 
13.5. 
HANDLING OF DROPOUTS AND MISSING DATA 
13.5.1. Dropouts 
The number of patients who withdraw from the study after their randomisation will be provided 
by treatment group for all treated patients (Safety Set). All withdrawn patients will be further 
described regarding their time to dropout and reasons for withdrawal. 
13.5.2. Repositioning of Visits 
No repositioning of visits will be done. 
13.5.3. Missing Data 
Missing values will not be substituted by estimated values, but considered as missing in statistical 
analysis. 
13.6. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Before the first trial drug intake, patient’s background, medical and surgical history, demographic 
data and disease characteristics will be described by treatment group on the Safety Set. 
- Quantitative parameters will be described by treatment group and overall using the 
following: number of patients, number of missing data, mean, standard deviation, 
minimum, median and maximum values. 
- Qualitative parameters will be described by treatment group and overall using 
frequencies. 
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Concomitant diseases, as well as medical and surgical histories will be tabulated descriptively by 
treatment group and overall using the MedDRA codes of System Organ Classes and preferred 
terms. 
If more than 10% of patients are excluded from the FAS and PP set, the description of patients by 
treatment group at selection and inclusion will be repeated on the FAS and PP set for all 
parameters. 
No statistical test of comparability of treatment groups at baseline will be performed.  
13.7. 
EFFICACY ANALYSIS  
13.7.1. Primary Criterion  
13.7.1.1. 
Primary Analysis 
The primary criteria, time to first recurrence, will be analysed using the Kaplan Meier method and 
compared with the Log rank test. Hazard ratios and 95% confidence intervals will be estimated 
with the Cox regression model. 
The primary analysis will be performed on the FAS. 
13.7.1.2. 
Supportive Analysis 
The primary analysis will be repeated on the PP set. 
13.7.2. Secondary Criteria 
All secondary analyses will be performed on the FAS. If more than 10% of patients are excluded 
from the PP set, the secondary analyses will be repeated on the PP set.  
13.7.2.1. Numbers of Atrial Fibrillation Episodes 
Both the numbers of AF episodes (symptomatic or not) lasting for at least 10 minutes and with 
duration less than 10 minutes (NSup10 and NInf10) will be described by treatment group and 
compared by the chi-square test (or CMH test adjusted for centre) or Fisher’s exact Test. 
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13.7.2.2. Duration of Atrial Fibrillation Episodes 
The duration of all AF Episodes will be described by treatment group and compared using the 
Student t (or using an ANOVA with treatment and centres effects) or Wilcoxon test. 
13.7.2.3. Time to first AF recurrence less than 10 minutes or symtomatic 
The time to the first AF recurrence less than 10 minutes and the time to the first symptomatic AF 
recurrence will be analysed as the primary analysis.  
13.7.2.4. Clinical parameters evaluation 
The EHRA score will be described by treatment group and analysed using a chi-squared test (or 
CMH test adjusted for centre) or Fisher’s exact Test.  
The frequency of presumed arrhythmia will be described by treatment group. 
The number of recurrence of symptomatic AF, of hospitalizations (for cardiovascular events, for 
thromboembolic stroke and for all causes), of spontaneous cardioversion, of successful 
cardioversion (including number of shocks distribution) and the number of patients needing 
cardioversion after initial ECV will be described by treatment group and compared using a chi-
square test or a Fisher Test (if the numbers are relevant).  
The duration of hospitalizations for cardiovascular events, for thromboembolic stroke and for any 
cause will be described by treatment group and compared using the Student t (or using an 
ANOVA with treatment and centre effects) or Wilcoxon test. 
The echocardiographic parameters values will be described at each time (V1, V2, V4, V6 and V9) 
and changes described from V4 to V9 and from V2 to V9. 
13.7.2.5. Biomarker analysis: red blood cell concentrations of DHA 
Values and changes from baseline for red blood cell concentration of DHA will be performed by 
treatment group and assessment time. 
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13.8. 
SAFETY ANALYSIS 
The Safety Set will be used to perform all analyses of the safety criteria. 
13.8.1. Adverse Events 
Any adverse event having been reported during the study for a given patient will be classified by 
preferred term and corresponding system organ class using the MedDRA terminology. 
Adverse events will be classified as: 
• Treatment emergent adverse events, i.e., any adverse event which occurs or worsens on 
study treatment during the randomised period. 
• Or non treatment emergent adverse events, i.e., any adverse event which occurs during the 
run-in period (before V2) or is reported as concomitant disease with the same intensity. 
For each study period, any patient with at least one reported adverse event will be classified as a 
patient: 
• With at least one adverse event 
• With at least one treatment emergent adverse event 
• With one TEAE 
• With two TEAEs 
• With at least three TEAEs 
• With at least one related TEAE 
• With an adverse event leading to the study treatment discontinuation (definitive or 
temporary) 
• With an adverse event leading to withdrawal 
• With at least one serious adverse event. 
Numbers and percentages of patient with at least one reported treatment emergent adverse event 
will be tabulated by treatment group: 
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• By system organ class 
• By system organ class and preferred term 
• By system organ class and preferred term, taking into consideration its most severe 
intensity 
• And by system organ class and preferred term, taking into consideration the most severe 
relationship to the study treatment. 
Recurring adverse events (i.e., adverse events classified with the same preferred term) for a given 
patient will only be counted once and only their most severe intensity or most severe relationship 
to the study treatment will be tabulated. 
The number and percentage of patient with at least one most common (reported in 1% patients in 
any group) drug related TEAE ("not excluded or unassessable") will be tabulated by Preferred 
Term and Treatment group in decreasing order for the treatment group (for all patients). 
The number and percentage of patients with at least one reported most common treatment 
emergent adverse event will also be plotted by treatment group. This graphical representation will 
highlight the frequencies of the most severe intensities reported by system organ class and 
preferred term. 
SAE will also be described on an individual basis: treatment group, patient's code, sex and age, 
Investigator's reported term, preferred term, time of onset according to the time of the first study 
treatment administration, duration, action taken regarding the study treatment administration, use 
of a corrective treatment, outcome and relationship to the study treatment in the Investigator’s 
opinion. 
13.8.2. Clinical Laboratory Evaluation  
For each laboratory parameter, data will be tabulated by treatment group and assessment time. 
The absolute changes post-trial drug administration - baseline (the baseline value being the value 
measured on the last blood sample collected before the first trial drug administration) will be 
calculated and tabulated by parameter, treatment group and post-trial drug administration 
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assessment time. Results of retests performed post-trial drug administration will not be analysed 
and tabulated. They will only be displayed in individual data listings. 
For all biochemistry parameters, scatter plots highlighting individual results will display the 
baseline and week 24 of the laboratory measurements for each patient by locating the point 
defined by the baseline value on the abscissa and respectively week 24 value in the ordinate.  
For all haematology parameters, scatter plots highlighting individual results will display the 
baseline and week 4, week 12 and week 24 of the laboratory measurements for each patient by 
locating the point defined by the baseline value on the abscissa and respectively week 4, week 12 
and week 24 value in the ordinate.  
Each treatment group will be differently identified. The first bisecting line (45° line), the lines of 
lower and upper normal range, the lines of Potentially Clinically Significant Change (PSC) range 
and Clinically noteworthy abnormal laboratory value (CNALV) range added on the plots (see 
Appendix 17.3). 
For all blood laboratory parameters, shift tables will be provided to depict the numbers of  patients 
with post-trial drug administration variations at each assessment time as compared to the baseline 
values (measured on the last blood sample collected before the first trial drug administration) by 
treatment group. A 3-point scale (low, normal, high) will be used as defined by the normal ranges 
in use in the laboratory in charge of the assays. 
CNALV (see in Appendix 17.3) will be identified and described on an individual basis. If 
relevant, five separate individual data listings by treatment group will be provided: 
• CNALV for haemoglobin (including corresponding individual results of erythrocytes and 
haematocrit) 
• CNALV for neutrophils or leucocytes (including corresponding individual results of 
basophils, eosinophils, lymphocytes and monocytes) 
• CNALV for platelets (including corresponding individual results of erythrocytes and 
leucocytes) 
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• CNALV for liver function parameters (including corresponding individual results of 
gamma-GT) 
• CNALV for serum creatinine  
13.8.3. Global Physical Examination 
Recorded data of the global physical examination performed will not be tabulated as any 
abnormal findings post-randomisation should be reported as AEs (if clinically significant). 
Physical examination assessments will be provided in the listings of individual data. 
13.8.4. Vital Signs, Physical Findings and Other Observations Related to Safety 
13.8.4.1. 
Vital Sign Measurements Over Time 
For each parameter (systolic blood pressure, diastolic blood pressure and HR in supine and 
standing positions), descriptive statistics over time of values and changes from baseline will be 
tabulated by treatment group and assessment time. 
13.8.4.2. 
Body weight 
Descriptive statistics over time of values and changes from baseline will be tabulated by treatment 
group and assessment time. 
13.8.4.3. 
Individual Patient Changes 
The number and percentage of patient with at least one Predefined Potentially Clinically 
Significant Change (PSC) and with at least one PSC Leading to Clinically Significant Value 
(PSCV) will be tabulated by treatment group (see Table 1 in Appendix 17.3).  
According to the pharmacological drug profile mentioned previously in this Protocol, the changes 
from baseline to the maximum and/or minimum post-baseline value could be categorized and 
tabulated by treatment group with frequencies and decreasing cumulative percentages. 
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If there is a signal of a drug effect toward one direction rather than the other, additionally shift 
tables of variations from baseline to the maximum or minimum post-baseline value could be also 
provided (see Table 2 to 4 in Appendix 17.3). 
An individual data listing of patients with symptomatic or asymptomatic orthostatic hypotension 
will be provided by treatment group (see Table 5 in Appendix 17.3). 
13.8.5. ECG 
Frequencies on the clinical interpretation (normal, abnormal CS or NCS) will be presented by 
treatment group and assessment time. Individual tabulated data for ECG abnormalities will be also 
displayed. 
13.8.6. Coagulation parameters 
Scatter plots highlighting individual results for coagulation parameters (prothrombin time/INR, 
activated partial thromboplastin time and thrombin clotting time) before and after study treatment 
administration will be produced. 
13.9. CONCOMITANT TREATMENTS 
Concomitant treatments will be tabulated by treatment group within a descriptive perspective. 
They will be classified by therapeutic area according to the WHO-DRUG dictionary using the 
"anatomical therapeutic chemical" classification on the safety set. 
13.10. 
COMPLIANCE 
 
The percentage of compliance will be described by treatment group using the quantity 
 
100
_
_
_
(%)
×
=
n
consumptio
l
Theoretica
n
consumptio
actual
Estimated
Compliance
 
 
 
with: Estimated actual consumption = number of tablets provided at the start of study (Visit 2) 
minus number of tablets returned at the end of study (Visit 9) 
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Theoretical consumption = number of days of treatment intake planned between the start and the 
end of study (168 days ± 7days) 
 
13.11. 
INTERIM ANALYSIS AND DATA MONITORING 
No interim analysis is planned. 
14. GENERAL ETHICAL CONSIDERATIONS  
14.1. 
ETHICAL CONDITIONS 
This study is performed in accordance with the principles stated in the Declaration of Helsinki 
(1964) and subsequent amendments and in accordance with the Good Clinical Practice Guideline 
(CPMP/ICH/135/95). 
14.2. 
ETHICS COMMITTEE AND LEGAL REQUIREMENTS 
All the documents required by National Regulations and any other informative documents that 
may be requested are submitted for review to an Ethics Committee whose procedures and 
operations meet the GCP and National Legal Requirements. 
Depending on National Regulations, the application is submitted to the Ethics Committee by the 
Sponsor (or representative) or by the Investigator. 
A copy of the formal written approval from the Ethics Committee is provided to the Sponsor 
(directly by the Ethics Committee or via the Investigator) with a list of names and qualifications 
of its members. 
The request for authorisation by the Competent Authority or its notification if required (depending 
on National Regulations) is carried out by the Sponsor. 
The screening of patients does not start before the approval of the Ethics Committee has been 
obtained and the study authorised by the Competent Authority or notified to the Competent 
Authority (depending on National Regulations). 
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14.3. 
PATIENT'S INFORMATION LEAFLET AND INFORMED CONSENT 
 
FORM 
An information must be given to the patients before their decision to participate or abstain from 
participation. 
This information is based on the elements set out in the Declaration of Helsinki and the ICH GCP 
Guidelines. It must also describe the measures taken to safeguard patient’s privacy and protection 
of personal data, according to European Directive 95/46 EC or other local regulation. 
Restraints and risks must be explained, as well as the right to discontinue participation in the 
study at any stage, without affecting their further relationship with the Investigator and/or their 
future care. 
The written information and consent form must be submitted to the patient with an oral 
explanation. It must be agreed and signed by the patient before any study-related procedure starts. 
This information and consent procedure is under the Investigator’s responsibility. 
The information and consent document are made in triplicate: the original copy is kept by the 
Investigator, one copy is given to the patient and the last copy is kept by the Clinical Quality 
Assurance Unit of the Sponsor in a sealed envelope at the end of study (except in case of specific 
country requirement). 
Specific areas of the Sponsor’s copy are not triplicated to avoid the reading of the patient’s 
surname (except the first 3 letters), first name, address and signature.  
If any information becomes available during the trial that may be relevant to the patient’s 
willingness to keep on participating in the trial, an updated written informed consent must be 
submitted to the patient to confirm  agreement to continue participating. 
14.4. 
PERSONAL DATA PROTECTION 
All information from this study (excluding data from the informed consent) is entered into a 
computer under the Sponsor’s responsibility in accordance with the French law, "Loi 
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Informatique et Libertés" (January 6, 1978, and subsequent amendments) and with the European 
Directive 95/46/CE. 
14.5. 
INSURANCE POLICY 
In accordance with the provisions of the law and the GCP, the Sponsor Pierre Fabre Médicament, 
has an insurance policy intended to guarantee against possible damage resulting from the research. 
The studies and/or experiments performed on behalf of the Sponsor Pierre Fabre Médicament are 
specifically and expressly guaranteed. 
It is advisable to underline that non compliance with the Research Legal Conditions is a cause for 
guarantee exclusion. 
15. ADMINISTRATIVE PROCEDURES 
15.1. 
PROTOCOL AMENDMENT 
Neither the Investigator nor the Sponsor may alter the protocol without the authorisation of the 
other party.  
All changes to the protocol are subject to an amendment which must be dated and signed by both 
parties and must appear as an amendment to the protocol. 
Substantial amendments are submitted for approval / authorisation to the Ethics Committees and 
Competent Authorities 
Urgent amendments are submitted for approval / authorisation to the Ethics Committees and 
Competent Authorities, but could be implemented immediately under specific conditions defined 
with the Sponsor. 
15.2. 
SOURCE DOCUMENTS, INVESTIGATOR'S FILE STORAGE 
The Investigator: 
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• Keeps all trial-related documents in appropriate file folders. Records of patient, original 
informed consent forms, source documents, a CD Rom containing a pdf copy of e-CRF, 
drug inventory, Ethics Committees and Sponsor correspondence pertaining to the study 
must be kept on file. 
• Retains all documents relating to the screening (consent and investigation results) of all 
patients included in the trial or not. 
• Retains a list of the patient’s names, addresses (and/or number of medical file), code 
numbers to allow checking of data reported on e-CRFs with those from source documents. 
• Authorises direct access to source documents for monitoring, audits and inspections. 
• The trial-related documents must be retained as strictly confidential at the Investigator’s 
site for at least 15 years or according to local requirements, whatever is the longest after 
the completion or discontinuation of the trial (European Directive 2003/63/EC). 
15.3. 
END OF THE STUDY 
15.3.1. Definition of the End of Study 
The end of study is the last visit of the last patient undergoing the trial. 
Any change to this definition during the study, for whatever reason, must be notified as a 
substantial amendment. 
15.3.2. Early Study Termination 
15.3.2.1. 
Early Study Termination Decided by the Sponsor 
The Sponsor may discontinue the study at any time for any of the following reasons: 
• Lack of recruitment 
• Deviations from good clinical practice and/or regulations 
• Poor product safety 
• New information that could jeopardise the patient’s safety 
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• Stopping of the development … 
15.3.2.2. 
Early Study Termination Decided by the Competent Authorities 
The Competent Authorities may suspend or prohibit a study if they consider that either the 
conditions of authorisation are not being met or has doubt about the safety or scientific validity of 
the study. 
15.4. 
AUDIT 
The Sponsor is responsible for making sure that both its representatives (Study Manager, CRA...) 
and the Investigator fulfil the requirements as specified by the GCP Guideline.  
An audit can be organised internally at Pierre Fabre Médicament and at the investigational site 
where the e-CRFs are matched against source documents. 
All study documentation must be directly accessible to auditors. 
The practical conditions for the audit are discussed between the Investigator and the Clinical 
Quality Assurance Department. 
Oral information about the audit results are given to the Investigator. 
15.5. INSPECTION 
The Health Authorities may inspect any investigation site or the Sponsor in the course of the study 
or after its completion, to verify the conduct of the study and quality of the data. The Investigator 
must provide to the inspectors direct access to study documents. 
15.6. CONFIDENTIALITY 
The present materials (protocol and related documentation, e-CRF, Investigator's Brochure) 
contain confidential information.  
Except if agreed in writing with the Study Manager, the Investigators must hold such information 
confidential, and must not disclose it to others (except where required by Applicable Law). 
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15.7. CLINICAL STUDY REPORT 
Data analysis and clinical study report writing are under the Sponsor’s responsibility.  
Upon data analysis completion, a final report including a review of the objectives and methods, a 
presentation and a discussion of the results is drawn up according to ICH Guidelines (Structure 
and Content of Clinical Study Reports, ICH-E3, CPMP/ICH/137/95). 
The report is a clinical and statistical integrated report. It must be signed by the Sponsor's 
representative(s) and the Coordinating Investigator. 
15.8. STUDY RESULTS COMMUNICATION 
Upon completion of the study, the global results of the Research are communicated to the 
Investigator. According to the Local Regulation, the patient can ask the Investigator for the 
results. 
15.9. STUDY RESULTS PUBLICATION 
The information and data collected during the conduct of this clinical study are considered 
confidential and are used by the Sponsor in connection with the development of the study drug. 
This information may be disclosed if deemed necessary by the Sponsor. 
To allow the use of the information derived from this clinical study and to insure compliance with 
Current Regulations, the Investigator must provide the Sponsor with complete test results and all 
data collected during the study.  
Only the Sponsor may make study information available to physicians and to Regulatory 
Agencies, except as required by Current Regulations. 
All the results of this study including data, reports, discoveries and inventions resulting from the 
study, are the property of the Sponsor. 
In the event the Sponsor chooses to publish study data, the manuscript must be provided to the 
author(s) at least 30 days prior to the expected date of submission to the intended publisher. 
The Investigator(s) can reserve the right to publish or present study data; if so, the manuscript or 
abstract must be provided to the Sponsor for review at least 30 days prior to the expected date of 
submission to the intended publisher or of planned presentation. 
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In addition, if necessary, (the) Investigator(s) shall withhold publication for an additional 60 days, 
to allow the filing of a patent application, or to allow the Sponsor to take any measures he deems 
appropriate to establish and preserve his proprietary rights. 
It is agreed that publication of study results by each site shall be made only as part of a 
publication of the study results obtained by all sites performing the protocol, once the study is 
completed and finalised.  
The authors list is agreed by all Investigators prior to publication. The names of the authors are 
provided according to their participation in the design of the protocol as well as their recruitment 
of eligible and analysable patients. 
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16. REFERENCES 
 
[1] 
F373280 INVESTIGATOR'S BROCHURE, version October 2013 
 
[2] 
NODARI S., TRIGGIONAI M., CAMPIA U., MANERBA A., MILESI G., CESANA 
M.B., GHEORGHIADE M., DEI CAS L. 
n-3 Polyunsaturated Fatty Acids in the prevention of atrial Fibrillation Recurrences after 
electrical cardioversion. A prospective, Randomised study 
Circulation, 2011; 124:1100-1106 
 
[3] 
NODARI S., TRIGGIANI M., CAMPIA U., MANERBA A., MILESI G., CESANA 
M B., GHEORGHIADE M., DEI CAS L. 
Effects of n-3 polyunsaturated fatty acids on left ventricular function and functional 
capacity in patients with dilated cardiomyopathy 
J. Am. Coll. Cardiol. 2011;57;870-879 
 
[4] 
MOERTL D., HAMMER A., STEINER S., HUTULEAC R., VONBANK K., 
BERGER R. 
Dose-dependant effects of omega-3-polyunsaturated fatty acids on systolic left ventricular 
function, endothelial function, and markers of inflammation in chronic heart failure of non 
ischemic origin: A double-blind, placebo-controlled, 3-arm study  
American Heart Journal 2011; 161:915.e1-915.e9 - volume 161, number 5 
 
[5] 
GISSI-HF INVESTIGATORS 
Effects of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GSSI-
HF Trial): a randomised, double-blind, placebo-controlled trial 
The lancet on line - August 2008 
 
[6] 
CAMM A.J., KIRCHHOF P., LIP G.Y., SCHOTTEN U., SAVELIEVA I., ERNST S., 
VAN GELDER I.C., AL-ATTAR N., HINDRICKS G., PRENDERGAST B., 
HEIDBUCHEL H., ALFIERI O., ANGELINI A., ATAR D., COLONNA P., DE 
CATERINA R., DE SUTTER J., GOETTE A., GORENEK B., HELDAL M., 
HOHLOSER S.H., KOLH P., LE HEUZEY J.Y., PONIKOWSKI P., RUTTEN F.H. 
Guidelines for the management of atrial fibrillation: the Task Force for the Management of 
Atrial Fibrillation of the European Society of Cardiology (ESC). 
European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery,  
Eur Heart J. 2010 Oct;31(19):2369-429 
 
 
[7] 
KOWEY PR, REIFFEL JA, ELLENBOGEN KA, NACCARELLI GV, PRATT CM. 
Efficacy and safety of prescription omega-3 fatty acids for the prevention of recurrent 
symptomatic atrial fibrillation: a randomised controlled trial. 
JAMA. 2010;304:2363–2372. 
 
 
 
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[8] 
BIANCONI L., CALO L., MENNUNI M., SANTINI L., MOROSETTI P., 
AZZOLINI P., BARBATO G., BISCIONE F., ROMANO P., SANTINI M.  
N-3 polyunsaturated fatty acids for the prevention of arrhythmia recurrence after electrical 
cardioversion of chronic persistent atrial fibrillation: a randomised, double-blind, 
multicentre study  
Europace (2011) 13, 174-181 
 
[9] 
OMACOR® SUMMARY PRODUCT CARACTERISTICS (SPC) dated 17/02/2012 
 
[10] 
BEPANTHENE ® SUMMARY PRODUCT CARACTERISTICS (SPC) 
 
[11] 
TOUBOUL P, BRUGADA J, CAPUCCI A, CRIJNS HJ, EDVARDSSON N, 
 
HOHNLOSER SH.  
Dronedarone for prevention of atrial fibrillation: a dose-ranging study.  
Eur Heart J 2003;24(16):1481-7. 
 
[12] LE HEUZEY JY AND ALL.  
A Short-Term, Randomised, Double-Blind, Parallel-Group Study to Evaluate the Efficacy 
and Safety of Dronedarone versus Amiodarone in Patients with Persistent Atrial 
Fibrillation: The DIONYSOS Study. 
J Cardiovasc Electrophysiol. 
 
[13] METCALF G.R., JAMES J.M., GIBSON A.R., EDWARDS J., STUBBERFIELD J., 
STUKLIS R., YOUNG D.G., ROBERTS-THOMSON K. & CLELAND G.L.M.L. & 
OKEN H. 
Effects of fish-oil supplementation on myocardial fatty acids in humans.  
Am J Clin Nutr (2007); 85 : 1225. 
 
[14] ARTERBURN M.L. & OKEN H. 
Distribution, interconversion and dose response of n-3 fatty acids in humans.  
Am J Clin Nutr (2006);83 : 1469-1473S. 
 
[15] TIELEMAN RG, VAN GELDER IC, CRIJNS HJ, DE KAM PJ, VAN DEN BERG 
MP, HAAKSMA J, VAN DER WOUDE HJ, AND ALLESSIE MA. 
Early recurrences of atrial fibrillation after electrical cardioversion: a result of 
fibrillation-induced electrical remodelling of the atria? 
J. Am. Coll. Cardiol. 1998;31;167-173 
 
[16] 
SALM P, TAYLOR PJ, KOSTNER K 
Simultaneous quantification of total eicosapentaenoic acid, docosahexaenoic acid and 
arachidonic acid in plasma by high-performance liquid chromatography-tandem mass 
spectrometry.  
Biomed Chromatogr 2011 Jun;25(6):652-9. 
 
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[17] LEGRAND P., SCHMITT B., MOUROT J., CATHELINE D., CHESNEAU G., 
MIREAUX M., KERHOAS N., WEILL P. 
The consumption of food products from linseed-fed animals maintains erythrocyte omega-3 
fatty acids in obese human 
Lipids, 2010, 45, 11-19. 
 
[18] HARRIS WS, VON SCHACKY C. 
The Omega-3 Index: a new risk factor for death from coronary heart disease? 
Prev Med. 2004 Jul; 39(1):212-20 
 
[19] ABSTRACT: P5161 . 
NODARI S, MANERBA A., MADURERI A., BERLINGHIERI N., PULCINI E., 
FRATTINI S., METRA M, DEI CAS L. 
Effects of Polyunsaturated Fatty Acids n-3 (PUFA n-3) in the prophylaxis of atrial 
fibrillation relapses after external electric cardioversion 
World Congress of Cardiology 2006, 2-6 September, Barcelona – Spain 
 
[20] 
KIRCHHOF P., AURICCHIO A., BAX J., CRIJNS H., CAMM J., DIENER HC., 
 
GOETTE A., HINDRICKS G., HOHNLOSER S., KAPPENBERGER L., KUCK 
 
KH., LIP HYG., OLSSON B., MEINERTZ T., PRIORI S., RAVENS U., 
 
STEINBECK G., SVERHAGE E., TIJSSEN J., VINCENT A., BREITHARDT G. 
 
Outcome parameters from a consensus conference organized by the German Atrial 
 
Fibrillation Competence NETwork and the European Heart Rhythm Association. 
 
Europace 2007, 9, 1006-1023 
 
[21] 
EUROPEAN MEDICINES AGENCY 
 
Addendum to the guideline on antiarrhythmics on atrial fibrillation and atrial flutter. 
 
EMA/CHMA/EWP/213056/2010 
 
[22] 
OWEN AJ, PETER-PRZYBOROWSKA BA, HOY AJ, MCLENNAN PL. 
Dietary fish oil dose- and time-response effects on cardiac phospholipid fatty acid 
composition. 
Lipids. 2004;39:955–961 
 
[23] 
ROBERTO M. LANG, MICHELLE BIERIG, RICHARD B. DEVEREUX, FRANK 
A. FLACHSKAMPF*, ELYSE FOSTER, PATRICIA A. PELLIKKA, MICHAEL H. 
PICARD, MARY J. ROMAN, JAMES SEWARD, JACK SHANEWISE, SCOTT 
SOLOMON, KIRK T. SPENCER, MARTIN ST. JOHN SUTTON, WILLIAM 
STEWART. 
 
Recommendations for chamber quantification 
 
Eur J Echocardiography (2006) 7, 79-108 
 
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17. APPENDICES 
 
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17.1. DECLARATION OF HELSINKI 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
ETHICAL PRINCIPLES FOR MEDICAL RESEARCH INVOLVING 
HUMAN SUBJECTS 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 29th WMA 
General Assembly, Tokyo, Japan, October 1975 35th WMA General Assembly, Venice, Italy, October 1983 41st 
WMA General Assembly, Hong Kong, September 1989 48th WMA General Assembly, Somerset West, Republic of 
South Africa, October 1996 52nd WMA General Assembly, Edinburgh, Scotland, October 2000 53th WMA General 
Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 55th WMA General Assembly, Tokyo 
2004 (Note of Clarification on Paragraph 30 added) 59th WMA General Assembly, Seoul, October 2008 
 
A. INTRODUCTION  
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of 
ethical principles for medical research involving human subjects, including research on identifiable 
human material and data. The Declaration is intended to be read as a whole and each of its constituent 
paragraphs should not be applied without consideration of all other relevant paragraphs.  
2. Although the Declaration is addressed primarily to physicians, the WMA encourages other participants 
in medical research involving human subjects to adopt these principles.  
3. It is the duty of the physician to promote and safeguard the health of patients, including those who are 
involved in medical research. The physician's knowledge and conscience are dedicated to the fulfilment 
of this duty.   
4. The Declaration of Geneva of the WMA binds the physician with the words, “The health of my patient 
will be my first consideration,” and the International Code of Medical Ethics declares that, “A physician 
shall act in the patient's best interest when providing medical care.”  
5. Medical progress is based on research that ultimately must include studies involving human subjects. 
Populations that are underrepresented in medical research should be provided appropriate access to 
participation in research.  
6. In medical research involving human subjects, the well-being of the individual research subject must 
take precedence over all other interests.  
7. The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic interventions 
(methods, procedures and treatments). Even the best current interventions must be evaluated continually 
through research for their safety, effectiveness, efficiency, accessibility and quality.  
8. In medical practice and in medical research, most interventions involve risks and burdens.  
9. Medical research is subject to ethical standards that promote respect for all human subjects and protect 
their health and rights. Some research populations are particularly vulnerable and need special 
protection. These include those who cannot give or refuse consent for themselves and those who may be 
vulnerable to coercion or undue influence.  
10. Physicians should consider the ethical, legal and regulatory norms and standards for research involving 
human subjects in their own countries as well as applicable international norms and standards. No 
national or international ethical, legal or regulatory requirement should reduce or eliminate any of the 
protections for research subjects set forth in this Declaration.  
 
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B. PRINCIPLES FOR ALL MEDICAL RESEARCH  
11. It is the duty of physicians who participate in medical research to protect the life, health, dignity, 
integrity, right to self-determination, privacy, and confidentiality of personal information of research 
subjects.  
12. Medical research involving human subjects must conform to generally accepted scientific principles, be 
based on a thorough knowledge of the scientific literature, other relevant sources of information, and 
adequate laboratory and, as appropriate, animal experimentation. The welfare of animals used for 
research must be respected.   
13. Appropriate caution must be exercised in the conduct of medical research that may harm the 
environment.  
14. The design and performance of each research study involving human subjects must be clearly described 
in a research protocol. The protocol should contain a statement of the ethical considerations involved 
and should indicate how the principles in this Declaration have been addressed. The protocol should 
include information regarding funding, sponsors, institutional affiliations, other potential conflicts of 
interest, incentives for subjects and provisions for treating and/or compensating subjects who are 
harmed as a consequence of participation in the research study. The protocol should describe 
arrangements for post-study access by study subjects to interventions identified as beneficial in the 
study or access to other appropriate care or benefits.   
15. The research protocol must be submitted for consideration, comment, guidance and approval to a 
research ethics committee before the study begins. This committee must be independent of the 
researcher, the sponsor and any other undue influence. It must take into consideration the laws and 
regulations of the country or countries in which the research is to be performed as well as applicable 
international norms and standards but these must not be allowed to reduce or eliminate any of the 
protections for research subjects set forth in this Declaration. The committee must have the right to 
monitor ongoing studies. The researcher must provide monitoring information to the committee, 
especially information about any serious adverse events. No change to the protocol may be made 
without consideration and approval by the committee.  
16. Medical research involving human subjects must be conducted only by individuals with the appropriate 
scientific training and qualifications. Research on patients or healthy volunteers requires the 
supervision of a competent and appropriately qualified physician or other health care professional. The 
responsibility for the protection of research subjects must always rest with the physician or other health 
care professional and never the research subjects, even though they have given consent.  
17. Medical research involving a disadvantaged or vulnerable population or community is only justified if 
the research is responsive to the health needs and priorities of this population or community and if 
there is a reasonable likelihood that this population or community stands to benefit from the results of 
the research.   
18. Every medical research study involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and communities involved in the research in 
comparison with foreseeable benefits to them and to other individuals or communities affected by the 
condition under investigation.  
19. Every clinical trial must be registered in a publicly accessible database before recruitment of the first 
subject.  
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20. Physicians may not participate in a research study involving human subjects unless they are confident 
that the risks involved have been adequately assessed and can be satisfactorily managed. Physicians 
must immediately stop a study when the risks are found to outweigh the potential benefits or when 
there is conclusive proof of positive and beneficial results.  
21. Medical research involving human subjects may only be conducted if the importance of the objective 
outweighs the inherent risks and burdens to the research subjects.  
22. Participation by competent individuals as subjects in medical research must be voluntary. Although it 
may be appropriate to consult family members or community leaders, no competent individual may be 
enrolled in a research study unless he or she freely agrees.  
23. Every precaution must be taken to protect the privacy of research subjects and the confidentiality of 
their personal information and to minimize the impact of the study on their physical, mental and social 
integrity.   
24. In medical research involving competent human subjects, each potential subject must be adequately 
informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional 
affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort 
it may entail, and any other relevant aspects of the study. The potential subject must be informed of the 
right to refuse to participate in the study or to withdraw consent to participate at any time without 
reprisal. Special attention should be given to the specific information needs of individual potential 
subjects as well as to the methods used to deliver the information. After ensuring that the potential 
subject has understood the information, the physician or another appropriately qualified individual 
must then seek the potential subject’s freely-given informed consent, preferably in writing. If the 
consent cannot be expressed in writing, the non-written consent must be formally documented and 
witnessed.  
25. For medical research using identifiable human material or data, physicians must normally seek consent 
for the collection, analysis, storage and/or reuse. There may be situations where consent would be 
impossible or impractical to obtain for such research or would pose a threat to the validity of the 
research. In such situations the research may be done only after consideration and approval of a 
research ethics committee.   
26. When seeking informed consent for participation in a research study the physician should be 
particularly cautious if the potential subject is in a dependent relationship with the physician or may 
consent under duress. In such situations the informed consent should be sought by an appropriately 
qualified individual who is completely independent of this relationship.  
27. For a potential research subject who is incompetent, the physician must seek informed consent from the 
legally authorized representative. These individuals must not be included in a research study that has 
no likelihood of benefit for them unless it is intended to promote the health of the population 
represented by the potential subject, the research cannot instead be performed with competent persons, 
and the research entails only minimal risk and minimal burden.   
28. When a potential research subject who is deemed incompetent is able to give assent to decisions about 
participation in research, the physician must seek that assent in addition to the consent of the legally 
authorized representative. The potential subject’s dissent should be respected.  
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29. Research involving subjects who are physically or mentally incapable of giving consent, for example, 
unconscious patients, may be done only if the physical or mental condition that prevents giving 
informed consent is a necessary characteristic of the research population. In such circumstances the 
physician should seek informed consent from the legally authorized representative. If no such 
representative is available and if the research cannot be delayed, the study may proceed without 
informed consent provided that the specific reasons for involving subjects with a condition that renders 
them unable to give informed consent have been stated in the research protocol and the study has been 
approved by a research ethics committee. Consent to remain in the research should be obtained as soon 
as possible from the subject or a legally authorized representative.  
30. Authors, editors and publishers all have ethical obligations with regard to the publication of the results 
of research. Authors have a duty to make publicly available the results of their research on human 
subjects and are accountable for the completeness and accuracy of their reports. They should adhere to 
accepted guidelines for ethical reporting. Negative and inconclusive as well as positive results should 
be published or otherwise made publicly available. Sources of funding, institutional affiliations and 
conflicts of interest should be declared in the publication. Reports of research not in accordance with 
the principles of this Declaration should not be accepted for publication.  
 
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE  
31. The physician may combine medical research with medical care only to the extent that the research is 
justified by its potential preventive, diagnostic or therapeutic value and if the physician has good 
reason to believe that participation in the research study will not adversely affect the health of the 
patients who serve as research subjects.   
32. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the 
best current proven intervention, except in the following circumstances:  
• 
The use of placebo, or no treatment, is acceptable in studies where no current proven intervention 
exists; or  
• 
Where for compelling and scientifically sound methodological reasons the use of placebo is 
necessary to determine the efficacy or safety of an intervention and the patients who receive 
placebo or no treatment will not be subject to any risk of serious or irreversible harm.  Extreme 
care must be taken to avoid abuse of this option.  
33. At the conclusion of the study, patients entered into the study are entitled to be informed about the 
outcome of the study and to share any benefits that result from it, for example, access to interventions 
identified as beneficial in the study or to other appropriate care or benefits.  
34. The physician must fully inform the patient which aspects of the care are related to the research. The 
refusal of a patient to participate in a study or the patient’s decision to withdraw from the study must 
never interfere with the patient-physician relationship.  
35. In the treatment of a patient, where proven interventions do not exist or have been ineffective, the 
physician, after seeking expert advice, with informed consent from the patient or a legally authorized 
representative, may use an unproven intervention if in the physician's judgement it offers hope of 
saving life, re-establishing health or alleviating suffering. Where possible, this intervention should be 
made the object of research, designed to evaluate its safety and efficacy. In all cases, new information 
should be recorded and, where appropriate, made publicly available.  
 
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17.2. SAE REPORT FORM 
 
 
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N O T I F I C A T I O N  O F  S E R I O U S  A D V E R S E  E V E N T  ( S A E )  O R  P R E G N A N C Y   
T O  P I E R R E  F A B R E  C O R P O R A T E  V I G I L A N C E S  D I V I S I O N   
 
TO 
BE 
TRANSMITTED 
TO 
THE 
CORPORATE 
VIGILANCES 
DIVISION 
BY 
E-MAIL 
WITHIN 
24H 
TO 
HQ.pharmacovigilance@pierre-fabre.com OR BY FAX WITHIN 24H – Fax N°: 33 (0) 1.49.10.80.90 
Transmission date  
 
 
  
 
  
 
 
 
(ddmmyyyy) 
Country :  
........................................
 
 
 
   SAE N° 
 
 
 
                      FIRST NOTIFICATION           FOLLOW-UP   N° 
 
 SUBJECT CHARACTERISTICS  
 
 
 
 
 
 
 
 
Birth date  
 
 
 
 
 
 
 
 
  
 
 
Gender 
 
1=M,    2=F 
   Height 
 
 
 
cm 
 Weight 
 
 
 
 
 
kg 
 
 
 DESCRIPTION OF THE EVENT 
The serious adverse event resulted in : 
 Death (whatever may be the cause) 
 Hospitalisation (*) or extension thereof 
 Life threatening 
 Invalidity or disability 
 
 Congenital abnormality or abnormal pregnancy outcome 
 Cancer 
 Other  (any other serious clinical or laboratory event 
     according to the investigator or the protocol, overdosage 
      meeting seriousness criteria, suicide attempts) 
Other fact to be notified : 
 Pregnancy exposure 
Nature of the event (if clinical nature, indicate the diagnosis or the major symptom) : 
........................................................................................................................................................................................................... 
........................................................................................................................................................................................................... 
........................................................................................................................................................................................................... 
AE onset date  |__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
 
Seriousness onset date  |__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
 
Summary description (if clinical cause, significant history, progression of event, available laboratory results, etc...) : 
 
 
 
 
 
 
(*) Except hospitalisations with durations and goals planned in the protocol 
 
 THE SAE IN RELATION TO THE TRIAL 
                                                      TREATMENT NUMBER         |___|___|___|___|___|___| 
• Time of occurrence of SAE 
 
 During the selection or run-in period 
 
 During the administration phase of the study treatment 
 
 After the administration phase of the study treatment 
• Date of first study treatment administration 
• Date of last study treatment administration 
   before the occurence of SAE 
|__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
 
|__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
• Was the blind broken ?       Yes         No          Not applicable 
   If yes, or if this is an open study, drug(s) administered : 
 
 
 
 
 
  Conditions of administration (cycles(s), daily dose(s), route(s) of administration, etc..) :  
 
 
 
 
 
 
 
 
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Transmission date 
 
 
  
 
  
 
 
 
  (ddmmyyyy) 
Country : ............................................ 
 
 
 
  SAE N° 
 
 
 
                     FIRST NOTIFICATION           FOLLOW-UP   N° 
 
 CONCOMITANT MEDICATION SINCE TRIAL INITIATION and UP UNTIL THE OCCURRENCE OF THE SAE 
     (EXCEPT THE TREATMENTS GIVEN FOR THE SAE)  
 
Trade name  
(or INN) 
 
 
Daily dose 
 
Start date 
(dd/mm/yy) 
Ongoing at 
occurence of the 
event 
 
Stop date 
(dd/mm/yy) 
Route of 
admin. 
 
Indication 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 MEASURES TAKEN FOLLOWING THE SAE 
• Study treatment 
 
 No change 
 
 Dosage modification, specify :……………………………..….      Modification Date : 
 
 Temporarily discontinued                                                       Readministration date : 
 
 Withdrawn                                                                                                  End date : 
 
 Not applicable 
 
 
 
 
 ____/____/_____ 
 ____/____/_____ 
 ____/____/_____ 
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• The event led to : 
 
 Prescription of corrective or symptomatic treatments: 
 
 
Trade name  
(or INN) 
 
 
Daily dose 
 
Start date 
(dd/mm/yy) 
Ongoing at 
occurence of the 
event 
 
Stop date 
(dd/mm/yy) 
Route of 
admin. 
 
Indication 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
 Discontinuation of concomitant treatments: 
 
 
Trade name  
(or INN) 
 
 
Daily dose 
 
Start date 
(dd/mm/yy) 
Ongoing at 
occurence of the 
event 
 
Stop date 
(dd/mm/yy) 
Route of 
admin. 
 
Indication 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
 Others, specify : 
 
 
 OUTCOME 
         Not recovered/Not resolved                  Recovering/Resolving               Recovered/Resolved 
         Recovered/Resolved with sequelae     Fatal                                          Unknown 
 
                In case of death, has an autopsy been conducted ?       Yes         No 
 
 INVESTIGATOR CAUSALITY ASSESSMENT (investigator’s assessment to be done as soon as possible) 
Study drug:                                                                         Related to study protocol: 
 Not Suspected                 Suspected                             Not Suspected                          Suspected                   
Comments: ............................................................................................................................................................. 
 
Enclose in the notification the results of carried out examinations, reports of hospitalisation, etc... 
 
 
 
 
 
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17.3. PREDEFINED LIMITS OF LABORATORY AND VITAL SIGN 
POTENTIALLY CLINICALLY SIGNIFICANT CHANGES AND VALUES  
 
List of Predefined Potentially Clinically Significant Change For Laboratory Values(¤) 
 
 
PARAMETERS 
UNIT 
PSC 
 
 
 
Decrease 
Increase 
MUSCLE 
Creatine  Phosphokinase 
U / l 
- 
236 
KIDNEY 
Creatinine 
Urea 
Uric acid 
Phosphate 
Calcium 
µmol/l 
mmol/l 
µmol/l 
mmol/l 
mmol/l 
- 
- 
- 
0.39 
0.30 
35 
3.2 
119 
0.39 
0.30 
ELECTROLYTES 
Sodium 
Potassium 
Chloride 
Bicarbonate 
mmol/l 
mmol/l 
mmol/l 
mmol/l 
8 
1.1 
8 
7 
8 
1.1 
7 
8 
METABOLISM/ 
NUTRITIONAL 
Glucose (random) 
Albumin 
Protein 
Cholesterol 
HDL cholesterol 
LDL cholesterol 
Triglycerides 
mmol/l 
g/l 
g/l 
mmol/l 
mmol/l 
mmol/l 
mmol/l 
3 
6 
11 
- 
0.91 
2.17 
- 
3.7 
6 
10 
1.97 
0.85 
2.04 
2.91 
ERYTHROCYTES 
Erythrocyte count 
Haemoglobin 
Haematocrit 
MCV  
MCH (Fe) 
MCHC (Fe) 
T/l 
g/l 
1 
fl 
fmol 
mmol/l 
0.7 
20 
0.06 
7 
0.19 
2 
0.7 
- 
0.06 
7 
0.19 
2 
LEUKOCYTES 
Leukocyte count 
G/l 
4.2 
3.8 
DIFFERENTIAL 
COUNT 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
G/l 
G/l 
G/l 
G/l 
G/l 
3.47 
1.76 
- 
- 
- 
3.19 
1.63 
0.49 
0.41 
0.14 
URINE 
Specific gravity 
pH 
- 
- 
0.017 
2 
0.015 
2 
LIVER 
Total bilirubin 
ASAT (SGOT) 
ALAT (SGPT) 
Gamma GT 
Alkaline phosphatase 
µmol/l 
U/l 
U/l 
U/l 
U/l 
- 
- 
- 
- 
-- 
10 
N x (23/36) 
N x (28/45) 
N x (25/38) 
N x (30/95) 
 
N = upper limit of normal range 
 
(¤) Delta-limits from « Routine Laboratory Tests in Clinical Trials » W. Leigh Thompson, Rocco 
L. Brunelle, Gregory G. Enas, Patrick J. Simpson and Randy L. Walker Lilly Research 
Laboratories, Lilly Corporate Centre, Indianapolis, Indiana in « Clinical Trials and Tribulations » 
1988. 
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Definition of Clinically Noteworthy Abnormal Laboratory Values (CNALV) 
 
 
PARAMETERS 
CNALV 
HAEMOGLOBIN 
 
• Decrease of at least 2g/dl and value < 10 g/dl whatever the baseline 
value 
• If missing baseline : value <10g/dl 
NEUTROPHILS 
• < 1 500/mm3 whatever the baseline value 
WBC 
(if missing value for neutrophils) 
• < 3 000/mm3 whatever the baseline value 
PLATELETS 
• < 100 000/mm3 whatever the baseline value 
SERUM CREATININE 
• Increase of at least 30 % as compared to baseline value and 
value > 150 µmol/l whatever the baseline value 
• If missing baseline : value > 150 µmol/l 
LIVER FUNCTION TESTS 
 
 
ALAT 
 
 If normal baseline :  
 
 
•ALAT > 2 N 
 If abnormal baseline : 
→if baseline value ≤ 2.5 N : 
  
• increase of at least 100 % as compared to baseline value 
→ if baseline value > 2.5 N :  
 
 
• value > 5 N 
and/or 
ASAT 
 
  If normal baseline :  
 
 
• ASAT > 2 N 
  If abnormal baseline : 
→ if baseline value ≤ 2.5 N : 
  
• increase of at least 100 % as compared to baseline value 
→ if baseline value > 2.5 N :  
 
 
• value > 5 N 
and/or 
Alkaline phosphatase (AP) 
 
  If normal baseline :  
 
 
• AP > 1.25 N 
  If abnormal baseline :  
 
 
• AP > 2 N 
and/or 
Total bilirubin (TB) 
  If normal baseline :  
 
 
• TB > 1.5 N 
  If abnormal baseline :  
 
 
• TB > 2 N 
N=upper limit of normal range 
International consensus Meeting. International Journal of Clinical Pharmacology, Therapy and Toxicology, 1990;28:317-322 
Standardisation of definitions and criteria of causality assessment of adverse drug reactions: drugs-induced liver disorders: report 
of an Standardisation of definitions and criteria of causality assessment of adverse drug reactions: drugs-induced cytopenia. 
International Journal of Clinical Pharmacology, Therapy and Toxicology, 1991;29:75-81 
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Cardiovascular Safety 
 
Table 1: Predefined Limits for Potentially Clinically Significant Changes (PSC) and PSC 
Leading to Clinically Significant Values (PSCV) 
 
Parameter 
PSC 
PSCV 
SBP 
Increase ≥ 20 mmHg 
Decrease ≥ 20 mmHg 
SBP ≥ 160 mmHg and increase ≥ 20 mmHg 
SBP ≤ 90 mmHg and decrease ≥ 20 mmHg 
DBP 
Increase ≥ 10 mmHg 
Decrease ≥ 10 mmHg 
DBP ≥ 100 mmHg and increase ≥ 10 mmHg 
DBP ≤ 50 mmHg and decrease ≥ 10 mmHg 
HR 
Increase ≥ 10 bpm 
Decrease ≥ 10 bpm 
HR ≥ 110 bpm and increase ≥ 10 bpm 
HR ≤ 50 bpm and decrease ≥ 10 bpm 
 
Table 2: Predefined Classes for changes from Baseline to the Maximum (and/ or Minimum) 
Post-baseline Value 
Classes of Change from Baseline to the Maximum 
Post-baseline Value 
Classes of Change from Baseline to the 
Minimum Post-baseline Value 
SBP  mmHg 
DBP  mmHg 
HR bpm 
SBP  mmHg 
DBP  mmHg 
HR bpm 
All 
All 
All 
All 
All 
All 
≥  0 
≥  0 
≥  0 
≤  0 
≤  0 
≤  0 
>  0 
>  0 
>  0 
<  0 
<  0 
<  0 
≥ 10 
≥  5 
≥ 10 
≤ -10 
≤ - 5 
≤ -10 
≥ 20 
≥ 10 
≥ 20 
≤ -20 
≤ -10 
≤ -20 
≥ 30 
≥ 15 
≥ 30 
≤ -30 
≤ -15 
≤ -30 
≥ 40 
≥ 20 
 
≤ -40 
≤ -20 
 
 
≥ 25 
 
 
≤ -25 
 
 
≥ 30 
 
 
≤ -30 
 
 
Table 3: Classes for Vital Signs Maximum or Minimum Values 
Classes  for  the Maximum Post-baseline Value 
for each parameter 
Classes  for  the Minimum Post-baseline Value 
for each parameter 
SBP  mmHg 
DBP  mmHg 
HR bpm 
SBP  mmHg 
DBP  mmHg 
HR bpm 
< 120 
< 80 
≤ 50 
≤ 90 
≤ 50 
≤ 50 
[120 ;140[ 
[80;90[ 
]50 ;75[ 
[90 ;120[ 
[50;80[ 
]50 ;75[ 
[140;160[ 
 [90;100[ 
[75;100[ 
[120;140[ 
 [80;90[ 
[75;100[ 
≥ 160 
≥ 100 
≥ 100 
≥ 140 
≥ 90 
≥ 100 
 
Table 4: Classes for Maximum or Minimum of BP in its entirety 
Classification of Maximum Values for Blood 
Pressure (mmHg) 
Classification of Minimum Values Blood 
Pressure (mmHg) 
SBP < 140 and DBP < 90 
SBP > 90 and DBP > 50 
SBP [140;160[ and DBP < 100 
or DBP [90;100[ and SBP < 160 
SBP ≤  90 or DBP ≤  50 
SBP ≥ 160 or DBP ≥ 100 
 
 
Table 5: Definition of orthostatic hypotension 
Orthostatic Hypotension * 
SBP Decrease ≥ 20 mmHg or DBP Decrease ≥ 10 mmHg between supine and standing positions 
* Consensus Committee of the American Autonomic Society and the American Academy of Neurolog :Consensus statement on the definition of 
orthostatic hypotension, pure autonomic failure and multiple system atrophy. Neurology 1996;46:1470-3. 
 
 
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16.1.1.6. 
Protocol and appendices 
(version 06: 02 December 2013) 
 
 
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F 373280 CA 2 01 
 
 
 
 
 
 
 
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Pierre Fabre Médicament 
Represented by: Institut de Recherche Pierre Fabre 
45, Place Abel Gance 
F-92100 Boulogne 
CLINICAL STUDY PROTOCOL 
 
Efficacy and safety study of F373280 for maintenance of sinus rhythm after 
electrical cardioversion in patients with persistent Atrial Fibrillation and 
Chronic Heart Failure. 
International, multicentric, randomised, double-blind, placebo controlled study 
F373280 / Soft Capsules / 1g  
Pierre Fabre Study Code: 
EudraCT Number: 
 
Sponsor's Representative: 
 
 
 
 
 
 
 
 
Study Coordinating Investigator 
F 373280 CA 2 01  
2012 – 003487 - 48 
 
Gaëlle ALCARAZ 
INSTITUT DE RECHERCHE PIERRE FABRE - Centre de 
R&D Pierre Fabre - BP 13562  
3 avenue Hubert Curien  
31035 TOULOUSE Cédex 1, FRANCE 
Phone: +33 5 34 50 62 16  
Fax:+33 5 34 50 69 69  
E-mail:gaelle.alcaraz@pierre-fabre.com  
 
Pr Savina NODARI 
Associate Professor of Cardiology 
Department of Clinical and Surgical Specialities, 
Radiological Science and Public Health 
Section of Cardiovascular Diseases 
University Medical School and Spedali Civili Hospital of 
Brescia 
c/o Spedali Civili di Brescia 
Piazzale Spedali Civili, 1 
25123 - BRESCIA, ITALY 
Phone: +39 030 3996 587 – +39 030 393849 
Fax: +39 030 3700 359 
E-mail: savinanodari@gmail.com; nodari@med.unibs.it 
 
Version 6 –02DEC2013 
 
The information contained in this document is confidential and is the property of the Sponsor, Pierre Fabre 
Medicament. This information is given for the needs of the study and must not be disclosed without prior written 
consent of the Sponsor Pierre Fabre Medicament. Persons to whom this information is given for the needs of the 
study must be informed that it is confidential and must not be disclosed. 
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SPONSOR PERSONNEL 
PIERRE FABRE MEDICAMENT 
represented by 
Institut de Recherche Pierre Fabre 
 
Clinical Study Manager (Monitor) 
Gaëlle ALCARAZ 
Phone: +33 5 34 50 62 16  
Fax: + 33 5 34 50 69 69 
E-mail: gaelle.alcaraz@pierre-
fabre.com 
Institut de Recherche Pierre Fabre 
Centre de R&D Pierre Fabre 
BP 13 562 
3, Avenue Hubert Curien 
31035 TOULOUSE Cedex 1, FRANCE 
 
 
Medical Director 
Richard ROCHE, MD 
Phone: +33 5 34 50 61 94 
Fax: +33 5 34 50 69 69 
E-mail: richard.roche@pierre-
fabre.com 
Institut de Recherche Pierre Fabre 
Centre de R&D Pierre Fabre 
BP 13 562 
3, Avenue Hubert Curien 
31035 TOULOUSE Cedex 1, FRANCE 
 
 
 
 
 
 
 
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CONTRACT RESEARCH ORGANISATIONS 
 
For Feasibility, Monitoring and Regulatory issues: 
Pharmaceutical Service Network (PSN) 
Rufino Gonzalez 
28 037 Madrid - SPAIN 
Phone: +34 91 375 6930 - Fax: +34 91 375 6931 
E-mail: www.psnglobal.org 
 
For Feasibility, Monitoring and Regulatory issues (in Spain): 
Alpha Bioresearch 
Paseo de la Castellana, 163 - 2º Izquierda 
28 046 Madrid - SPAIN 
Phone: +34 91 745 2520 - Fax: +34 91 745 0653 
E-mail: teresa.bricio@alphabioresearch.com 
 
For Centralised Randomisation and Electronic Case Report Form 
S-Clinica 
6, Chaussée de Boondael 
B-1050 Brussels - BELGIUM 
Phone: +32 2 645 0567 - Fax: +32 2 645 0569 
E-mail: irena.seredina@s-clinica.com 
 
For Centralised Reading of Holder ECG and TTEM and equipment supply: 
Biomedical System 
1945 Chaussée de Wavre 
B-1160 Brussels - BELGIUM 
Phone: +32 2 661 20 70 - Fax: +32 2 661 20 71 
E-mail: sjacobs@biomedsys.com 
 
For intra erythrocyte DHA dosage: 
Agrocampus Ouest 
Laboratoire de Biochimie 
65 rue de Saint Brieuc – CS 84215 
35042 RENNES Cedex - FRANCE 
Phone: +33 2 23 48 55 49 - Fax: +33 2 23 48 55 50 
E-mail: daniel.catheline@agrocampus-ouest.fr 
 
For transportation of blood sample to the Analytical centre (Agrocampus) and material 
supply: 
Theradis Pharma 
41, chemin des Presses 
06800 CAGNES-SUR-MER – FRANCE 
Phone: +33 (0)4 97 02 07 07 - Fax: +33 (0)4 97 10 08 78 
E-mail: chantal.raffy@theradis.pharma.com 
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For refund of patients expenses linked to the study (in France): 
CLINACT 
6-10 rue TROYON 
92310 SEVRES – FRANCE 
Phone: +33 1 46 90 27 27 - Fax: +33 1 46 23 01 56 
Email: sebastien.beaumont@clinact.com 
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Final version
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Protocol F 373280 CA 2 01 
COUNTRY COORDINATING INVESTIGATOR  
SIGNATURE FORM 
Protocol Version 6 – 02 DEC 2013 
 
 
Country: …………………….. 
 
Country Coordinating Investigator:  
"Name"  
Date:   
 
 
 
 
 
 
Signature:  
 
 
 
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Protocol F 373280 CA 2 01 
INVESTIGATOR SIGNATURE FORM 
Protocol Version 6 – 02 DEC 2013 
 
 
 
By my signature below, I, Dr / Pr "                                         ", hereby confirm that I agree: 
♦ to conduct the trial described in the protocol F 373280 CA 2 01, dated 02 December 2013 in 
compliance with GCP, with applicable regulatory requirements and with the protocol 
agreed upon by the Sponsor Pierre Fabre Médicament and given approval / favourable* 
opinion by the Ethics Committee; 
♦ to document the delegation of significant study-related tasks and to notify the Sponsor of 
changes in site personnel involved in the study; 
♦ to comply with the procedure for data recording and reporting; 
♦ to allow monitoring, auditing and inspection; 
♦ to retain the trial-related essential documents until the Sponsor informs that these documents 
are no longer needed. 
Furthermore, I hereby confirm that I will have and will use the available adequate resources, 
personnel and facilities for conduct this trial. 
 
I have been informed that certain regulatory authorities require the Sponsor Pierre Fabre 
Médicament to obtain and supply details about the investigator’s ownership interest in the 
Sponsor or the study drug, and more generally about his/her financial relationships with the 
Sponsor. The Sponsor will use and disclose the information solely for the purpose of complying 
with regulatory requirements. 
Hence I agree: 
♦ to supply the Sponsor with any information regarding ownership interest and financial 
relationships with the Sponsor (including those of my spouse and dependent children); 
♦ to promptly update this information if any relevant changes occur during the course of the 
study and for 1 year following completion of the study; 
♦ that the Sponsor may disclose this information about such ownership interests and financial 
relationships to regulatory authorities. 
* To be adapted  
 
Date:  
Signature:  
 
 
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TABLE OF CONTENTS OF CLINICAL STUDY PROTOCOL 
 
1. 
INTRODUCTION AND STUDY RATIONALE ................................................................ 22 
1.1. 
TARGET PATHOLOGY AND THERAPY ........................................................................ 22 
1.2. 
INFORMATION ON THE TEST PRODUCT .................................................................... 24 
1.2.1. 
Chemical and pharmaceutical characteristics .................................................................... 25 
1.2.1.1. 
Nomenclature and structure ............................................................................................ 25 
1.2.1.2. 
Physical and chemical general properties ...................................................................... 25 
1.2.2. 
Non-clinical Data .............................................................................................................. 26 
1.2.2.1. 
Pharmacological profile ................................................................................................. 26 
1.2.2.2. 
Safety pharmacology ...................................................................................................... 27 
1.2.2.3. 
Toxicology profile .......................................................................................................... 27 
1.2.2.4. 
Pharmacokinetic data ..................................................................................................... 27 
1.2.3. 
Clinical data ....................................................................................................................... 27 
1.3. 
STUDY RATIONALE ......................................................................................................... 30 
1.4. 
OVERALL RISK AND BENEFIT ASSESSMENT ............................................................ 30 
2. 
STUDY OBJECTIVES ......................................................................................................... 33 
2.1. 
PRIMARY OBJECTIVE ..................................................................................................... 33 
2.2. 
SECONDARY OBJECTIVES ............................................................................................. 33 
3. 
ETHICAL CONSIDERATIONS RELATING TO THE STUDY .................................... 33 
4. 
STUDY DESIGN ................................................................................................................... 35 
4.1. 
OVERALL DESCRIPTION ................................................................................................ 35 
4.2. 
DISCUSSION OF THE STUDY DESIGN .......................................................................... 35 
4.2.1. 
Choice of the Study Population ......................................................................................... 35 
4.2.2. 
Choice of the Study Design ............................................................................................... 36 
4.2.3. 
Choice of the Dose ............................................................................................................ 38 
4.2.4. 
Choice of the Sample Size ................................................................................................. 38 
5. 
STUDY POPULATION ........................................................................................................ 38 
5.1. 
INCLUSION CRITERIA ..................................................................................................... 38 
5.2. 
NON INCLUSION CRITERIA ........................................................................................... 39 
5.3. 
NUMBER OF PATIENTS ................................................................................................... 40 
5.4. 
RECRUITMENT MODALITIES ........................................................................................ 41 
5.5. 
PATIENT IDENTIFICATION ............................................................................................ 41 
5.6. 
WITHDRAWAL CRITERIA ............................................................................................... 41 
5.7. 
REPLACEMENT OF PATIENTS ....................................................................................... 42 
5.8. 
POST-STUDY EXCLUSION PERIOD .............................................................................. 42 
5.9. 
STUDY CARD AND LETTER FOR GENERAL PRACTITIONER(S) ............................ 42 
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6. 
STUDY TREATMENT ......................................................................................................... 43 
6.1. 
SOURCE, PRESENTATION AND COMPOSITION OF  INVESTIGATIONAL 
PRODUCT ........................................................................................................................... 43 
6.2. 
PACKAGING AND LABELLING ..................................................................................... 43 
6.2.1. 
Packaging .......................................................................................................................... 44 
6.2.2. 
Labelling ............................................................................................................................ 44 
6.3. 
DISTRIBUTION TO CENTRE AND STORAGE .............................................................. 45 
6.4. 
ALLOCATION OF TREATMENTS AND DISPENSATION TO PATIENT ................... 46 
6.5. 
DRUG ADMINISTRATION ............................................................................................... 47 
6.5.1. 
Duration of Treatment ....................................................................................................... 47 
6.5.2. 
Dose Schedule ................................................................................................................... 47 
6.5.3. 
Route and Conditions of Administration ........................................................................... 47 
6.6. 
ACCOUNTABILITY ON SITE AND RETURN/DESTRUCTION OF  
INVESTIGATIONAL PRODUCT ...................................................................................... 47 
6.7. 
RECALL OF INVESTIGATIONAL PRODUCTS ............................................................. 48 
7. 
CONCOMITANT TREATMENTS ..................................................................................... 48 
7.1. 
ANTI-VITAMIN K TREATMENT ..................................................................................... 49 
7.2. 
PROHIBITED TREATMENTS ........................................................................................... 49 
7.3. 
AUTHORISED TREATMENTS ......................................................................................... 49 
8. 
EVALUATION CRITERIA ................................................................................................. 50 
8.1. 
PRIMARY EFFICACY CRITERION ................................................................................. 50 
8.1.1. 
Time to the first Atrial Fibrillation Recurrence ................................................................. 50 
8.1.1.1. 
Definition ........................................................................................................................ 50 
8.1.1.2. 
Schedule ......................................................................................................................... 50 
8.1.1.3. 
Evaluation Methods ........................................................................................................ 50 
8.1.2. 
Secondary Efficacy Criteria .............................................................................................. 51 
8.1.2.1. 
Numbers of AF episodes in the first week following visit 3 (ECV visit) ...................... 51 
8.1.2.2. 
Duration of AF episodes in the first week following visit 3 (ECV visit) ....................... 52 
8.1.2.3. 
Clinical parameters evaluation ....................................................................................... 52 
8.1.2.4. 
Cardioversion assessment ............................................................................................... 53 
8.1.2.5. 
Evolution of echocardiographic parameters ................................................................... 53 
8.2. 
BIOMARKER ASSESSMENT: RED BLOOD CELL  CONCENTRATIONS OF 
DHA ..................................................................................................................................... 54 
8.2.1. 
Definition ........................................................................................................................... 54 
8.2.2. 
Blood samples ................................................................................................................... 54 
8.2.2.1. 
Collection schedule ........................................................................................................ 54 
8.2.2.2. 
Technical handling ......................................................................................................... 55 
8.2.3. 
DHA concentration measurement ..................................................................................... 55 
8.3. 
SAFETY ASSESSMENT .................................................................................................... 55 
8.3.1. 
Adverse Events .................................................................................................................. 55 
8.3.2. 
Laboratory Investigations .................................................................................................. 56 
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8.3.2.1. 
Schedule ......................................................................................................................... 56 
8.3.2.2. 
Technical Procedures and Parameters ............................................................................ 56 
8.3.3. 
Global Physical Examination ............................................................................................ 57 
8.3.4. 
Vital Signs ......................................................................................................................... 57 
8.3.4.1. 
Schedule ......................................................................................................................... 57 
8.3.4.2. 
Technical Procedure and Parameters.............................................................................. 57 
8.3.5. 
Electrocardiogram (ECG) .................................................................................................. 58 
8.3.5.1. 
Schedule ......................................................................................................................... 58 
8.3.5.2. 
Technical Procedure and Parameters.............................................................................. 58 
8.3.6. 
Coagulation parameters ..................................................................................................... 58 
8.3.7. 
Concomitant Treatments ................................................................................................... 59 
8.4. 
COMPLIANCE .................................................................................................................... 59 
9. 
STUDY PROCEDURES ....................................................................................................... 59 
10. ADVERSE EVENTS: DEFINITION AND REPORTING ............................................... 65 
10.1. ADVERSE EVENTS ........................................................................................................... 65 
10.1.1. Definition of Adverse Events ............................................................................................ 65 
10.1.2. Grading of Adverse Events ............................................................................................... 66 
10.1.3. Reporting of Adverse Events ............................................................................................ 66 
10.2. SERIOUS ADVERSE EVENTS (SAE) .............................................................................. 66 
10.2.1. Definition ........................................................................................................................... 66 
10.2.2. Reporting of SAE .............................................................................................................. 67 
10.2.3. Follow-up of SAE ............................................................................................................. 67 
10.2.4. SAE Occurring After the Study ......................................................................................... 68 
10.3. REPORTING OF OVERDOSAGE TO THE SPONSOR ................................................... 68 
10.4. REPORTING OF PREGNANCY TO THE SPONSOR ...................................................... 68 
10.5. SPONSOR'S RESPONSIBILITIES FOR SAFETY REPORTING  PURPOSES ............... 69 
11. DATA COLLECTION AND STUDY MONITORING ..................................................... 69 
11.1. DATA COLLECTION ......................................................................................................... 69 
11.1.1. Case Report Form .............................................................................................................. 69 
11.1.2. Source Documents ............................................................................................................. 70 
11.2. STUDY MONITORING ...................................................................................................... 70 
11.2.1. Monitoring visits ............................................................................................................... 70 
11.2.1.1. Site Preselection Visit .................................................................................................... 71 
11.2.1.2. Initiation Visit ................................................................................................................. 71 
11.2.1.3. Follow-up Visits ............................................................................................................. 71 
11.2.1.4. Closing Visit ................................................................................................................... 72 
11.2.2. Direct Access to Source Documents ................................................................................. 72 
11.3. INDEPENDENT DATA MONITORING COMMITTEE ................................................... 72 
12. DATA MANAGEMENT ...................................................................................................... 73 
12.1. DATA ENTRY ..................................................................................................................... 73 
12.2. DATA CLEANING ............................................................................................................. 73 
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12.3. DATA CODING .................................................................................................................. 73 
12.4. DATA STORAGE ............................................................................................................... 74 
12.5. DATABASE LOCK ............................................................................................................. 74 
13. STATISTICAL ANALYSIS ................................................................................................. 74 
13.1. GENERAL CONSIDERATIONS ........................................................................................ 74 
13.2. SAMPLE SIZE ..................................................................................................................... 75 
13.3. PROTOCOL DEVIATIONS ................................................................................................ 75 
13.4. DATA SETS ANALYSED .................................................................................................. 75 
13.5. HANDLING OF DROPOUTS AND MISSING DATA ..................................................... 76 
13.5.1. Dropouts ............................................................................................................................ 76 
13.5.2. Repositioning of Visits ...................................................................................................... 76 
13.5.3. Missing Data ...................................................................................................................... 76 
13.6. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ............................... 76 
13.7. EFFICACY ANALYSIS ...................................................................................................... 77 
13.7.1. Primary Criterion ............................................................................................................... 77 
13.7.1.1. Primary Analysis ............................................................................................................ 77 
13.7.1.2. Supportive Analysis ....................................................................................................... 77 
13.7.2. Secondary Criteria ............................................................................................................. 77 
13.7.2.1. Numbers of Atrial Fibrillation Episodes ........................................................................ 77 
13.7.2.2. Duration of Atrial Fibrillation Episodes ......................................................................... 78 
13.7.2.3. Time to first AF recurrence less than 10 minutes or symtomatic .................................. 78 
13.7.2.4. Clinical parameters evaluation ....................................................................................... 78 
13.7.2.5. Biomarker analysis: red blood cell concentrations of DHA ........................................... 78 
13.8. SAFETY ANALYSIS .......................................................................................................... 79 
13.8.1. Adverse Events .................................................................................................................. 79 
13.8.2. Clinical Laboratory Evaluation ......................................................................................... 80 
13.8.3. Global Physical Examination ............................................................................................ 82 
13.8.4. Vital Signs, Physical Findings and Other Observations Related to Safety ....................... 82 
13.8.4.1. Vital Sign Measurements Over Time ............................................................................. 82 
13.8.4.2. Body weight ................................................................................................................... 82 
13.8.4.3. Individual Patient Changes ............................................................................................. 82 
13.8.5. ECG ................................................................................................................................... 83 
13.8.6. Coagulation parameters ..................................................................................................... 83 
13.9. CONCOMITANT TREATMENTS ..................................................................................... 83 
13.10. COMPLIANCE .................................................................................................................... 83 
13.11. INTERIM ANALYSIS AND DATA MONITORING ........................................................ 84 
14. GENERAL ETHICAL CONSIDERATIONS .................................................................... 84 
14.1. ETHICAL CONDITIONS ................................................................................................... 84 
14.2. ETHICS COMMITTEE AND LEGAL REQUIREMENTS ................................................ 84 
14.3. PATIENT'S INFORMATION LEAFLET AND INFORMED CONSENT  FORM ........... 85 
14.4. PERSONAL DATA PROTECTION ................................................................................... 85 
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14.5. INSURANCE POLICY ........................................................................................................ 86 
15. ADMINISTRATIVE PROCEDURES ................................................................................ 86 
15.1. PROTOCOL AMENDMENT .............................................................................................. 86 
15.2. SOURCE DOCUMENTS, INVESTIGATOR'S FILE STORAGE ..................................... 86 
15.3. END OF THE STUDY ......................................................................................................... 87 
15.3.1. Definition of the End of Study .......................................................................................... 87 
15.3.2. Early Study Termination ................................................................................................... 87 
15.3.2.1. Early Study Termination Decided by the Sponsor ......................................................... 87 
15.3.2.2. Early Study Termination Decided by the Competent Authorities.................................. 88 
15.4. AUDIT .................................................................................................................................. 88 
15.5. INSPECTION ....................................................................................................................... 88 
15.6. CONFIDENTIALITY .......................................................................................................... 88 
15.7. CLINICAL STUDY REPORT ............................................................................................. 89 
15.8. STUDY RESULTS COMMUNICATION .......................................................................... 89 
15.9. STUDY RESULTS PUBLICATION ................................................................................... 89 
16. REFERENCES ...................................................................................................................... 91 
17. APPENDICES ....................................................................................................................... 94 
17.1. DECLARATION OF HELSINKI ........................................................................................ 95 
17.2. SAE REPORT FORM .......................................................................................................... 99 
17.3. PREDEFINED LIMITS OF LABORATORY AND VITAL SIGN POTENTIALLY 
CLINICALLY SIGNIFICANT CHANGES AND VALUES ............................................ 103 
 
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SYNOPSIS 
 
Name of Sponsor: 
Pierre Fabre Médicament represented by the Institut de Recherche Pierre Fabre (IRPF) 
Name of Finished Product: 
Not applicable 
Name of Active Substance:  
F373280 (Panthenyl-Ester of DHA) 
Title of the Study: 
Efficacy and safety study of F373280 for maintenance of sinus rhythm after electrical 
cardioversion in patients with persistent Atrial Fibrillation and Chronic Heart Failure. 
International, multicentric, randomised, double-blind, placebo controlled study 
Abbreviated Title: 
Not applicable 
Study Coordinating Investigator: 
Pr Savina NODARI 
 
Study Centres: 
International, multicentric 
Publication / Rationale: 
F373280 is a new therapy based on DHA delivery (pro-drug) developed for the maintenance 
of sinus rhythm after electrical cardioversion in persistent atrial fibrillation (AF) patients with 
chronic heart failure. 
The results of a pharmacological study performed in animals evidenced that DHA reduces the 
duration of AF induced by burst pacing.[1] 
Moreover, the effectiveness of PolyUnsaturated Fatty Acid (PUFA) has been proven in the 
following conditions: 
− 
prevention of AF recurrence in patients with persistent AF, in co-administration 
with amiodarone (add on therapy) [2]  
− 
Improvement of ventricular functional parameters, morbi-mortality and duration of 
hospitalisation in patients with heart failure [3, 4, 5] 
Taking into account these studies, it seems that DHA might be of therapeutic interest in the 
treatment of patients with both persistent atrial fibrillation and chronic heart failure. 
This phase IIa study is designed to assess the efficacy and the safety of the investigational 
product (F373280) for maintenance of sinus rhythm after electrical cardioversion (ECV) in 
patients with persistent atrial fibrillation and chronic heart failure. 
Planned Study Period: 
January 2013 –  January 2015 
Clinical Phase: IIa 
 
Objectives: 
Primary: 
- Efficacy of F373280 on the maintenance of sinus rhythm after direct electrical 
cardioversion in patients with persistent atrial fibrillation and chronic heart failure 
Secondary: 
- Efficacy of F373280 on the efficiency of direct electrical  cardioversion 
- Effect of F373280 on echocardiographic parameters 
- Safety and tolerability of F373280 
Methodology: 
- International, multicentre, randomised, double-blind, placebo-controlled 
- Selection period 
- Start of treatment 4 weeks before ECV 
• 
Condition to ECV:  
− 
INR 2-3 anti-vitamin K should be given at least 3 weeks before ECV) 
− 
No spontaneous cardioversion before ECV 
- Follow-up 20 weeks after visit 3 (ECV visit) 
• 
Condition: successful ECV or spontaneous CV 
- Cardiac monitoring: 
• 
7-days continuous ECG ambulatory recording (Holter ECG) between visit 3 (ECV 
visit) and visit 4 (week 5) in patients with sinusal rhythm 
• 
TTEM: daily transmission from week 6 to week 8; then every two days from week 
9 to week 24, and in case of AF symptoms 
- Treatment duration: 24 weeks 
Study Schedule 
9 visits will be scheduled: 
- V1/ W-4 to W-1: selection visit (7 to 28 days before the inclusion visit)  
- V2/ D1: Inclusion visit (start of treatment) 
- V3/ W4 (D28 -2/+7 days): cardioversion visit (outpatient or hospitalization according to 
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clinical practice of the centre) (installation of the Holter device) 
- V4/ W5 (D35 -2/+7 days): follow-up visit (removing of the Holter device and installation 
of the TTEM) 
- V5/ W8 (D56± 7 days): follow-up visit 
- V6/ W12 (D84 ± 7 days): follow-up visit 
- V7/ W16 (D112 ± 7 days): follow-up visit 
- V8/ W20 (D140 ± 7 days): follow-up visit 
- V9/ W24 (D168 ± 7 days): final study visit 
 
Number of  Patients: 
76 x 2 patients  
Diagnosis and Criteria for Inclusion: 
Inclusion Criteria: 
Demographic Characteristics and Other Baseline Characteristics: 
1. 
Men or women aged more than 18 years (inclusive) 
2. 
Patients with current episode of persistent AF between 7 days and 6 months duration for 
whom electrical cardioversion is warranted 
3. 
History of first documented persistent AF less than 3 years. 
4. 
History of ischemic or non ischemic heart failure  
5. 
NYHA class I or II chronic heart failure at selection and at inclusion 
6. 
Reduced left ventricular ejection fraction between 30% and 45% inclusive (using the 
two-dimensional echocardiography biplane Simpson’s rule) at selection and at inclusion 
7. 
On appropriate, stable medical treatments for heart failure, including a diuretic and/or 
angiotensin-converting enzyme, and/or angiotensin-receptor blocker and/or 
mineralocorticoid receptor (MR) antagonists, and/or betablockers 
8. 
Left atrial area ≤ 40 cm² at selection and at inclusion 
9. 
Patients treated or having to be treated by anti-vitamin K 
10. For female patient of child-bearing potential:  
• 
in all the countries except Italy:  
- 
use of an effective method of contraception (hormonal contraception or intra-
uterine device) assessed by the investigator, for at least 2 months before the 
selection in the study, and agreement to go on using it during the whole duration of 
the study and up to 1 month after the last dose of the study treatment 
- 
documented as surgically sterilized 
 
• 
in Italy only:  
- 
absolute abstention from sexual intercourse during the whole duration of the study 
and for a month after the end of the study or 
- 
use of double barrier contraception method (use of effective medical contraception 
method) from at least 2 months before the start of the study to the entire duration of 
the study and for a month after the end of the study or 
- 
documented as surgically sterilized 
 
11. For female patient of child-bearing potential: negative urine pregnancy test at inclusion 
12. For male with a child-bearing potential partner (In Italy only): 
- 
Absolute abstention from sexual intercourse during the whole duration of the study 
and for 3 months after the end of the study or 
- 
 use of double barrier contraception method (use of condom for male and effective 
contraception method for the partner) from the entire duration of the study to 3 
months after the end of the study. 
 
 
Ethical /legal considerations: 
13. Having signed his/her written informed consent, 
14. Affiliated to a social security system, or is beneficiary (if applicable in the national 
regulation) 
 
Non-Inclusion Criteria: 
Criteria related to pathologies: 
1. 
History of first documented episode of persistent AF more than 3 years 
2. 
More than two successful cardioversions (electrical or pharmacological) in the last 6 
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months 
3. 
Secondary Atrial Fibrillation due to alcohol or severe valvular heart disease (grade III to 
IV) 
4. 
NYHA class III or IV heart failure at selection or at inclusion 
5. 
Thyroid disease uncontrolled by treatment: TSH ± T4L ± T3L to be checked in case of 
treatment for thyroid disease 
6. 
Myocardial infarction or unstable angina or presence of unstable ischemic 
coronaropathy assessed by coronarography or cardiac stress test (Echo stress, exercise 
stress test, nuclear or MR perfusion evaluation methods) within 6 months before 
selection 
7. 
Severe chronic kidney disease (creatinine ≥ 25 mg/L or estimated glomerular filtration 
rate < 30 mL/min) at selection 
8. 
Bradycardia (HR ≤ 50 bpm) 
9. 
Hyperkalemia or hypokalemia (according to the standards of local laboratories) at 
selection  
10. Cardiac surgery within 3 months before selection or planned during the study duration 
 
 
Criteria related to treatments: 
11. Previously ineffective pharmacological or electrical cardioversion 
12. Concomitant treatment with ranolazine or any antiarrhythmic drug (within 7 days prior 
to selection), except stable dose of digoxin, betablockers, calcium-blockers 
13. Oral amiodarone: 
              13a  Previous treatment with oral amiodarone within 4 months prior to inclusion 
              13b  Intake of oral amiodarone for more than 1 month within 4 to 12 months before 
inclusion 
14. Previous treatment with intravenous amiodarone within 4 weeks prior to inclusion 
15. Patient requiring a cardiac resynchronization therapy (CRT) or having undergone CRT 
implantation within the last 6 months  
16. Treatment with any Polyunsaturated Fatty Acid (PUFA) within the last 3 months 
17. Dietary supplement with ω 3 or ω 6 according to investigator’s judgement 
18. Having undergone any form of ablation therapy for AF 
19. Patient treated with other anticoagulant treatment than antivitamin K: thrombin inhibitor 
such as Dabigatran or treated with antiaggregant P2Y12 inhibitors such as Clopidogrel 
or Prasugrel 
 
Other criteria: 
20. Patient liable not to comply with protocol instructions and/or with treatment, in the 
investigator’s opinion 
21. Patient having taken part in a clinical trial in the preceding 2 months or taking part 
in a trial at the time of selection 
22. Patient linguistically or mentally unable to understand the nature, objectives and 
possible consequences of the trial, or refusing to patient himself/herself to its 
constraints 
23. Patient family member or work associate (secretary, nurse, technician,..) of the 
Investigator 
24. Patient having forfeited his / her freedom by administrative or legal award or being 
under guardianship 
25. Breastfeeding female patient 
 
Exclusion criteria before V3: 
Patients not stabilized for INR (i.e. values not between 2 and 3) on at least 3 consecutive 
weekly tests performed before ECV will be excluded from the study, unless the presence of 
atrial thrombosis may be excluded with ECHO –TE (trans-esophageal echocardiograph) 
performed  in the same day (before ECV) 
ECV will be performed in patients without dyskalemia 
If necessary for obtaining stabilized INR between 2 and 3, the ECV (and following visits) 
could be postponed by 7 days. 
Test Product:  
F373280  
Soft Capsules  
Dose: 
Arm with 1g of F373280 
Mode of Administration: 
Oral, one capsule each evening with dinner. 
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Duration of Treatment: 
24 weeks of treatment exposure with F373280 (25 weeks if ECV postponed by 1 week) 
Reference Therapy 
Placebo soft capsules 
Placebo will be administered in the same conditions as the tested product. 
Mode of Administration: 
Oral, one capsule each evening with dinner 
Evaluation Criteria: 
Efficacy evaluation variables: 
 
Primary evaluation variable: 
- Time to first Atrial Fibrillation recurrence defined by the first episode of AF lasting for at 
least 10 minutes (Follow up of 20 weeks after visit 3 (ECV visit). 
Handling of AF recurrences: 7-day continuous ECG (5-leads/2 or 3 channels) ambulatory 
recording (holter ECG) between visit 3 (ECV visit) and visit 4 (week 5). Then, the follow 
up will be documented using the TTEM: daily transmission from week 6 to week 8. Then, 
every two days from week 9 to week 24. 
For randomised patients with spontaneous cardioversion before ECV, the recurrence of AF 
will be assessed after visit 3 (week 5).  
Moreover, during this TTEM period, if patient experiences any AF symptoms, it should be 
recorded and documented using the TTEM.  
All ECG traces will be evaluated by a Central Reading Laboratory. 
 
Secondary evaluation variables: 
During the 7-day continuous ECG monitoring, 
• 
Numbers of AF episodes 
• 
Duration of AF episodes 
 
Clinical parameters: 
During the whole study: 
• 
Number of recurrence of symptomatic AF episodes 
• 
EHRA score 
• 
Hospitalization for cardiovascular events 
• 
Hospitalization for thromboembolic stroke 
• 
All causes of hospitalization 
 
Cardioversion: 
• 
Assessment of spontaneous cardioversion 
• 
Assessment of successful cardioversion 
• 
Number of patients needing an other cardioversion after the initial ECV 
 
Other: 
• 
Evolution of echocardiographic parameters (from V4 to V6 and V9) (Left atrial 
diameter (mm), Left atrial area (cm²), Left atrial volume (mL), Left atrial 
volume/BSA (mL/m2), Left ventricular ejection fraction (%), Left ventricular end 
diastolic volume/BSA (mL/m2), Left ventricular end systolic volume/BSA(mL/m2), 
Left ventricular end diastolic diameter (mm), Left ventricular end diastolic volume 
(mL) Left ventricular end systolic diameter (mm), Left ventricular end systolic 
volume (mL)) 
• 
Evolution of omega 3 index and intra erythrocyte DHA (For this assessment 
samples will be centralized). 
 
Safety criteria: 
- Adverse events (observed and / or spontaneously reported) 
- Vital signs (Blood pressure (supine and standing), heart rate 
- Physical examination (body weight)  
- Standard 12-lead ECG: heart rate (bpm), PR (ms), QRS (ms), QT (ms), repolarisation 
patterns (ECG not centralized) 
- Haematology: haematocrit, haemoglobin, red blood cell (RBC) count, white blood cell 
(WBC) count, WBC differential count, reticulocytes, platelets 
- Biochemistry: sodium, potassium, bicarbonate, chloride, alkaline phosphatase, gamma 
GT, albumin, total bilirubin, conjugated bilirubin, creatinin, aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), fasting glucose, total cholesterol, cholesterol 
(HDL, LDL), triglycerides, creatin phosphokinase (CPK) fibrinogen (local laboratory) 
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- Coagulation parameters: Activated partial thromboplastin time (aPTT), thrombin clotting 
time (TCT), INR (local laboratory), Prothrombine Time (PT) 
Statistical Methods: 
Sample Size: 
Assuming an AF recurrence rate under placebo of 85%, a power of 80%, an alpha risk of 5% 
and a rate of not assessable patients of 15%, 76 randomised patients per group will be 
necessary, using a log-rank test of survival curves, a difference between groups of 20%.  
Primary Efficacy Analysis 
The primary analysis, performed on the Full Analysis Set (FAS: all randomised patients with 
at least one dose of treatment and with a successful cardioversion observed at visit 3), will be 
a survival analysis using the Kaplan Meier method and Cox regression model. 
Secondary Analyses  
All secondary efficacy criteria will be described and compared using appropriate tests on the 
FAS. 
Safety Analyses 
Descriptive statistics will be performed on the Safety Set (all randomised patients with at 
least one dose of treatment).  
 
 
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STUDY FLOW-CHART 
F373280 CA 201 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
Weeks 
W-4 to W-1 
D1 
W4 
(28 -2D/+7 D) 
W5 
(35 -2D/+7 D) 
W8 
(56+/-7D) 
W12 
(84+/-7D) 
W16 
(112+/-7D) 
W20 
(140+/-7D)  
W24 
(168+/-7D) 
  
  
  
  
  
  
  
  
  
  
Outpatient or Hospitalization (1) 
  
  
X 
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
  
  
  
  
  
  
  
  
Demographic characteristics 
X 
  
  
  
  
  
  
  
  
Medico-surgical history 
X 
  
  
  
  
  
  
  
  
Concomitant disease 
X 
  
  
  
  
  
  
  
  
Concomitant treatment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Habits 
X 
  
  
  
  
  
  
  
  
Global physical examination (body weight) 
X 
X 
X 
 
X 
X 
X 
X 
X 
Echocardiography 
X 
X 
  
X 
  
X 
  
  
X 
Eligibility criteria check 
X 
X 
  
  
  
  
  
  
  
Blood pressure, heart rate  
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead  ECG Recording 
X 
X 
X 
  
X 
X 
X 
X 
X 
INR  
 
 
                     (2) 
  
X 
X 
X 
X 
X 
aPTT, TCT  
X 
X 
X 
  
X 
X 
X 
X 
X 
Biochemistry 
X 
  
  
  
  
  
  
  
X 
Hematology 
X 
  
X 
  
  
X 
  
  
X 
Urinary pregnancy test 
  
X 
  
  
  
  
  
  
X 
Red Blood Cell concentrations of DHA  
  
X 
X 
  
  
X 
  
  
X 
Treatment allocation 
  
X 
  
  
  
X 
  
  
  
IVRS/IWRS 
X 
X 
  
  
 
X 
  
  
  
ECV (3) 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Drug administration  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Adverse events recording 
  
X 
X 
X 
X 
X 
X 
X 
X 
Holter ECG 
                (4) 
  
 
                (5) 
 
 
 
 
 
TTEM (6) 
  
  
 
 
 
  
  
  
  
(1) Outpatient or hospitalization according to clinical practice of the centre (less or more than 24 hours) 
(2) In case of AVK introduction: INR 2 to 3 times a week, then weekly until the ECV, then every 4 weeks after ECV 
(3) In patients with AF 
(4) 24-hour Holter ECG 
(5) 7-day Holter ECG 
(6) TTEM: everyday from week 6 to week 8;. then every 2 days from week 9 to week 24; at any time in case of AF symptoms. 
In case of AF recurrence for at least 10 minutes and if the patient does not stop the study treatment, then TTEM once a week 
 
 
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LIST OF ABBREVIATIONS 
 
aPTT 
: 
Activated partial thromboplastin time 
AE 
: 
Adverse event 
AF 
: 
Atrial fibrillation 
ALA 
: 
Alpha-linoleic acid 
ALT 
: 
Alanine aminotransferase 
AST 
: 
Aspartate aminotransferase 
AUC 
: 
Area under the plasma concentration versus time curve 
AUCinf 
: 
Total area under the curve extrapolated to infinity 
AVK 
: 
Anti-vitamin K 
βHCG 
: 
beta human chorionic gonadotrophin 
BLQ 
: 
Below the limit of quantification 
BMI 
: 
Body mass index 
BP 
: 
Blood pressure 
BSA 
: 
Body Surface Area 
CEP 
: 
Protocol evaluation committee 
CHMP 
: 
Committee for medicinal products for human use 
Cmax 
: 
Maximum concentration 
Cmin 
: 
Minimum concentration 
CNALV 
: 
Clinically noteworthy abnormal laboratory value 
CPK 
: 
Creatin phosphokinase 
CPP 
: 
Comité de protection des personnes  
CRA 
: 
Clinical research associate 
CRT 
: 
Cardiac resynchronization therapy 
CSC 
: 
“Clinically Significant Change”, i.e., Predefined potentially clinically significant 
change leading to a potentially clinically significant value (vital signs) 
CV 
: 
Coefficient of variation 
DBP 
: 
Diastolic blood pressure 
DHA 
: 
Docosahexaenoic acid 
EC 
: 
Ethics committee 
ECG 
: 
Electrocardiogram 
ECHO –TE : 
Trans-esophageal echocardiograph 
ECV 
: 
Electrical cardioversion 
EHRA 
: 
European heart rhythm association 
EPA 
: 
Eicosapentaenoic acid 
e-CRF 
: 
Electronic case report form 
FAS 
: 
Full analysis set 
Fe 
: 
Fraction of the administered drug excreted in urine 
GCP 
: 
Good clinical practice 
GFR 
:  Glomerular Filtration Rate 
HBs 
: 
Hepatitis B antigen 
HCV 
: 
Hepatitis C virus 
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HDL 
: 
High density lipoprotein 
HF 
: 
Heart failure 
HIV 
: 
Human immunodeficiency virus 
HR 
: 
Heart rate 
ICH 
: 
International conference on harmonisation of technical requirements for 
registration of pharmaceuticals for human use 
IDMC 
: 
Independent data monitoring committee 
INR 
: 
International normalized ratio 
IRPF 
: 
Institut de Recherche Pierre Fabre 
IVRS 
: 
Interactive voice response system 
LAA 
: 
Left atrial area 
LC/MS-MS : 
Liquid chromatography with tandem mass spectrometry 
LDL 
: 
Low density lipoprotein 
LOQ 
: 
Limit of quantification 
LVEF 
: 
Left ventricular ejection fraction 
MedDRA 
: 
Medical dictionary for regulatory activities 
MR 
: 
Mineralocorticoid receptor 
MR perfusion : 
Magnetic Resonance perfusion 
MTD 
: 
Maximum tolerated dose 
N 
: 
Number of determinations or replicates 
NOAEL 
: 
No observed adverse effect level 
NYHA 
: 
New York heart association 
od 
: 
Once a day 
PC 
: 
“Predefined Change”, i.e., Predefined potentially clinically significant change (lab 
or vital signs) 
PCA 
: 
PC leading to an out-of-range value (lab values) 
PFB 
: 
Pierre Fabre Biométrie 
PSC 
: 
Potentially Clinically Significant Change 
PSCV 
: 
Potentially Clinically Significant Value 
PUFA 
: 
PolyUnsaturated fatty acid 
p.o. 
: 
Per os 
PP 
: 
Per protocol data set 
RBC 
: 
Red blood cells 
SAE 
: 
Serious adverse event 
SBP 
: 
Systolic blood pressure 
SD 
: 
Standard deviation 
T1/2 
: 
Terminal half-life 
T0 
: 
Time of drug administration 
Tmax 
: 
Time to reach the maximal concentration 
TCT 
: 
Thrombin clotting time 
TEAEs 
: 
Treatment emergent adverse events 
TTEM 
: 
TransTelephonic ECG monitoring 
WBC 
: 
White blood cells 
WHO-DRUG : 
World health organization drug reference list 
 
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1. INTRODUCTION AND STUDY RATIONALE 
1.1. 
TARGET PATHOLOGY AND THERAPY 
Atrial Fibrillation (AF) is a supraventricular arrhythmia characterized by uncoordinated atrial 
electric activity with consequent deterioration of atrial mechanical function. It is the most 
common sustained cardiac rhythm disorder, increasing in prevalence with age. Haemodynamic 
impairment and thromboembolic events related to AF result in significant morbidity and mortality 
[7]. 
In 2009, Decision Resources estimated that there were 7.8 million diagnosed prevalent cases of 
AF in US, Europe and Japan. This age-related pathology should increase to 9.4 million cases in 
2019.  
Except for the conventional class I and class III anti-arrhythmic agents, the Polyunsaturated Fatty 
Acids (PUFAs) constitute one emerging antiarrhythmic therapy. These compounds potently 
address the AF substrate by directly targeting both the electrical and the structural remodelling of 
the deficient atria. The n-3 PUFAs, essential for human, are alpha-linoleic acid (ALA), 
eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). First, PUFAs specifically 
modulate ionic channels by fastening their inactivating mode which renders these compounds 
selective for pathological situations (such as AF) without any major effect in normal conditions. 
PUFAs are “open Kv1.5 channel blockers” leading to a lengthening of atrial action potential 
duration and are “persistent Nav1.5 channel blockers” leading to hyperpolarization of diastolic 
resting potential. Second, PUFAs influence structural remodelling through their anti-inflammatory 
effects as they directly compete with arachidonic acid in the production of inflammatory 
eicosanoids. In summary, PUFAs share unique, well-tolerated antiarrhythmic potential by 
interacting with the electrical and structural remodelling during sustained AF. In animal studies, it 
was recently demonstrated that DHA is particularly effective in pathologic conditions such as 
ischemia and/or AF. 
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The potential anti-arrythmic effects of a PUFA were previously developed in AF: nicotinyl ester 
of DHA (pro-drug based on DHA delivery) was assessed in a two-week ventricular tachypaced 
canine model. Dogs were subjected to 4 weeks of medication prior to undergoing an 
electrophysiology study, and received either placebo or nicotinyl ester of DHA. Dogs were 
tachypaced at 240 beats per min for the final two weeks of the treatment plan. The results showed 
that the tested PUFA reduced the duration of AF induced by burst pacing, and the incidence of 
sustained AF, compared to dogs treated with the placebo [1]. 
In clinical practice, Nodari and coll [2] assessed n-3 PUFAs in the prevention of AF recurrences 
after electrical cardioversion (ECV). All included patients were treated with amiodarone and a 
renin-angiotensin-aldosterone system inhibitor. The 199 patients were assigned either to placebo 
or n-3 PUFAs 2 g/d and then underwent direct ECV 4 weeks later. The primary end point was the 
maintenance of sinus rhythm at 1 year after cardioversion. At the 1-year follow up, the 
maintenance of sinus rhythm was significantly higher in the n-3 PUFAs treated patients compared 
with the placebo group (hazard ratio, 0.62 [95% confidence interval, 0.52 to 0.72] and 0.36 [95% 
confidence interval, 0.26 to 0.46], respectively; p = 0.0001). The study concludes that in patients 
with persistent AF on amiodarone and a renin-angiotensin-aldosterone system inhibitor, the 
addition of n-3 PUFAs 2 g/d improves the probability of the maintenance of sinus rhythm after 
direct current cardioversion. Previously, during the World Congress of Cardiology in 2006, an 
abstract reported the effectiveness of PUFAs on top of traditional treatment (amiodarone, beta 
blockers, renin-angiotensin-aldosterone system inhibitor) in the prevention of AF relapses in 
patients having undergone ECV. In the PUFA group, AF relapses were significantly lower than in 
the placebo group at 1 month (3.3% vs 10%; p = 0.043), at 3 months (10% vs 25%; p = 0.004) and 
at 6 months (13.3% vs 40%; p < 0.0001) [19]. 
In contrast, in the general AF population (paroxystic atrial fibrillation and persistent atrial 
fibrillation), PUFAs failed to prove their efficacy [7] because of the absence of cardiac 
remodelling or because of a short pre-treatment duration before ECV (1 week) [8]. The effects of 
PUFAs were only observed in patients with persistent AF on add on therapy and after a sufficient 
pre-treatment before ECV. Persistent AF is commonly associated to heart failure. Previous studies 
performed in heart failure population demonstrated the benefit of PUFAs on the improvement of 
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functional ventricular parameters and morbi-mortality, and on the reduction of hospitalisation [3, 
4, 5]. 
Nodari and coll [3] performed a trial in patients with chronic heart failure (NYHA I to III and 
LVEF< 45%). After a treatment of 133 patients with PUFAs (n=67) or placebo (n=66) at a dosage 
of 5 g/day for 1 month, then 2 g/day for 11 months, the n-3 PUFAs group and the placebo group 
differed significantly (p <0.001) in regard to:  
− LVEF (increased by 10.4% and decreased by 5.0%, respectively) 
− peak VO2 (increased by 6.2% and decreased by 4.5%, respectively) 
− exercise duration (increased by 7.5% and decreased by 4.8%, respectively) 
− mean New York Heart Association functional class (decreased from 1.88+/- 0.33 to 1.61 
+/- 0.49 and increased from 1.83+/- 0.38 to 2.14 +/- 0.65, respectively).  
The hospitalization rates for patients with HF were 6% in the n-3 PUFAs and 30% in the placebo 
group (p <0.0002). 
Moertl and coll [4] performed a dose-ranging study in patients with a more severe chronic heart 
failure (NYHA III and IV and LVEF < 35%). It was a double-blind, randomised, controlled pilot 
trial in 43 patients treated with PUFAs or placebo for 3 months (1 g/d n3-PUFA (n = 14), 4 g/d 
n3-PUFA (n = 13), or placebo (n = 16)). After treatment, left ventricular ejection fraction 
increased in a dose-dependent manner (p = 0.01 for linear trend) in the 4 g/d (baseline vs 3 
months [mean ± SD]: 24% ± 7% vs 29% ± 8%, p = 0.005) and 1 g/d treatment groups (24% ± 8% 
vs 27% ± 8%, p = 0.02). 
No changes in any investigated parameters were noted with placebo. 
Taking into account these studies performed with PUFAs, it seems that the best target for DHA is 
persistent AF in patients with heart failure. The aim of this proof of concept study is to assess in 
stand alone therapy (without association of other anti-arrhythmic treatments), the effect of 
F373280 in patients with persistent AF and heart failure in the maintenance of sinus rhythm after 
ECV. 
1.2. 
INFORMATION ON THE TEST PRODUCT 
F373280 or panthenyl ester of DHA is the mono-ester of panthotenic alcohol and DHA, selected 
to be developed for the management of AF.  
F373280 is a prodrug of DHA. 
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A brief summary of F373280 known characteristics is presented in this section. For further details, 
please refer to the F373280 Investigator’s Brochure. [1] 
1.2.1. 
Chemical and pharmaceutical characteristics 
1.2.1.1. 
Nomenclature and structure 
Chemical name (IUPAC):  
(4Z,7Z,10Z,13Z,16Z,19Z)-3-((R)-2,4-dihydroxy-3,3-diméthylbutanamido) 
propyl 
docosa-
4,7,10,13,16,19-hexaenoate 
Structural formula: 
O
O
O
O
NNHH
O
O
OHH
O
OHH
 
Laboratory code: F373280 
Molecular formula: C31H49NO5 
Molecular mass: 515.7 
1.2.1.2. 
Physical and chemical general properties 
Appearance: Clear oily viscous liquid 
Solubilities:  
− Water: Practically insoluble 
− Alcohol: Very soluble  
− Trimethylpentane: Slightly soluble  
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1.2.2. 
Non-clinical Data 
Non-clinical data are exhaustively detailed in the Investigator’s brochure [1]. A brief summary is 
provided below. 
1.2.2.1. 
Pharmacological profile 
F373280 (mono-ester of panthotenic alcohol and DHA) is a novel pro-drug of DHA which exerts 
antiarrhythmic properties by interacting with the electrical and structural remodelling of the atria.  
Experimental investigations were conducted in HEK293 cell line transfected with human Kv1.5 
channel using the whole cell patch clamp technique to evaluate whether F373280 could block the 
sustained component of IKv1.5. F373280 concentration-dependently reduced Kv1.5 channel activity 
with an IC50 value of 13.7 µM. 
The effects of F373280 on atrial effective refractory period were investigated in anesthetized pig 
using a conventional pacing protocol through epicardial electrodes placed on the left atrium. 
F373280 administered as a bolus and an infusion (10 mg/kg) significantly increased atrial 
effective refractory period (23.8 ± 2.2 ms versus -7.3 ± 11.5 ms in the presence of vehicle, p < 
0.05). In addition, F373280 was devoid of significant effect on the hemodynamic and the 
electrocardiogram (ECG) intervals.  
Proof of the pharmacological concept was performed with a different DHA derivative named: 
Nicotinyl ester of DHA (pro-drug based on DHA delivery). Ventricular tachypacing-induced 
congestive heart failure provides a clinically-relevant animal model of AF associated with 
structural remodelling, as is often seen clinically. It has been shown that sustained oral PUFA 
administration suppresses congestive heart failure-induced AF-promotion and fibrosis in the 
ventricular tachypacing canine model. Nicotinyl ester of DHA was tested in this model, at 1 g/day 
and 5 g/day, during 4 weeks, to prevent congestive heart failure-related atrial structural 
remodelling and AF promotion in dogs. Nicotinyl ester of DHA dose dependently reduced heart 
failure-induced increases in AF duration (989 ± 111 sec, n=5 in the presence of placebo versus 
637 ± 196 sec, n=5 in the presence of 1 g/kg/d Nicotinyl ester of DHA and 79 ± 51 sec, n=5, in 
the presence of 5 g/kg/d Nicotinyl ester of DHA). The protective effect of Nicotinyl ester of DHA 
was associated with a marked increase of plasma level of DHA and important incorporation of 
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DHA in the left atrial tissue. Because F373280 similarly to Nicotinyl ester of DHA increases 
plasma level of DHA, it could be estimated that the compound may exert a similar protective 
effect [1]. 
1.2.2.2. 
Safety pharmacology 
A battery of safety pharmacology studies was performed to evaluate the effects of F373280 on the 
central nervous, cardiovascular and respiratory systems. Data of these studies are exhaustively 
detailed in the Investigator’s brochure [1]. 
No particular alerts were evidenced with F373280. 
1.2.2.3. 
Toxicology profile 
 
Concerning the toxicological data, 4-week and 26-week repeat-dose studies in rat and dog were 
performed. Compared to the high administered doses of F373280 (500 to 2000 mg/kg/day), low 
circulating concentrations of F373280 were measured.  
During these toxicity studies, no toxicity was observed in rat after 4 and 26 weeks of dosing and 
in dog after 4 weeks of dosing. A NOAEL of 2000 mg/kg/day was established in these repeat 
toxicity studies.  
During the 26-week toxicity study in dogs, the NOAEL was set at 1000 mg/kg/day based on 
changes observed on red blood cell parameters. 
Based on toxicological profiles, F373280 is considered to support the proposed clinical trial. 
 
1.2.2.4. 
Pharmacokinetic data  
According to animal studies described in the Investigator’s brochure [1], the non-clinical 
pharmacokinetic profile of F373280 is not associated with particular alerts concerning the 
proposed clinical phase IIa study. 
1.2.3. 
Clinical data 
Part A: single dose 
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Six consecutive single ascending doses were tested (0.5 g, 1 g, 2 g, 4 g, 8 g and 16 g) on 6 
independent cohorts of 8 subjects (6 verum + 2 placebo). 49 subjects were treated and 48 
completed the study. 
No Serious Adverse Events (SAE) occurred in the course of the study. 
Regarding the reported Treatment Emergent Adverse Events (TEAEs) that were judged by the 
Investigator as having a causal relationship with the study drug administration in the absence of 
an alternative explanation, 3 TEAEs were observed in the placebo group (palpitation, dizziness in 
standing position, symptomatic orthostatic hypotension without loss of consciousness) and 4 in 
the group of F373280 at the dosage of 16 g (meteorism, liquid stool, symptomatic orthostatic 
hypotension and dizziness in standing position). None of these adverse events (AE) were reported 
in the groups of F373280 at the dosages of 0.5 g, 1 g, 2 g, 4 g and 8 g. 
After a single administration of the different tested doses no difference between the tested product 
and placebo has been reported, regarding vital signs (heart rate, systolic blood pressure and 
diastolic blood pressure), biological parameters (related to coagulation: platelets and fibrinogen) 
and coagulation parameters (bleeding time, prothrombin time/INR, activated partial 
thromboplastin time, thrombin clotting time). Variations of these parameters were within the 
physiological ranges. 
After single oral administration of F373280 from 0.5 g to 16 g in 36 young healthy male subjects 
(6 per dose level), the following was observed: 
 
- F373280: Whatever the tested dose there is no circulating F373280 in plasma: only few, 
sparse and non consecutive samples with quantifiable level of F373280 close to LOQ were 
observed. This confirms that F373280 is a prodrug. 
- Panthenol: Cmax and AUC increased with the administered dose between 0.5 and 16 g. 
Panthenol concentrations were rapidly cleared from plasma with a mean terminal half-life 
around 2 hours. 
- DHA: after 0.5 and 1 g, low increased in DHA plasma concentrations compared to the 
baseline levels led to a high inter-individual variability of the corresponding 
Pharmacokinetics parameters. Plasma exposure in DHA increased with the administered dose 
between 2 and 16 g with no departure from proportionality (baseline corrected parameters). 
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Part B: Multiple doses  
Three consecutive repeated ascending doses (1, 2 and 4 g) were tested on 3 independent cohorts of 
12 subjects (9 verum + 3 placebo, double blind). 36 subjects completed the study. Each treatment 
was administered over a period of 28 days. Pharmacokinetic parameters were assessed over a 
period of 14 days.  
Among the TEAE judged by the investigator as suspected to F373280, 5/9 TEAEs were classified 
according the System Organ Class in vascular system disorder with orthostatic hypotension (2 in 
the 1 g group, 1 in the 2 g group and 2 in the 4 g group) and 4/9 were classified in nervous system 
disorder with 3 dizziness (2 in the 2 g group and 1 in the 4 g group) and 1 migraine (in the 1 g 
group). These TEAEs have already been reported with PUFAs and are commonly observed in 
phase I studies. 
After a repeated administration of the different tested doses, no difference between the tested 
products and placebo was reported regarding vital signs (heart rate, systolic blood pressure and 
diastolic blood pressure), biological parameters. The assessment of coagulation parameters and 
platelet function after administration of repeated dose of F373280 did not report any bleeding 
issue. The reported changes in coagulation parameters and platelet function were within 
physiological ranges. 
After a 14-day repeated oral administration of F373280 from 1 g to 4 g, the following was 
observed: 
 Panthenol: Cmax and AUC increased with the administered dose between 1 and 4 g. No 
accumulation of panthenol in plasma was observed. 
 
 DHA: Plasma exposure increased with dose. A 2-fold accumulation in total plasma exposure 
of DHA was observed after 14 days of administration, whatever the administered dose. 
 
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1.3. 
STUDY RATIONALE 
F373280 is a new therapy based on DHA delivery (pro-drug) developed for the maintenance of 
sinus rhythm after ECV in persistent AF patients with chronic heart failure. 
The results of a pharmacological study performed in animals evidenced that DHA reduces the 
duration of AF induced by burst pacing [1]. 
Moreover, the effectiveness of PUFAs has been proven in the following conditions: 
- 
Prevention of AF recurrence in patients with persistent AF in co-administration with 
amiodarone (add on therapy) [2], 
- 
Improvement of ventricular functional parameters, morbi-mortality and duration of 
hospitalisation in patients with heart failure [3, 4, 5]. 
Taking into account these studies, it seems that DHA might be of therapeutic interest in the 
treatment of patients with both persistent AF and chronic heart failure. 
This phase IIa study is designed to assess the efficacy and the safety of the investigational product 
(F373280) for maintenance of sinus rhythm after ECV in patients with persistent AF and chronic 
heart failure. 
1.4. 
OVERALL RISK AND BENEFIT ASSESSMENT 
F373280 is a new pro-drug of DHA.  
DHA is a well-known long chain PUFAs with a long-term clinical experience in cardiovascular 
diseases. DHA is contained in several medicinal products such as Omacor, (1 g of Omacor 
contains about 320 mg of DHA acid) marketed by Laboratoires Pierre Fabre for 
hypertriglyceridemia and as an adjuvant treatment for secondary prevention after myocardial 
infarction. According to the summary product characteristics of Omacor [9]: 
 
- The frequencies of adverse reactions are ranked according to the following: common 
(>1/100, <1/10); uncommon (>1/1000, <1/100); rare (>1/10000, <1/1000); very rare (<1/10000), 
not known (cannot be estimated from the available data). 
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- The reported adverse events are: 
• Infection and infestations: 
Uncommon: gastroenteritis 
• Immune system disorders: 
Uncommon: hypersensitivity 
• Metabolism and nutrition disorders: 
Rare: hyperglycaemia 
• Nervous system disorders: 
Uncommon: dizziness, dysgeusia 
Rare: headache 
• Vascular disorders: 
Very rare: hypotension 
• Respiratory thoracic and mediastinal disorders:  
Very rare: nasal dryness 
• Gastrointestinal disorders: 
Common: dyspepsia, nausea 
Uncommon: abdominal pain, gastrointestinal disorders, gastritis, abdominal pain upper 
Rare: gastrointestinal pain 
Very rare: lower gastrointestinal haemorrhage 
• Hepatobiliary disorders:  
Rare: hepatic disorders  
• Skin and subcutaneous tissue disorders:  
Rare: acne, rash pruritic 
Very rare: urticaria 
• General disorders and administration site conditions: 
Rare: malaise sensation 
• Investigations: 
Very rare: white blood count increased, blood lactate dehydrogenase increased 
Moderate elevation of transaminases has been reported in patients with hypertriglyceridaemia. 
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Panthenol is a well-known substance with a long-term experience in medical, nutraceutic and 
cosmetic uses. According to the summary product characteristics of a product such as 
Bépanthene (tablet indicated in alopecia) which contains panthenol (100 mg), adverse event 
observed are rare cases of urticaria and erythema [10]. Panthenol is metabolised in panthotenic 
acid, i.e. B5 vitamin. 
Concerning toxicological studies performed results can support the administration of F373280 in 
the proposed clinical phase II study without particular alert [1]. 
Any safety warning was reported during a phase I study performed with F373280 administered to 
84 healthy volunteers in single dose in a range between 500 mg and 16 g or in repeated dose 
during 28 days in a range between 1 g and 4 g. Adverse events reported and related to study 
treatment were minor to moderate. The adverse events were palpitations, orthostatic hypotension, 
dizziness, meteorism and liquid stool. Most were reported in both groups (placebo and F373280) 
without a dose relationship. The assessment of coagulation parameters and platelet function after 
administration of repeated dose of F373280 did not report any bleeding concern: the reported 
changes in coagulation parameters and platelet function were within physiological ranges. 
Moreover, DHA has been associated with anticoagulant products in AF studies [2, 8]. The range 
of PUFAs doses tested was between 2 g to 3 g (640 mg to 960 mg of DHA) and the range of study 
durations between 6 to 12 months. This association did not report a significant side effect of 
bleeding. 
DHA has already been used in HF patients in several studies without safety concern [3, 4, 5]. The 
range of PUFAs doses tested was between 1 g to 5 g (1 g of the tested PUFAs contains about 320 
mg of DHA acid) and the range of study durations was between 3 months to 3.9 years. 
Thus, inclusion of patients with no specific antiarrhythmic treatment is acceptable. They will 
receive an anticoagulant treatment to prevent the thrombo-embolic complications of AF 
(particularly stroke) and the adequate treatments to control the heart rate and heart failure.   
In conclusion, the overall available data allow in safe conditions the treatment of patients with 
persistent AF and chronic heart failure with F373280 in safe conditions. 
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2. STUDY OBJECTIVES 
2.1. 
PRIMARY OBJECTIVE 
The primary objective of the study is to assess the efficacy of F373280 on the maintenance of 
sinus rhythm after direct ECV in patients with persistent AF and chronic heart failure. 
2.2. 
SECONDARY OBJECTIVES 
The secondary objectives of the study are to assess: 
• the efficacy of F373280 on the efficiency of direct ECV 
• the effect of F373280 on echocardiographic parameters 
• the safety and tolerability of F373280 
3. ETHICAL CONSIDERATIONS RELATING TO THE STUDY 
The trial is conducted according to Good Clinical Practices (CPMP/ICH/135/95), the National 
regulations and the Declaration of Helsinki and its subsequent amendments (see Appendix 17.1). 
This protocol and the informed consent form will be submitted for approval to independent local 
or national Institutional Review Boards/Ethics Committees before the study set up, according to 
national regulation. 
All the protocol amendments or critical events liable to increase the risks incurred by the patients 
or to compromise the validity of the study or patients' rights will be submitted to the coordinator 
and to the Ethics Committees. 
After being informed orally and in writing of all potential risks and constraints of the trial, as well 
as their freedom to withdraw their participation at any time, patients will then sign a consent form.  
A time of reflection will be given to the patients, before giving a written consent and starting the 
study procedures. 
The use of a placebo is in accordance with EMA Addendum to the guideline on antiarrhythmics 
on AF and atrial flutter (EMA/CHMP/EWP/213056/2010) [21] and is acceptable because the 
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included patients will remain under the standard treatment of AF and chronic heart failure. Except 
antiarrythmics, they will receive anticoagulant (anti-vitamin K), rate control treatment, chronic 
heart failure treatment. During the study, in case of AF recurrence that would require 
cardioversion or the introduction of an anti-arrhythmic because of intolerable and/or 
uncomfortable clinical symptoms for instance, patients will be withdrawn and the tested product 
stopped. These patients will be considered as treatment failure. 
In this study, patients will be carefully screened, particularly for their cardiac condition, with 
ECG, 24-hour holter monitor and echocardiographic data, and their biologic and coagulation 
condition. 
The study will be addressed only to patients requiring an ECV due to their persistent AF, in the 
following conditions: 
- 
ECV in patients not presenting a contra-indication 
- 
Anticoagulation with anti-vitamin K (AVK) for at least 3 weeks before ECV 
- 
ECV in patients with stabilized INR (i.e. values between 2 and 3;sp to ) on at least 3 
consecutive weekly tests performed. Patients not stabilized for INR (i.e. values not 
between 2 and 3) on at least 3 consecutive weekly tests performed before ECV will be 
excluded from the study, unless the presence of atrial thrombosis may be excluded 
with ECHO –TE (trans-esophageal echocardiograph) performed in the same day 
(before ECV). Patients who do not revert to sinus rhythm or present an early relapse 
within the observation period after ECV will be withdrawn and the tested product 
stopped. 
During the whole study, patients will remain under medical control: visits in cardiology units will 
be scheduled at least every month. This follow up will include clinical signs, ECG, biological and 
coagulation parameters. Moreover, patient’s cardiac rhythm will be monitored between visits 
using daily, then every 2 days Trans Telephonic ECG Monitoring (TTEM) reviewed by a Central 
Reading Laboratory. 
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Patients may withdraw from the study at any time without having to give a reason and can expect 
to receive regular conventional therapy. 
4. STUDY DESIGN 
4.1. 
OVERALL DESCRIPTION 
This phase IIa trial will be conducted as an international, multicentric, 24 weeks, double-blind, 
placebo-controlled, randomised, parallel group design, trial in 152 patients suffering from 
persistent AF and chronic heart failure. 
After a 1 to 4-week of run-in period without treatment, patients will be randomised into one of the 
following treatment groups: F373280 1 g or placebo for 24 weeks.  
Nine visits are planned for the study: 
- 
Visit 1 (V1): W-4 to W-1: Selection visit (7 to 28 days before the Inclusion Visit) 
- 
Visit 2 (V2): D1: Inclusion visit (start of treatment)  
- 
Visit 3 (V3): W4 (D28 -2/+7D): cardioversion visit (outpatient or hospitalization 
according to clinical practice of the centre) (installation of the Holter ECG device) 
- 
Visit 4 (V4): W5 (D35 -2/+7D): follow-up visit (removing of Holter ECG device and 
installation of the TTEM) 
- 
Visit 5 (V5): W8 (D56 ± 7D): follow-up visit 
- 
Visit 6 (V6): W12 (D84 ± 7D): follow-up visit 
- 
Visit 7 (V7): W16 (D112 ± 7D) : follow-up visit 
- 
Visit 8 (V8): W20 (D140 ± 7D): follow-up visit 
- 
Visit 9 (V9): W24 (D168 ± 7D): final study visit 
4.2. 
DISCUSSION OF THE STUDY DESIGN 
4.2.1. 
Choice of the Study Population 
The target indication of F373280 will be the maintenance of sinus rhythm after cardioversion of 
patients with persistent AF and chronic heart failure. In the present proof of concept study, the 
evaluation will focus on patients within this indication. This target population is justified by: 
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− The proved efficacy of PUFAs in patients with persistent AF with or without heart failure 
in co-administration with amiodarone (add on therapy) [2] 
− The proved efficacy of PUFAs on the improvement of ventricular functional parameters, 
morbi-mortality and duration of hospitalisation in patients with heart failure [3, 4, 5] 
The study aim is to investigate the product effect in patients with: 
− Persistent AF history (less than three years) with a duration of the current episode from 7 
days to 6 months. 
− a moderately abnormal systolic heart failure (Left Ventricular Ejection Fraction (LVEF) 
between 30 to 45% as defined in the report from the American Society of 
Echocardiography’s Guideline). According to a sub-group analysis performed in patients 
with persistent AF associated to heart failure (Nodari S. personnal data), PUFAs would 
be effective to prevent recurrence of AF after cardioversion in patients with moderately 
abnormal LVEF. 
 
− a Left Atrial Area (LAA) not severely abnormal (less than 40 cm2 as defined in the report 
from the American Society of Echocardiography’s Guideline). According to a sub-group 
analysis performed in patients with persistent AF associated to heart failure (Nodari S. 
personnal data), PUFAs would not be effective to prevent recurrence of AF after 
cardioversion of patients with severely abnormal LAA. 
For the successful rate of ECV, patients should have a stable medical treatment of heart failure 
and should not have any myocardial infarction or unstable angina or unstable ischemic 
coronaropathy assessed by coronarography or cardiac stress test (Echo stress, exercise stress 
test, nuclear or MR perfusion evaluation methods) within 6 months before selection.  
4.2.2. 
Choice of the Study Design 
As the target indication would be the prevention of AF recurrence after ECV, the study design 
meets 
the 
requirements 
of 
EMA 
guideline 
on 
antiarrhythmics 
in 
AF 
(EMA/CHMP/EWP/213056/2010) [21]. 
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As F373280 aims to be a safe treatment for the prevention of AF recurrence, it will not be tested 
as an add-on therapy during the study. To avoid any interaction with the tested product, 
antiarrhythmic class I and III will be forbidden during the study. 
The study design is defined in order to avoid methodological bias. A double blind study is 
appropriate to assess the efficacy and safety of the use of F373280 to prevent recurrence of AF 
episodes. Moreover, this study design is similar to the design of almost all trials that have assessed 
intervention for rhythm control [2, 8, 11, 12].  
According to the target indication, only patients with persistent AF and requiring an ECV will be 
included in order to assess the time to first documented recurrence of AF since cardioversion. 
To confirm the persistent nature of AF, a 24-hour holter monitoring will be performed during the 
selection visit.  
Eligible participants will enter a selection phase in which anticoagulant treatment (AVK) will be 
adjusted to achieve an International Normalized Ratio (INR) of 2.0 to 3.0 before ECV. According 
to guidelines for the management of AF [6], AVK should be given at least 3 weeks before 
cardioversion because of risk of thrombo-embolism due to post-cardioversion.  
Experimental data suggest that the maximal incorporation of n-3 PUFAs in the myocardial cell 
membrane takes up to 28 days to occur [22]. In addition, as shown in Nodari’s study [2], the 
duration of pre-treatment with PUFAs before cardioversion appears to be a contributing factor in 
success. Therefore, before starting follow up for the assessment of AF recurrence, treatment with 
F373280 should be started 28 days before ECV.  
Detection of AF recurrence will be performed using systematic (scheduled) ECG recording, thus 
allowing detection of asymptomatic (about 50% of episodes) as well as symptomatic AF episodes. 
According to previous studies, most of AF recurrences occurred during the first days after 
cardioversion [11, 15]. So that, the heart rhythm will be closely monitored during the first week 
after successful cardioversion using an ambulatory continuous 7-day holter ECG recording in 
order to increase sensibility to detect asymptomatic AF episodes. Thereafter, to improve patient 
compliance, this follow up will be continued using an easier device  to carry and to use, i.e. a 
TTEM.  
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Finally, during the study, patients will be scheduled for a clinical visit every month (with an 
additional visit 7 days after visit 3 (ECV visit)) in order to ensure a close medical monitoring and 
to assess efficacy and safety parameters. 
4.2.3. 
Choice of the Dose  
According to a previous study in patients with AF [2], the tested PUFA product (Omacor) at the 
dose of 2 g (i.e. 640 mg of DHA acid) was effective in the prevention of AF after cardioversion. 
Moreover, PUFAs at dosage of 1 g and 2 g were also effective on the improvement of ventricular 
functional parameters, morbi-mortality and duration of hospitalisation in patients with heart 
failure [3, 4, 5].  
From the F373280 phase I study, after a 14-day repeated administration of F373280 (1 g/day), 
observed plasma concentrations of DHA measured before treatment (Cmin) were similar to that of 
an effective dose of Omacor at 2 g/day (60 to 95 mg/mL and 60 to 90 mg/mL, respectively) 
(phase I study of F373280 and [16]). With regard to the rhythm of administration, mean 
peak/trough fluctuation (baseline corrected) was around 0.3. This value supports an once-daily 
administration allowing a 24-hour plasma exposure in DHA. Therefore, a 1 g daily dose of 
F373280 is considered to be appropriate for this proof of concept study. 
4.2.4. 
Choice of the Sample Size 
See chapter 13. 
5. STUDY POPULATION 
Each patient fulfilling all the inclusion criteria and none of the non inclusion criteria will be 
eligible. 
5.1. 
INCLUSION CRITERIA 
Demographic Characteristics and Other Baseline Characteristics: 
1. Men or women aged more than 18 years (inclusive) 
2. Patient with current episode of persistent AF between 7 days and 6 months duration for 
whomelectrical cardioversion is warranted 
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3. History of first documented persistent AF less than 3 years 
4. History of ischemic or non ischemic heart failure 
5.  NYHA class I or II chronic heart failure at selection and at inclusion 
6. Reduced left ventricular ejection fraction between 30% and 45% inclusive (using the two-
dimensional echocardiography biplane Simpson’s rule) at selection and at inclusion 
7. On appropriate, stable medical treatments for heart failure, including a diuretic and/or 
angiotensin-converting enzyme, and/or angiotensin-receptor blocker and/or mineralocorticoid 
receptor (MR) antagonists, and/or betablockers 
8. Left atrial area ≤ 40 cm² at selection and at inclusion 
9. Patient treated or having to be treated by anti-vitamin K 
10. For female patient of child-bearing potential:  
• in all the countries except Italy: 
 
- 
use of an effective method of contraception (hormonal contraception or intra-uterine 
device) assessed by the investigator for at least 2 months before the selection in the 
study and agreement to go on using it during the whole duration of the study and up to 
1 month after the last dose of the study treatment or 
- 
documented as surgically sterilized 
 
• in Italy only: 
- 
absolute abstention from sexual intercourse during the whole duration of the study and 
for a month after the end of the study or 
- 
use of double barrier contraception method (use of effective medical contraception 
method) from at least 2 months before the start of the study to the entire duration of the 
study and for a month after the end of the study or 
- 
documented as surgically sterilized  
 
11. For female patient of child-bearing potential: negative urine pregnancy test at inclusion 
12. For male with a child-bearing potential partner (In Italy only): 
- 
absolute abstention from sexual intercourse during the whole duration of the study and 
for 3 months after the end of the study or 
- 
use of double barrier contraception method (use of condom for male and effective 
contraception method for the partner) from the entire duration of the study to 3 months 
after the end of the study. 
 
Ethical /legal considerations: 
13. Having signed his/her written informed consent, 
14. Affiliated to a social security system, or is a beneficiary (if applicable in the national 
regulation) 
5.2. 
NON INCLUSION CRITERIA 
Criteria related to pathologies: 
1. History of first documented episode of persistent AF more than 3 years, 
2. More than two successful cardioversions (electrical or pharmacological) in the last 6 months, 
3. Secondary Atrial Fibrillation due to alcohol or severe valvular heart disease (grade III to IV), 
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4. NYHA class III or IV heart failure at selection or at inclusion 
5. Thyroid disease uncontrolled by treatment: TSH ± T4L ± T3L to be checked in case of 
treatment for thyroid disease  
6. Myocardial infarction or unstable angina or presence of unstable ischemic coronaropathy 
assessed by coronarography or cardiac stress test (Echo stress, exercise stress test, nuclear or 
MR perfusion evaluation methods) within 6 months before selection 
7. Severe chronic kidney disease (creatinine ≥ 25 mg/L or estimated glomerular filtration rate < 
30 mL/min) at selection 
8. Bradycardia (HR ≤ 50 bpm) 
9. Hyperkalemia or hypokalemia (according to the standards of local laboratories) at selection 
10. Cardiac surgery within 3 months before selection or planned during the study duration 
Criteria related to treatments: 
11. Previously ineffective pharmacological or electrical cardioversion 
12. Concomitant treatment with ranolazine or any anti-arrhythmic drug (within 7 days prior to 
selection), except stable dose of digoxin, beta-blockers, calcium-blockers. 
13. Oral amiodarone: 
13a   Previous treatment with oral amiodarone within 4 months prior to inclusion 
      13b   Intake of oral amiodarone for more than 1 month within 4 to 12 months before inclusion 
14. Previous treatment with intravenous amiodarone within 4 weeks prior to inclusion 
15. Patient requiring a cardiac resynchronization therapy (CRT) or having undergone CRT 
implantation within the last 6 months 
16. Treatment with any Polyunsaturated Fatted Acid within the last 3 months 
Dietary supplement with ω3 or ω6 according to investigator’s judgment 
18. Having undergone any form of ablation therapy for AF 
19. Patient treated with other anticoagulant treatment than antivitamin K: thrombin inhibitor such 
as Dabigatran or treated with antiaggregant P2Y12 inhibitors such as Clopidogrel or Prasugrel 
Others criteria:  
20. Patient liable not to comply with protocol instructions and/or with treatment, in the 
investigator’s opinion, 
21. Patient having taken part in a clinical trial in the preceding 2 months or taking part in a trial at 
the time of selection, 
22. Patient linguistically or mentally unable to understand the nature, objectives and possible 
consequences of the trial, or refusing to patient himself / herself to its constraints, 
23. Patient family member or work associate (secretary, nurse, technician…) of the Investigator, 
24. Patient having forfeited his / her freedom by administrative or legal award or being under 
guardianship, 
25. Breastfeeding female patient. 
5.3. 
NUMBER OF PATIENTS 
76 x 2 patients (taking into account 15 % of non evaluable patients). 
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5.4. 
RECRUITMENT MODALITIES 
Patients will be recruited within the medical consultation of each centre involved in the study. If 
necessary and when authorized by local and national regulation, some specific supports or tools 
will be used to improve the recruitment (announcement, mailing to general practitioners, leaflet, 
website including ClinicalTrials.gov, CRO…). 
Before implementation, the documents will be submitted to and approved by the Ethics 
Committee. 
5.5. 
 PATIENT IDENTIFICATION 
Patient's code will contain 7 digits: the 2 first digits corresponding to the country number, the 
following 2 digits corresponding to the centre number and the last 3 digits corresponding to the 
patient's chronological order once having signed the written informed consent. 
5.6. 
WITHDRAWAL CRITERIA 
Reasons for a patient's premature withdrawal from the study may be the following: 
• Patient's decision. A patient who wishes to withdraw from the study for any reason may 
do so at any time but must inform the investigator. In all cases, the Investigator should 
attempt to contact the patient as soon as possible for a final assessment in order to: 
− have the patient's decision written on the consent form 
− obtain the reason(s) for withdrawal and report it/them in the case report form 
− evaluate the patient's clinical condition 
− if necessary, take appropriate therapeutic measures: management of an adverse effect or 
concomitant disease, prescription of another treatment. 
• Investigator's decision in the patient's interest, particularly if a serious adverse event 
occurs and is considered by the Investigator liable to threaten the health of the patient. The 
monitor will be informed by phone or fax and a letter or report explaining the withdrawal 
will be forwarded to the monitor as soon as possible. 
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• Erroneous inclusion according to the study protocol. Any inclusion not respecting 
inclusion/non inclusion criteria will immediately be withdrawn and an appropriate 
treatment will be given by the investigator under his/her responsibility. Erroneous 
inclusions will not be paid to the investigator. 
• Patients who could not be treated with AVK for at least 3 weeks before ECV. 
• Patients who will not have a stabilized INR between 2 and 3 on at least 3 consecutive 
weekly tests. 
• Patients with only 2 consecutives INR tests between 2 and 3 in the last 3 weeks for whom 
a trans-oesophagoal echocardiography can not be performed before ECV or for whom a 
trans-oesophagoal echocardiography shows a thrombus in the atria.  
• Patients who will not revert to sinus rhythm (i.e. unsuccessful ECV) or with early relapse 
within the observation period after ECV will be considered to have finished follow-up. 
• Occurrence of AF recurrence that would require, at the investigator’s judgement, a 
cardioversion or an introduction of an anti-arrhythmic because of intolerable and/or 
uncomfortable clinical symptoms for instance. 
5.7. 
REPLACEMENT OF PATIENTS 
Withdrawn patients will not be replaced. 
5.8. 
POST-STUDY EXCLUSION PERIOD  
Patients will not be allowed to participate to another clinical trial during 3 months following the 
study termination. 
5.9. 
STUDY CARD AND LETTER FOR GENERAL PRACTITIONER(S) 
The patient will receive from the Investigating Centre at Visit 1 - Selection Visit:  
- a personal card to be kept all along the study duration and providing the following information: 
patient's name, sponsor's name, study code, EUDRACT number, start date and expected end date 
of the study, complete address of the Investigating Centre with the name and phone number of the 
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Investigator and a sponsor 24H/24 phone contact number in case of emergency (French and 
English languages): 33 (0)5 63 35 25 83. For Italy, this card will be in Italian only, without any 
English mention. 
- in Italy, a letter to be given to his/her general practitioner. This letter intends to inform the 
general practitioner(s) (and any other doctors who take care of the patient) that the patient 
participates to the clinical study. It describes the study treatment and includes some information 
on the forbidden treatment during the study.  
 
6. STUDY TREATMENT 
The Clinical Pharmacy Department of the Institut de Recherche Pierre Fabre (IRPF) will supply 
the investigational centres with the treatment necessary for the conduct of the trial.  
6.1. 
SOURCE, PRESENTATION AND COMPOSITION OF 
 
INVESTIGATIONAL PRODUCT 
F373280 and placebo will be prepared in Soft Capsules similar presentation.  
• F373280 
Formulation of F373280, 1 g, Soft Capsules: oral administration, oblong size 20, off-white, Soft 
Capsules containing: Panthenyl ester of DHA, gelatine, glycerol, titanium, dioxide, purified water. 
• Placebo 
Formulation of placebo matching tested product, Soft Capsules: oral administration, oblong size 
20, off-white, Soft Capsules containing: paraffin liquid, fish flavour, gelatine, glycerol, titanium, 
dioxide, purified water. 
 
Placebo and F373280 capsules will be packaged in opaque blisters. 
6.2. 
PACKAGING AND LABELLING 
The treatment units will be packed and labelled by the Clinical Pharmacy Department of the IRPF 
according to European Directive and local requirements. 
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6.2.1. 
Packaging 
Each treatment unit will be composed of 3 cases for a 12-week treatment period. 
The Investigator will provide the patient with the treatment according to the following schedule: 
At Inclusion Visit (V2): a 12-week treatment unit will contain 3 cases, each case containing: 
− 10 blister packs of four 1 g F373280 soft capsules or placebo soft capsules each. 
At Visit 6 (V6): a 12-week treatment unit will contain 3 cases, each case containing: 
− 10 blister packs of four 1 g F373280 soft capsules or placebo soft capsules each. 
6.2.2. 
Labelling 
Investigational Products will be labelled according to the following rules: 
Labelling should comply with the local requirements for Investigational Medicinal Products. 
On the treatment units and cases, the labels will bear the following indications:  
a) name and address of the sponsor 
b) protocol number 
c) packaging batch number 
d) treatment number 
e) storage conditions 
f) expiry date 
g) pharmaceutical dose form 
h) route of administration 
i) quantity of dosage units 
j) direction for use 
k) legal statements:  
    -“for clinical trial only”, “keep out of the reach and the sight of children”, “please return to 
your doctor any unused product”, respect the prescribed dose” 
On the treatment unit, another label will be affixed with the mention of the Investigator’s name 
and patient’s code (completed by the Investigator). 
In addition, on each case will be mentioned the case number, and a detachable label will bear the 
following indications: 
− Protocol number 
− Packaging batch number 
− Expiry date 
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− Case number 
− Treatment number 
On the blister pack, the label will mention the protocol number, the packaging batch number, the 
case number and the treatment number. 
6.3. 
DISTRIBUTION TO CENTRE AND STORAGE 
The Clinical Pharmacy Department of the IRPF will supply the Investigational Centre with the 
treatment units along the study according to the need, upon request triggered by the patient’s 
selection.  
As soon as the Pharmacist or the Investigator receives the trial medication, he/she will check the 
contents and immediately acknowledges the receipt in the IVRS/IWRS. The copy of the 
acknowledgement will be kept in the Investigator’s or the Pharmacist’s file. The same procedure 
will be applied to all further supplies during the course of the trial. 
At the time of the delivery to the Centre, the following information will be provided: 
• Details of storage conditions that should be respected 
• And, upon request and for the 1st delivery only, a letter of release for the Investigational 
Medicinal Product from the Sponsor's Qualified Person 
The CRA will ensure during the monitoring visits that trial medications have been received in 
good conditions and the acknowledgment of receipt has been performed adequately. 
Treatment units should remain intact until dispensation to the patients. They should be kept at 
temperature below 30°C in an appropriate lockable room only accessible to the person authorised 
to dispense them, under the responsibility of the Pharmacist or the Investigator. 
In the case of undue delay in study execution, the Pharmacist or the Investigator should ensure 
that the expiry date has not been exceeded.  
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6.4. 
ALLOCATION OF TREATMENTS AND DISPENSATION TO PATIENT 
A randomisation list will be established by the Clinical Pharmacy Department of the IRPF. This 
list will be computer-generated with internal software. The randomisation methodology is 
validated by the Biometry Department before generation. 
Treatments F373280 or placebo will be balanced in a 1:1 ratio. 
As the treatment units are prepared for 12-week treatment periods, the Investigator will have to 
allocate a treatment number at inclusion visit (V2) and another one at visit 6.  
For each patient, the treatment number given at visit 6 will not be the same that the one given at 
inclusion visit (V2). 
The treatment numbers will be given through the IVRS/IWRS. 
Practically, once patient’s eligibility is confirmed at selection visit (V1):  
• The Investigator: 
− Contacts the IVRS/IWRS 
− Answers the questions relating to the patient  
− In return, the treatment number to be allocated for the first 12-week period to the patient is 
given by the IVRS/IWRS.  
• The IVRS/IWRS company: 
− Confirms this information by fax/email to the Investigator 
− Fills the “Request for Delivery of Investigational Product” form and sends it by email 
and/or fax to the Clinical Pharmacy Department of the IRPF.  
• The Clinical Pharmacy Department of the IRPF sends the corresponding treatment unit to 
the Investigator within 5 days from reception of the email request form. 
The Investigator will dispense to the patient the case which label indicates the treatment number 
and the administration period. 
At visit 6, the Investigator will contact again the IVRS/IWRS to obtain the treatment number for 
the last 12-week period of treatment according to the same process as described above. 
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6.5. 
DRUG ADMINISTRATION 
6.5.1. 
Duration of Treatment 
For a patient completing the study, the theoretical study treatment exposure to F373280 or 
placebo will be 24 weeks. 
If the ECV is postponed by 1 week to allow INR stabilization, the treatment duration will be 25 
weeks. 
6.5.2. 
Dose Schedule 
One soft capsule of 1g of F373280 or placebo to be taken each day during 24 weeks. 
6.5.3. 
Route and Conditions of Administration 
The soft capsules are to be taken orally. One soft capsule is to be taken each evening with the 
dinner during 24 weeks.  
6.6. 
ACCOUNTABILITY ON SITE AND RETURN/DESTRUCTION OF 
 
INVESTIGATIONAL PRODUCT 
The Investigator should maintain accurate written records of drug received, dispensed, returned 
and any remaining treatment units, on the drug accountability form. These records should be made 
available for Clinical Research Associate (CRA) monitoring. The packaging of the medication 
should remain intact until just before the dispensation. 
At each visit, the Investigator will record the number of soft capsules returned by each patient 
using the appropriate page of the e-CRF. 
At the end of the study, all used and unused treatments including packaging should be noted, and 
return is organised by the CRA to the Clinical Pharmacy Department of the IRPF for destruction. 
A copy of the drug accountability form should be provided by the Investigator to the CRA. 
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6.7. 
RECALL OF INVESTIGATIONAL PRODUCTS  
In case of recall of investigational products (decided by the Competent Authorities or the 
Sponsor), the Investigator will immediately be informed by the Sponsor. 
The Investigator in collaboration with the Sponsor’s representatives (Study Manager, CRA) must 
urgently: 
• Stop the delivery of the concerned investigational products to the patients. 
• Inform the concerned patients that they must immediately stop taking these investigational 
products and bring them back. 
The Study Manager/CRA organises the return of the recalled products to the Clinical Pharmacy 
Department of the IRPF according to the Sponsor’s procedures. 
7. CONCOMITANT TREATMENTS 
Any existing concomitant treatment (at selection visit), any new concomitant treatment or change 
in the dosage of an existing concomitant treatment during the course of the study must be noted 
on the electronic Case Report Forms (e-CRF). All treatments should be evaluated by the 
Investigator at patient’s selection, and treatment prolongation or stop during the study should be 
considered. 
For all concomitant treatments taken during the study, the following information must be noted in 
the relevant section(s) of the e-CRF: 
• The name of the treatment and its form 
• The reason for prescription 
• The route of administration 
• The daily dose 
• The duration of treatment. 
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7.1. 
ANTI-VITAMIN K TREATMENT 
AVK should be given for at least 3 weeks before ECV and continued for the whole study 
duration. The AVK used will be left to the decision of the each Investigator according to his/her 
local practice. 
7.2. 
PROHIBITED TREATMENTS 
- 
Class I and class III antiarrhythmic treatments: 
− Class I 
- 
Class IA: Disopyramide, Procainamide, Quinidine 
- 
Class IB: Lidocaine, Mexiletine 
- 
Class IC: Flecainide, Propafenone 
 
− Class III: Dofetilide, Ibutilide, Sotalol, Amiodarone, Dronedarone. 
 
- 
Ranolazine 
- 
Any PUFA 
- 
Any anticoagulant treatment other than AVK: thrombin inhibitor such as Dabigatran or 
antiaggregant P2Y12 inhibitors such as Clopidogrel or Prasugrel 
- 
Dietary supplement with Omega 3 or Omega 6 
Prohibited treatments at selection must not be prescribed for the duration of the study except in 
case of occurrence of an adverse event or AF episode that requires a corrective treatment in the 
interest of the patient’s health. 
7.3. 
AUTHORISED TREATMENTS 
Other treatments will be authorised during the study duration. 
However, if medication other than study drugs is administered at any time from the start of the 
study, details must be recorded in the e-CRF. During the study, patients must be asked whether 
they have been on a course of prescribed drug treatment or have taken any OTC or herbal drugs 
since the visit. 
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8. EVALUATION CRITERIA 
8.1. 
PRIMARY EFFICACY CRITERION  
8.1.1. 
Time to the first Atrial Fibrillation Recurrence 
8.1.1.1. 
Definition 
Time to first AF recurrence is defined by the first episode of AF (symptomatic or not) lasting for 
at least 10 minutes. 
8.1.1.2. 
Schedule 
The heart rhythm follow up will be performed from the end of ECV visit (visit 3) to the final 
study visit (visit 9).  
For randomised patients with spontaneous cardioversion before ECV, the recurrence of AF will be 
assessed after visit 3 (week 5). 
8.1.1.3. 
Evaluation Methods 
• 7-day holter monitor: 
The heart rhythm monitoring will be carried out from visit 3 to visit 4 using a 7-day continuous 
ECG (5-leads/2 or 3 channels) ambulatory recording (holter ECG) fixed after ECV visit. 
Following holter monitoring, the heart rhythm will be documented using Trans Telephonic ECG 
Monitoring (TTEM). 
• Trans Telephonic ECG Monitoring: 
The ECG follow up will be documented using the TTEM: daily transmission from visit 4 (week 5) 
to visit 5 (week 8). Then every two days from visit 5 (week 8) to visit 9 (week 24 – End of study). 
Moreover, if patient experiences AF symptoms during this TTEM period, it should be 
documented using the TTEM. 
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In case of AF recurrence and provided that the patient does not required a cardioversion or an 
introduction of an anti-arrhythmic at Investigator’s judgement, the patient could be maintained in 
the study with the treatment in order to assess a spontaneous cardioversion. For that purpose the 
patient will continue to transmit a TTEM once a week. 
The TTEM will be centralized by the Central Reading Laboratory. The patient will be requested 
to contact the Central Reading Laboratory for transmission of each stored TTEM. The TTEM will 
be validated by a trained technician, then analysed by a cardiologist. The cardiologist 
interpretation will be faxed to the site. The investigator will be asked to review and sign this 
document. 
The TTEM process will be fully described in a separate document. 
8.1.2. 
Secondary Efficacy Criteria 
8.1.2.1. 
Numbers of AF episodes in the first week following visit 3 (ECV visit) 
8.1.2.1.1. 
Definition 
Number of AF episodes will consist in the assessment of AF episodes with duration at least 10 
minutes (NSup10) and of less than 10 minutes (NInf10), respectively. 
8.1.2.1.2. 
Schedule 
The heart rhythm follow up will be performed from the end of successful ECV visit (visit 3) to the 
study visit 4.  
8.1.2.1.3. 
Evaluation Methods 
• 7-day holter monitor: 
The heart rhythm monitoring will start using a 7-day continuous ECG (5-leads/2 or 3 channels) 
ambulatory recording (holter ECG) after ECV visit from visit 3 to visit 4. 
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8.1.2.2. 
Duration of AF episodes in the first week following visit 3 (ECV visit) 
8.1.2.2.1. 
Definition 
Duration of AF episodes will consist in the sum of duration of each AF episode. 
8.1.2.2.2. 
Schedule 
The heart rhythm follow up will be performed from the end of successful ECV visit (visit 3) to the 
follow up study visit (visit 4).  
8.1.2.2.3. 
Evaluation Methods 
Duration of AF episodes will be assessed using the 7-day continuous ECG (5-leads/2 or 3 
channels) ambulatory recording. 
8.1.2.3. 
Clinical parameters evaluation 
8.1.2.3.1. 
EHRA score assessment 
8.1.2.3.1.1. Definition 
AF related symptoms will be evaluated by the EHRA (European Heart Rhythm Association) score 
[20]. The following items “during presumed arrhythmia episodes" are checked to determine the 
score: palpitation, fatigue, dizziness, dyspnea, chest pain and anxiety. 
Classification of AF-related symptoms (EHRA score) are as follows: 
• EHRA I          - ‘No symptoms’ 
• EHRA II         - ‘Mild symptoms’; normal daily activity not affected 
• EHRA III       - ‘Severe symptoms’; normal daily activity affected 
• EHRA IV       - ‘Disabling symptoms’; normal daily activity discontinued  
This classification relates exclusively to the patient-reported symptoms. 
In addition to this score, the frequency will be classified in three groups, namely occasionally 
(less than once per month), intermediate (1/month to almost daily) and frequent at least daily. 
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8.1.2.3.1.2. Schedule 
EHRA evaluation will be performed in case of evocative symptoms of arrhythmia. 
8.1.2.3.1.3. Evaluation Methods 
EHRA evaluation will be collected by Central Reading Laboratory during all the study period. 
8.1.2.3.2. 
Number of recurrence of symptomatic AF  
It consists of the number of AF recurrences associated with a symptom (palpitation, fatigue, 
dizziness, dyspnea, chest pain and anxiety) and confirmed by an ECG. 
8.1.2.3.3. 
Number and duration of hospitalizations 
• Number and duration of hospitalizations for cardiovascular events 
− Hospitalization for AF treatment 
− Hospitalization for worsening of heart failure 
− Hospitalization for myocardial infarction 
− All cause of hospitalization 
• Number and duration of hospitalizations for thromboembolic stroke  
8.1.2.4. 
Cardioversion assessment 
• Assessment of spontaneous cardioversion before visit 3 
• Assessment of successful cardioversion at visit 3 (i.e. return to sinus rhythm) 
• Shock distribution (1, 2 or 3 shocks) 
• Number of patients needing another cardioversion after initial ECV 
8.1.2.5. 
Evolution of echocardiographic parameters 
8.1.2.5.1. 
Definition 
The following echocardiographic parameters will be assessed: Left atrial diameter (mm), LAA 
(cm2), Left atrial volume (mL), Left atrial volume/BSA (mL/m2), LVEF (%), Left ventricular end 
diastolic volume/BSA (mL/m2), Left ventricular end systolic volume/BSA (mL/m2), Left 
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ventricular end diastolic diameter (mm), Left ventricular end diastolic volume (mL), Left 
ventricular end systolic diameter (mm) and Left ventricular end systolic volume (mL). 
8.1.2.5.2. 
 Schedule 
Measurements will be performed at visit 1 and visit 2 to check the eligibility of the patient.  
Measurements performed at visit 4, visit 6 and visit 9 are done to follow the echocardiographic 
evolution of the patients in sinus rhythm. 
8.1.2.5.3. 
Evaluation method 
The echography evaluations will be carried out according to the recommendations for chamber 
quantification drawn up by the American Society of Echocardiography and the European 
Association of Echocardiography [23]. So, the recommended method for volume measurements is 
to use the biplane method of discs (modified Simpson’s rule) from 2-D measurement. 
8.2. 
BIOMARKER ASSESSMENT: RED BLOOD CELL 
 
CONCENTRATIONS OF DHA 
8.2.1. 
Definition 
Because of the limited human tissue accessibility for biopsy, red blood cell DHA contents is a 
marker of tissue DHA concentration [13], [14]. 
8.2.2. 
Blood samples 
8.2.2.1. 
Collection schedule 
Blood samples will be collected to determine the red blood cells (RBC) concentrations of DHA.  
Blood samples will be performed at visit 2 before treatment, visit 3, visit 6 and visit 9. 
Actual sampling times will be individually reported in the e-CRFs. 
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8.2.2.2. 
Technical handling 
Two blood samples (4 ml) will be collected in EDTA tubes. They will be gently shaken, stored at 
+4°C (no freezing will be allowed) and sent to Analytical Centre in refrigerated conditions 
(between +2°C and +8°C). Analysis will be performed within 2 weeks following reception at the 
Analytical Centre. 
8.2.3. 
DHA concentration measurement 
Analytical determination of RBC concentrations of DHA will be carried out by the Analytical 
Centre. 
Lipids will be extracted from red blood cells samples with a mixture of hexane/isopropanol after 
acidification [17]. Total lipid extracts will be saponified and methylated. The fatty acid methyl 
esters (FAME) will be extracted and analyzed by Gas Chromatography. 
Identification of FAME will be based on retention times obtained for FAME prepared from fatty 
acid standards. The area under peaks will be determined using ChemStation Software (Agilent) 
and results will be expressed as % of total fatty acids. DHA concentration will be calculated using 
the internal standard and expressed as µg/g for red blood cells samples. Thus, omega-3 index will 
be assessed. The omega-3 index represents the content of EPA plus DHA in red blood cells 
(expressed as a percent of total fatty acids). It is a biomarker considered as a new marker of risk 
for death from coronary disease [18]. 
Results of this analytical determination will be kept confidential by the dosing centre until the end 
of the study, and will be provided only at the end of the study (after database lock) in a separate 
file. 
8.3. 
SAFETY ASSESSMENT 
8.3.1. 
Adverse Events 
At selection, any concomitant disease will be reported on the e-CRF. At each further visit, the 
occurrence of AEs since the last visit will be based on the patient's spontaneous reporting, the 
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Investigator's non-leading questioning and his/her clinical evaluation. All AEs will be reported on 
the e-CRF (see section 10). 
8.3.2. 
Laboratory Investigations 
8.3.2.1. 
Schedule 
Laboratory investigations will be performed at visit 1 (before treatment) and visit 9 (end of 
treatment) or End of Treatment visit. 
At visit 3 and 6, only a standard haematologic dosage will be performed.  
Furthermore the kaliemia will be checked before electrical cardioversion at visit 3. 
The total volume of blood samples taken for haematology and biochemistry analysis should not 
exceed 30 mL. 
8.3.2.2. 
Technical Procedures and Parameters 
The following tests will be performed: 
 
Haematology: 
hematocrit, haemoglobin, RBC count, white blood cells (WBC) count, WBC 
differential counts (% and absolute), reticulocytes, platelets.  
 
Chemistry: 
sodium, potassium, bicarbonate, chloride, alkaline phosphatase, gamma GT, 
albumin, total bilirubin, conjugated bilirubin, creatinin, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), fasting glucose, 
total cholesterol, cholesterol (HDL, LDL), triglycerides, creatine 
phosphokinase (CPK), fibrinogen. 
Blood samples will be taken in the morning in fasting conditions.  
The estimation of GFR at selection relies on the measurement of serum creatinine and the 
Cockcroft- Gault formula: 
Cockcroft-Gault formula 
- with serum creatinine expressed as mg/L:  
in men: 
GFR (mL/min) = [(140-age)] x weight / 7.2 x serum creatinine in mg/L] 
 
in women: 
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GFR (mL/min) = [(140-age)] x weight / 7.2 x serum creatinine in mg/L] x 0.85 
 
- with serum creatinine expressed as μmol/l: 
GFR (mL/min) = [(140-age) x weight / serum creatinine in μmol/l] x k,where k = 1.23 for men, 
1.04 for women. 
 
(weight in kg, age in years) 
Additional tests may be done at the Investigator’s discretion, in the patient’s interest. In case of 
any abnormal or clinically significant results, the Investigator will order laboratory control tests. 
8.3.3. 
Global Physical Examination 
A global physical examination including the measurement of body weight will be carried out on 
each body system at visit 1, visit 2, visit 3, visit 5, visit 6, visit 7, visit 8 and visit 9. 
The physical examination will be globally evaluated as “normal/abnormal”. Further target 
inspection will be undertaken for any abnormal finding. 
8.3.4. 
Vital Signs 
Vital signs will consist in blood pressure and heart rate at rest.  
8.3.4.1. 
Schedule 
Vital signs will be measured at each visit. 
8.3.4.2. 
Technical Procedure and Parameters 
Systolic blood pressure (SBP) and diastolic blood pressure (DBP), expressed in mmHg, will be 
measured after at least 5 minutes in supine position and after 2 minutes in standing position.  
The heart rate (HR), expressed in beats per minute (bpm), will be measured by auscultation by 
counting the beats for at least 30 seconds, after at least 5 minutes in supine position and after 2 
minutes in standing position. 
Bodyweight will be measured with patient in underwear and with the same balance at each visit.  
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8.3.5. 
Electrocardiogram (ECG)  
8.3.5.1. 
Schedule 
An ECG will be recorded at visit 1, visit 2, visit 3, visit 5, visit 6, visit 7, visit 8 and visit 9 using 
an usual standardised 12-lead cardiograph. 
8.3.5.2. 
Technical Procedure and Parameters 
• Electrocardiogram: 
The global interpretation from manual reading (normality, clinical relevance) and HR (bpm), PR 
(ms), QRS (ms), QT (ms), repolarisation patterns will be reported in the e-CRF. Each print-out 
will include the patient’s code, date, time, technician's initials and investigator's signature. 
In case of thermic paper ECG print out, a photocopy will be made by the centre to ensure safe 
filing. 
• 24 hour-Holter - ECG 
An ambulatory continuous 24-hour ECG (5-leads/2 or 3 channels) will be recorded at selection 
visit using a holter ECG, in order to confirm persistent AF.  
8.3.6. 
Coagulation parameters 
Coagulation assessment will be evaluated by the following parameters: 
− Prothrombin Time/INR (PT/INR) 
− Activated Partial Thromboplastin Time (aPTT) 
− Thrombin Clotting Time (TCT) 
During the pre-cardioversion period, if the anticoagulation by AVK should be initiated, then the 
INR monitoring will be as follow:  
− INR 2-3 times a week for the first week of treatment 
− INR weekly up to ECV 
− INR every 4 weeks after ECV 
For patients already treated with AVK, INR monitoring will be as follow: 
− INR weekly up to ECV 
− INR every 4 weeks after ECV 
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aPTT and TCT will be performed at visit 1, visit 2, visit 3, visit 5, visit 6, visit 7, visit 8 and visit 
9. 
Anti-coagulation by AVK should be given at least 3 weeks before ECV and continued for the 
whole study duration. 
The quantity of blood samples collected at each time for coagulation parameters will be 2 mL. 
8.3.7. 
Concomitant Treatments 
Concomitant treatments will be evaluated at each study visit. 
Requirements relating to patient's concomitant treatments started before screening visit and 
continued throughout the trial, or started during the trial, can be found in section 7.  
8.4. 
COMPLIANCE 
The patient will be reminded at each visit to bring back at the following visit any used or unused 
remaining soft capsule, blister and case. 
At each visit, the Investigator will record the number of supplied and remaining soft capsules in 
the e-CRF. 
9. STUDY PROCEDURES 
Visit 1 - Selection Visit (Week -4 to Week -1) 
The patient considered eligible for selection by the Investigator will be informed of the 
characteristics and the consequences of the trial both verbally and by reviewing the patient's 
information sheet and consent form (see section 14.3). If the patient accepts to participate in the 
study, he/she will sign the informed consent form and will keep a copy. 
The patient will be assessed for the following: 
• Demographic characteristics (gender, age, height, body surface area) 
• Personal and medico-surgical history 
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• Habits (Tobacco, alcohol consumption, dietary habits including fish consumption…) 
• Cardiovascular diseases, mainly detailed history of Heart Failure and AF characteristics  
• Echocardiography using a two-dimensional echocardiography 
• 12-lead ECG 
• Concomitant diseases, adverse signs or symptoms (able to be used for treatment emergent 
AE determination) 
• Concomitant treatments (authorised, disallowed) 
• Global physical examination/bodyweight 
• Vital signs 
• Biology: haematology, biochemistry, assessment of coagulation parameters: Prothrombin 
Time/INR (PT/INR), Activated Partial Thromboplastin Time (aPTT), Thrombin Clotting 
Time (TCT) 
• Biology assessment of renal function: creatinine or estimated glomerular filtration rate 
If the results of the above assessments are compatible with the selection criteria 
• A 24-hour continuous ECG ambulatory recording (Holter ECG) device will be installed 
on the patient to monitor the patient heart rhythm. The patient will be requested to bring 
back the device after the termination of 24 hours recording. The recording will be 
transmitted from the Investigational site to the Central Reading Laboratory. The Central 
Reading Laboratory will send his/her assessment regarding the confirmation of persistent 
AF within 2 working days to the Investigator. 
• The patient will enter the selection period in which anticoagulant (AVK) will be adjusted 
to achieve an International Normalized Ratio (INR) of 2 to 3 before ECV.  
At the end of the visit, the Investigator will contact the IVRS/IWRS to confirm the patient 
selection (which will automatically order the treatment delivery) and organise the appointment for 
the next visit.  
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The patient will receive from the investigational centre the study card to be kept for the duration 
of the study. 
Visit 2 - Inclusion Visit (Day 1)  
If the patient's behaviour during the selection period and/or the result of complementary 
examinations particularly the confirmation of the presence of persistent AF by the Central 
Reading Laboratory during this period, the INR and laboratory tests, are compatible with the 
inclusion criteria, the patient will be assessed for the following: 
• Adverse events 
• Concomitant treatments (authorised, disallowed) 
• Laboratory examination: red blood cell concentrations of DHA and coagulation 
parameters Prothrombin Time/INR (PT/INR), Activated Partial Thromboplastin Time 
(aPTT), Thrombin Clotting Time (TCT) 
• Global Physical examination/bodyweight 
• Vital signs 
• Echocardiography using a two-dimensional echocardiography 
• 12-lead ECG 
• Urine pregnancy test for women of child bearing potential 
If the results of the above assessments are compatible with the inclusion criteria, the patient will 
be included and allocated a treatment number using the IVRS/IWRS.  
Between this Inclusion visit and the next visit (V3), the INR will be closely monitored (refer to 
paragraph 8.3.6) in order to ensure that the INR is stable (between 2 to 3 before electrical 
cardioversion). 
At the end of the visit, the Investigator will organise the appointment for the next visit and will 
give the treatment for the next 4-week period. 
Visit 3 (Week 4: D28 -2/+7 days) cardioversion 
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Patient will be assessed for the following criteria: 
• Adverse events 
• Concomitant treatments (authorised, disallowed) 
• Laboratory examination: Haematology, RBC concentrations of DHA, Prothrombin 
Time/INR (PT/INR), Activated Partial Thromboplastin Time (aPTT), Thrombin Clotting 
Time (TCT) 
• Global Physical examination /bodyweight 
• Vital signs  
• 12-lead ECG 
• Electrocardioversion (ECV): ECV has to be scheduled 4 weeks after randomization and 
after target international normalized ratio levels will be stabilized (between 2 and 3) on at 
least 3 consecutive weekly tests in patients with AF. Patients not stabilized for INR (i.e. 
values not between 2 and 3) on at least 3 consecutive weekly tests before ECV will be 
excluded from the study, unless the presence of atrial thrombosis may be excluded with 
ECHO –TE performed in the same day (and before ECV). ECV will be performed in the 
morning, with the patient in the fasting state and without dyskalemia. Anesthesia will be 
induced and patients will be cardioverted with administration of a synchronized, biphasic 
current. The initial shock will be set at 100 J if the body weight is less than 70 kg and at 
150 J for higher body weights. Successful cardioversion will be defined as recovery of 
sinus rhythm lasting at least 1 minute after the shock. If unsuccessful, a second 200-J 
shock, and eventually a third 200-J shock, will be administered. Failure of ECV is defined 
as the persistence of AF after the third attempt at cardioversion. After the procedure, 
patients will be monitored on telemetry for at least 6 hours before discharge. Patients who 
will not revert to sinus rhythm or with early relapse within the observation period after 
ECV will be withdrawn from the study and will be considered to have finished their 
follow-up. 
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At the end of the visit, a 7-day continuous ECG (5-leads/2 or 3 channels) ambulatory recording 
(holter ECG) will be installed on the patient in order to monitor the patient heart rhythm after 
ECV.  
At the end of the visit, the Investigator will organise the appointment for the next visit and give 
the treatment to be taken during the next 4-week period. 
Visit 4 (Week 5: D35 -2/+7 days) 
After removal of the continuous ECG ambulatory device, the patient will be assessed for the 
following criteria: 
• Assessment of AE 
• Concomitant treatments (authorised, disallowed) 
• Body weight (body weight measured at V3 to be used) 
• Vitals Signs 
• Echocardiography using a two-dimensional echocardiography 
At the end of the visit, the patient will be given the TTEM device for cardiac monitoring. The 
patient will be clearly instructed on the frequency and modalities of transmission. The patient will 
be requested to performed daily transmission from week 6 to week 8, then every 2 days from 
week 9 to week 24. Moreover, in case of AF symptoms, additional transmissions may be 
performed. 
Visit 5 (Week 8: D56 ± 7 days) – Visit 6 (Week 12: D84 ± 7 days) - Visit 7 (Week 16: D112 ± 
7 days) - Visit 8 (Week 20: D140 ± 7 days) 
Patient will be assessed for the following criteria: 
• Adverse events 
• Concomitant treatments (authorised, disallowed) 
• Laboratory 
examination: 
Prothrombin 
Time/INR 
(PT/INR), 
Activated 
Partial 
Thromboplastin Time (aPTT), Thrombin Clotting Time (TCT). However, in case of 
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discontinuation of anticoagulation after ECV, the monitoring of INR, aPTT and TCT 
should be stopped. 
• Global Physical examination/bodyweight  
• Vital signs  
• 12-lead ECG 
• The cardiac monitoring will be continued using a TTEM device. The device will be given 
to the patient who will be requested to perform daily transmission from week 6 to week 8, 
then every 2 days from week 9 to week 24. Moreover, in case of AF symptoms, additional 
transmissions may be performed. 
The Investigator will collect all unused cases, blisters and soft capsules, and will count the unused 
capsules for each 4-week treatment period. 
At the end of the visit, the Investigator will organise the appointment for the next visit and give 
the treatment to be taken during the next 4-week treatment period. 
In addition: 
- at visit 6: 
• the investigator will contact the IVRS/IWRS to obtain the treatment unit number to 
be dispensed at visit 6 for the last 12-week period. 
• an echocardiography will be performed, an haematology examination will be done 
and the RBC concentration of DHA will be measured.  
 
End-of-Study Visit - Visit 9 (Week 24: D168 ± 7 days) 
Patient will be assessed for the following: 
• Adverse events 
• Concomitant treatments (authorised, disallowed) 
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• Global Physical examination/bodyweight 
• Vital signs 
• 12-lead ECG 
• Laboratory examination: haematology, biochemistry, assessment of coagulation 
parameters: Prothrombin Time/INR (PT/INR), Activated Partial Thromboplastin Time 
(aPTT), Thrombin Clotting Time (TCT), Red blood cell concentration of DHA. 
• Urine pregnancy test for women of childbearing potential 
• Echocardiography using a two-dimensional echocardiography 
The Investigator will collect all unused cases, blisters and soft capsules, and will count the unused 
soft capsules. 
10. ADVERSE EVENTS: DEFINITION AND REPORTING 
10.1. 
ADVERSE EVENTS 
10.1.1. Definition of Adverse Events 
An AE is any adverse change from the patient's baseline condition, i.e. any subjective signs and 
symptoms or change in a concomitant disease present at the Selection Visit considered or not 
related to the treatment. 
AE includes intercurrent signs, symptoms, illnesses and significant deviations from baseline for 
vital signs and laboratory values which may occur during the course of the clinical study. 
All laboratory tests for which abnormal results are collected after study treatment initiation should 
be repeated until the values return to normal or to a stable status. Abnormal results are defined as 
those falling out of the laboratory normal ranges and that are clinically significant. The frequency 
of such checks should be defined by the Investigator according to the degree of abnormality. 
In all cases, the aetiology should, as much as possible, be identified and Pierre Fabre Médicament 
notified. 
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10.1.2. Grading of Adverse Events 
Adverse or intercurrent events are graded as follows: 
• Mild: awareness of signs or symptoms, but easily tolerated 
• Moderate: uncomfortable enough to cause interference with usual activity 
• Severe: incapacity with inability to work or do usual activity 
10.1.3. Reporting of Adverse Events 
The records of AE in the e-CRF describe the nature (diagnosis, signs and symptoms), severity, 
onset date, stop date, outcome and actions taken, and relationship to study treatment (in the 
Investigator's opinion). It must be specified whether the event is serious or not. 
10.2. 
SERIOUS ADVERSE EVENTS (SAE) 
10.2.1. Definition 
A SAE includes, but is not necessarily restricted to, any event which: 
• Results in death (whatever may be the cause) 
• Is life-threatening 
• Results in persistent or significant disability/incapacity 
• Requires the patient's hospitalisation or prolongation of current hospitalisation * 
• Is a congenital anomaly or birth defect 
Other events such as cancer and any additional adverse experience or abnormal laboratory values 
occurring during the study period, defined by the protocol as serious or which the Investigator 
considers significant enough or that suggest a significant hazard, contra-indications, side effect or 
precaution, must be handled as serious adverse events. 
Any overdosage meeting a seriousness criteria should be reported as a SAE (see section 10.3). 
Any pregnancy occurring during/after exposure to the study drug(s) should be reported on the 
SAE notification form (see section 10.4). 
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* any hospitalisation, or prolongation of hospitalisation due to the circumstances listed below: 
− planned (as per protocol) medical/surgical procedure 
− preparation for routine health assessment/procedure (e.g. routine colonoscopy) 
− planned medical/surgical admission (planned prior to entry into study trial, appropriate 
documentation required) 
− administrative or social reasons (e.g. lack of housing, economic inadequacy, care-giver 
respite, family circumstances) 
will not be reported as a SAE. 
10.2.2. Reporting of SAE 
All Serious Adverse Events, according to the above-mentioned definitions and regardless of 
treatment or relationship to study drug, and occurring once the informed consent form has been 
signed, must be reported by the Investigator as soon as he/she is informed of the event. 
The Investigator must notify the Sponsor of this event by sending, within 24 hours, the 
"Notification of serious adverse event" form ("first notification") with all the available 
information about the event (see appendix 17.2), to the Sponsor's Corporate Vigilances e-mail 
dedicated box: 
HQ.pharmacovigilance@pierre-fabre.com 
 
 In case it is not possible to send the report by e-mail it can be sent by FAX at the 
following number: 
+ 33 1 49 10 80 90 
In case of non-inclusion, the reporting period ends when the non-inclusion is documented. 
10.2.3. Follow-up of SAE 
The Investigator must draw-up a specific clinical report and use the "Notification of serious 
adverse event" form ("follow-up") (see appendix 17.2) and collect the results of the carried out 
examinations and the reports of hospitalisation. 
The serious adverse events must be followed up until resolution or stabilisation. 
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10.2.4. SAE Occurring After the Study 
Any SAE occurring during 30 days following the end of the study for the patient should be 
notified to the Sponsor. 
Must also be notified to the Sponsor any event occurring at any time after the end of the study for 
the patient which may be related to the study treatment in the Investigator's opinion. 
10.3. 
REPORTING OF OVERDOSAGE TO THE SPONSOR 
For the purpose of this trial, an overdosage will be defined as any dose exceeding the planned 
prescribed dose of the study drug or the administration of any dose of an associated product that is 
considered both excessive and medically important. 
In the absence of seriousness criteria, the overdosage and associated adverse event if any, are 
reported only on the Adverse Event page of the e-CRF. If the definition of seriousness criteria is 
met, the SAE notification form must also be transmitted to the Sponsor. 
10.4. 
REPORTING OF PREGNANCY TO THE SPONSOR 
Pregnancies discovered in the period in between the informed consent form signed but before any 
study drug exposure are not to be reported to the Sponsor unless associated to a seriousness 
criteria (e.g. serious adverse event study-protocol related procedure). If pregnancy is confirmed, 
the women must not be administered the study drug and must be withdrawn immediately from the 
study.  
If pregnancy is suspected while the patient is receiving study treatment, the study drug should be 
discontinued immediately until the result of the pregnancy testing is known. If pregnancy is 
confirmed, then the study treatment is permanently discontinued in an appropriate manner and the 
patient is withdrawn from the study.  
The Investigator must report to the Sponsor any pregnancy which occurs during or after the 
patient has been exposed to the study drug and until 30 days after the last study drug 
administration. The Investigator must immediately notify the Sponsor using the SAE notification 
form and also report the pregnancy on the AE page of the e-CRF. 
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Women who become pregnant after exposure to the study drug must be followed by the 
Investigator until the completion/termination of the pregnancy. If the pregnancy goes to term, the 
outcome will have to be reported to the Sponsor (baby's healthy status). 
10.5. 
SPONSOR'S RESPONSIBILITIES FOR SAFETY REPORTING 
 
PURPOSES 
Sponsor will submit expedited and periodic reports to both Competent Authorities and Ethics 
Committees per corporate standard operating procedures as regards to the EU directive 
2001/20/EC taking into account local specific requirements. 
11. DATA COLLECTION AND STUDY MONITORING 
11.1. 
DATA COLLECTION 
11.1.1. Case Report Form 
An e-CRF will be used to record all patient data required by the protocol except the central ECG 
(Holter ECG, TTEM) and DHA data which will be transferred from vendors to the subcontractor 
as electronic data files that will be loaded into the study database.  
The e-CRF should be fully validated, compliant with ICH-GCP requirements and European 
regulations and should include a traceability system for data corrections and deletions (audit trail). 
Prior to the start of the study, the Investigator will complete a "Delegation of significant study-
related duties" form. The signature and initials of all personal in charge of e-CRF completion 
should be recorded on this form. Each person involved in e-CRF completion, review, correction 
and / or validation will be trained and will have an individual login and access code to the e-CRF. 
Training sessions will be held by the subcontractor for all participants using this tool. An e-CRF 
user manual will be available for investigators and CRAs.  
All the information included into the e-CRF will be recorded from source documents onto the e-
CRF by an authorised person. 
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The Investigator is responsible for the management and accuracy of the information on the e-
CRF. At each monitoring visit, the e-CRF(s) should be at the CRA's disposition for review and 
validation.  
At the end of the study, a CD-ROM containing the pdf version of all e-CRFs (including audit-
trail) will be sent by the subcontractor to the Sponsor and to the investigational sites for archiving. 
The subcontractor must store all study data for at least 15 years after the end of the study and 
ensure their legibility and accessibility during all the storage period. 
11.1.2. Source Documents 
A source document is an original record or certified copy of an original record of clinical findings, 
observations or any other medical or paramedical activities performed during the clinical trial, 
necessary for the transcription and the verification of the collected data. 
Source documents along with all other trial-related documents (copies of all "informed consent" 
forms, e-CRFs CD-ROM, drug inventories and any correspondence related to the study) must be 
kept in the investigator's file throughout the study, and then, must be stored in the study centre's 
archives for a period of at least 15 years or as per local legal requirements, whatever is the 
longest.  
For further details see section 15.2. 
11.2. 
STUDY MONITORING 
11.2.1. Monitoring visits 
On-site visits will be carried out by a representative of the Sponsor's staff (Study Manager or 
CRA) prior to study initiation and at regular intervals (every 4 to 6 weeks) throughout the study. 
Additional visits and communication by telephone fax or meeting may be performed if necessary. 
Any site visit performed by the Sponsor's representatives will be recorded in the Investigator's 
study file. 
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11.2.1.1. 
Site Preselection Visit 
Before selecting a centre for the study, a visit will be carried out by the CRA and/or the Study 
Manager to ensure that the Investigator has the necessary capacities (availability, patient's 
recruitment, environment), technical means and staff to carry out the study. 
11.2.1.2. 
Initiation Visit 
Before the start of the study at all investigational sites, an initiation visit will be carried out by the 
CRA to check at the latest that: 
• The Investigator: 
− has received the technical protocol, administrative and financial agreement signed by all 
parties 
− has received the written statement of the Ethics Committee approval and the list of its 
members and their functions 
• The original dated and signed curriculum vitae of the investigator(s) has been collected 
• Laboratory normal ranges have been collected  
• All study materials are available on the study site 
• All participants agree with the monitoring procedures and know the study procedures 
• All participants are aware of a possible audit or inspection 
The CRA has also to provide training on the study protocol requirements and study specific 
procedures. 
11.2.1.3. 
Follow-up Visits 
Throughout the study, regular follow-up visits will be carried out by the CRA to check 
compliance with GCP, patient’s informed consents, strict application of the protocol, conformity 
of the data entered on the e-CRF with the source documents and ensure its correct completion, 
adverse events reporting, proper retention, storage and management of the study medication, as 
well as the source and other trial-related documents. 
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11.2.1.4. 
Closing Visit 
At the end of the study, a final visit will be carried out by the CRA to: 
• Verify that the e-CRFs CD-ROM with pdf files are correctly stored 
• Control the accountability of intact and used treatment units and return them to the 
Clinical Pharmacy Department of the IRPF for destruction 
• Obtain the last data clarifications and/or solutions if any 
• Collect the patient's consent forms in sealed envelopes (except in case of specific country 
requirements),  
• Make an on-site review of all study documentation and complete it if necessary 
• And finally, remind the Investigator of his regulatory obligations, study document 
archiving process and duration. 
11.2.2. Direct Access to Source Documents 
In accordance to the requirements of the GCP, all Sponsor representatives (Study Manager, CRA 
and Auditors) have to be given a direct access to all source and study data to perform quality 
monitoring/audit, thus ensuring accuracy and completeness of data).  
Investigators are reminded that all Sponsor representatives keep professional confidentiality with 
regards to the patient data. 
11.3. 
INDEPENDENT DATA MONITORING COMMITTEE 
An Independent Data Monitoring Committee (IDMC) will be established to assess at intervals the 
progress of the clinical trial, the compliance with the inclusion criteria, the quality of follow up, 
the quality of primary end point measures, the safety data. The IDMC will thereafter recommend 
to the Sponsor whether to continue, modify, or stop the study.  
The IDMC operating procedures will be described in an independent document.  
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12. DATA MANAGEMENT  
All clinical data related to the study will be collected and saved in a computerised database by the 
Data Management Department of the subcontractor and under the supervision of the Data 
Manager of Pierre Fabre Biometry (PFB) according to the following procedures.  
12.1. DATA ENTRY 
All required data will be collected by the Investigator or authorised designee (duly identified into 
the delegation task list) on the e-CRFs.  
The e-CRFs used for this study will be developed and maintained by the Data Management 
Department of the subcontractor and approved by the Sponsor.  
Electronic data (Holter ECG, TTEM and DHA) will be transferred by the 3rd party vendor 
according to the specifications given by the Data Manager of the subcontractor. These data will be 
captured and handled in accordance with the European GCP ICH E6 guideline. 
12.2. 
DATA CLEANING 
The subcontractor will define in the Data Validation Plan for reviewing and querying data, 
descriptions of both manual and electronic edit checks. Upon Sponsor approval, the subcontractor 
will program the checks.  
The subcontractor will review the data over the course of the study, working with the Sponsor to 
identify data inconsistencies. The Investigator will be asked to resolve queries by making changes 
directly into the e-CRF.  
12.3. 
DATA CODING 
Adverse events, concomitant diseases, medical/surgical histories will be coded by the 
subcontractor using the MedDRA dictionary (latest version in use). 
Concomitant medication will be coded by the subcontractor using the WHO-DRUG dictionary 
(latest version in use).  
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The Sponsor Clinical Development Physician will validate the coding. 
12.4. 
DATA STORAGE 
Computer data files as well as their modifications will be archived by the subcontractor and kept 
available upon request of the Sponsor. 
12.5. 
DATABASE LOCK 
The validated database will be locked by the subcontractor upon request of the Data Manager of 
PFB following the completion of all steps required, i.e. data entry and check of all data, resolution 
of all queries, validation of the coding, Clinical and Products Safety databases reconciliation and 
validation committee.  
Then, the subcontractor will transfer the locked database in SAS format to the Data Manager of 
PFB who assume storage on the PFB secured server. 
13. STATISTICAL ANALYSIS 
After the database lock and the randomisation code release, the statistical analysis will be 
performed by PFB or under the supervision of the statistician of PFB using SAS® software, 
according to the Statistical Analysis Plan approved by the Validation Committee. 
13.1. 
GENERAL CONSIDERATIONS 
The main objective of the study is to assess the efficacy of F373280 versus placebo on the 
maintenance of sinus rhythm after direct ECV in patients with persistent AF and chronic heart 
failure. 
Only the primary analysis of the primary efficacy criterion, on which is based the sample size 
justification, may lead to a causal interpretation. All other statistical results are to be regarded 
within a descriptive perspective. 
The statistical significance level of the various two sided tests of all analyses will be 5 %. 
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13.2. 
SAMPLE SIZE 
Assuming an AF recurrence rate of 85% under placebo and 65% under active group, i.e. a 
clinically relevant difference ∆ of 20%, a sample size of 64 assessable patients per group is 
required, using a log-rank test of survival curves with a 80 % power and a 5 % two-sided 
significance level. 
According to the previous assumptions and assuming a rate of not assessable patients of 15%, a 
minimum of 76 patients will have to be randomised per group. 
13.3. PROTOCOL DEVIATIONS 
Prior to the database lock and the randomisation code release, the Validation Committee members 
will review the protocol deviations and will classify them as either minor or major. A protocol 
deviation will be considered major when it is likely to bias significantly the treatment effect 
estimate based on the primary efficacy criterion. 
Patients with major deviation(s) will be excluded from the Per Protocol data set (see section 13.4). 
A listing of all protocol deviations will be provided for all randomised patients, including the type 
(major/minor) of protocol deviations according to the decisions made by the members of the 
Validation Committee. 
The number and percentage of patients with major protocol deviations will be tabulated by 
treatment group and type of major protocol deviations on the Full Analysis Set defined in section 
13.4. 
13.4. DATA SETS ANALYSED 
The following 3 data sets will be analysed (as defined by the Validation Committee):  
 
• The Safety Set composed of all randomised patients having received at least one dose of 
the study treatment. This data set will be used to perform analyses of Safety. 
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• The Full Analysis Set (FAS) composed of all randomised patients having received at least 
one dose of the study treatment and with a successful cardioversion observed at visit 3. 
This data set will be used to perform analyses of Efficacy.  
• The Per Protocol Set (PP) which is the subset of the Full Analysis Set composed of all 
patients with a primary efficacy criteria available and without any major protocol 
deviation or other source of bias for primary criteria analyses. This data set will be used to 
perform the supportive analysis of the primary efficacy criterion. 
13.5. 
HANDLING OF DROPOUTS AND MISSING DATA 
13.5.1. Dropouts 
The number of patients who withdraw from the study after their randomisation will be provided 
by treatment group for all treated patients (Safety Set). All withdrawn patients will be further 
described regarding their time to dropout and reasons for withdrawal. 
13.5.2. Repositioning of Visits 
No repositioning of visits will be done. 
13.5.3. Missing Data 
Missing values will not be substituted by estimated values, but considered as missing in statistical 
analysis. 
13.6. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Before the first trial drug intake, patient’s background, medical and surgical history, demographic 
data and disease characteristics will be described by treatment group on the Safety Set. 
- Quantitative parameters will be described by treatment group and overall using the 
following: number of patients, number of missing data, mean, standard deviation, 
minimum, median and maximum values. 
- Qualitative parameters will be described by treatment group and overall using 
frequencies. 
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Concomitant diseases, as well as medical and surgical histories will be tabulated descriptively by 
treatment group and overall using the MedDRA codes of System Organ Classes and preferred 
terms. 
If more than 10% of patients are excluded from the FAS and PP set, the description of patients by 
treatment group at selection and inclusion will be repeated on the FAS and PP set for all 
parameters. 
No statistical test of comparability of treatment groups at baseline will be performed.  
13.7. 
EFFICACY ANALYSIS  
13.7.1. Primary Criterion  
13.7.1.1. 
Primary Analysis 
The primary criteria, time to first recurrence, will be analysed using the Kaplan Meier method and 
compared with the Log rank test. Hazard ratios and 95% confidence intervals will be estimated 
with the Cox regression model. 
The primary analysis will be performed on the FAS. 
13.7.1.2. 
Supportive Analysis 
The primary analysis will be repeated on the PP set. 
13.7.2. Secondary Criteria 
All secondary analyses will be performed on the FAS. If more than 10% of patients are excluded 
from the PP set, the secondary analyses will be repeated on the PP set.  
13.7.2.1. Numbers of Atrial Fibrillation Episodes 
Both the numbers of AF episodes (symptomatic or not) lasting for at least 10 minutes and with 
duration less than 10 minutes (NSup10 and NInf10) will be described by treatment group and 
compared by the chi-square test (or CMH test adjusted for centre) or Fisher’s exact Test. 
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13.7.2.2. Duration of Atrial Fibrillation Episodes 
The duration of all AF Episodes will be described by treatment group and compared using the 
Student t (or using an ANOVA with treatment and centres effects) or Wilcoxon test. 
13.7.2.3. Time to first AF recurrence less than 10 minutes or symtomatic 
The time to the first AF recurrence less than 10 minutes and the time to the first symptomatic AF 
recurrence will be analysed as the primary analysis.  
13.7.2.4. Clinical parameters evaluation 
The EHRA score will be described by treatment group and analysed using a chi-squared test (or 
CMH test adjusted for centre) or Fisher’s exact Test.  
The frequency of presumed arrhythmia will be described by treatment group. 
The number of recurrence of symptomatic AF, of hospitalizations (for cardiovascular events, for 
thromboembolic stroke and for all causes), of spontaneous cardioversion, of successful 
cardioversion (including number of shocks distribution) and the number of patients needing 
cardioversion after initial ECV will be described by treatment group and compared using a chi-
square test or a Fisher Test (if the numbers are relevant).  
The duration of hospitalizations for cardiovascular events, for thromboembolic stroke and for any 
cause will be described by treatment group and compared using the Student t (or using an 
ANOVA with treatment and centre effects) or Wilcoxon test. 
The echocardiographic parameters values will be described at each time (V1, V2, V4, V6 and V9) 
and changes described from V4 to V9 and from V2 to V9. 
13.7.2.5. Biomarker analysis: red blood cell concentrations of DHA 
Values and changes from baseline for red blood cell concentration of DHA will be performed by 
treatment group and assessment time. 
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13.8. 
SAFETY ANALYSIS 
The Safety Set will be used to perform all analyses of the safety criteria. 
13.8.1. Adverse Events 
Any adverse event having been reported during the study for a given patient will be classified by 
preferred term and corresponding system organ class using the MedDRA terminology. 
Adverse events will be classified as: 
• Treatment emergent adverse events, i.e., any adverse event which occurs or worsens on 
study treatment during the randomised period. 
• Or non treatment emergent adverse events, i.e., any adverse event which occurs during the 
run-in period (before V2) or is reported as concomitant disease with the same intensity. 
For each study period, any patient with at least one reported adverse event will be classified as a 
patient: 
• With at least one adverse event 
• With at least one treatment emergent adverse event 
• With one TEAE 
• With two TEAEs 
• With at least three TEAEs 
• With at least one related TEAE 
• With an adverse event leading to the study treatment discontinuation (definitive or 
temporary) 
• With an adverse event leading to withdrawal 
• With at least one serious adverse event. 
Numbers and percentages of patient with at least one reported treatment emergent adverse event 
will be tabulated by treatment group: 
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• By system organ class 
• By system organ class and preferred term 
• By system organ class and preferred term, taking into consideration its most severe 
intensity 
• And by system organ class and preferred term, taking into consideration the most severe 
relationship to the study treatment. 
Recurring adverse events (i.e., adverse events classified with the same preferred term) for a given 
patient will only be counted once and only their most severe intensity or most severe relationship 
to the study treatment will be tabulated. 
The number and percentage of patient with at least one most common (reported in 1% patients in 
any group) drug related TEAE ("not excluded or unassessable") will be tabulated by Preferred 
Term and Treatment group in decreasing order for the treatment group (for all patients). 
The number and percentage of patients with at least one reported most common treatment 
emergent adverse event will also be plotted by treatment group. This graphical representation will 
highlight the frequencies of the most severe intensities reported by system organ class and 
preferred term. 
SAE will also be described on an individual basis: treatment group, patient's code, sex and age, 
Investigator's reported term, preferred term, time of onset according to the time of the first study 
treatment administration, duration, action taken regarding the study treatment administration, use 
of a corrective treatment, outcome and relationship to the study treatment in the Investigator’s 
opinion. 
13.8.2. Clinical Laboratory Evaluation  
For each laboratory parameter, data will be tabulated by treatment group and assessment time. 
The absolute changes post-trial drug administration - baseline (the baseline value being the value 
measured on the last blood sample collected before the first trial drug administration) will be 
calculated and tabulated by parameter, treatment group and post-trial drug administration 
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assessment time. Results of retests performed post-trial drug administration will not be analysed 
and tabulated. They will only be displayed in individual data listings. 
For all biochemistry parameters, scatter plots highlighting individual results will display the 
baseline and week 24 of the laboratory measurements for each patient by locating the point 
defined by the baseline value on the abscissa and respectively week 24 value in the ordinate.  
For all haematology parameters, scatter plots highlighting individual results will display the 
baseline and week 4, week 12 and week 24 of the laboratory measurements for each patient by 
locating the point defined by the baseline value on the abscissa and respectively week 4, week 12 
and week 24 value in the ordinate.  
Each treatment group will be differently identified. The first bisecting line (45° line), the lines of 
lower and upper normal range, the lines of Potentially Clinically Significant Change (PSC) range 
and Clinically noteworthy abnormal laboratory value (CNALV) range added on the plots (see 
Appendix 17.3). 
For all blood laboratory parameters, shift tables will be provided to depict the numbers of  patients 
with post-trial drug administration variations at each assessment time as compared to the baseline 
values (measured on the last blood sample collected before the first trial drug administration) by 
treatment group. A 3-point scale (low, normal, high) will be used as defined by the normal ranges 
in use in the laboratory in charge of the assays. 
CNALV (see in Appendix 17.3) will be identified and described on an individual basis. If 
relevant, five separate individual data listings by treatment group will be provided: 
• CNALV for haemoglobin (including corresponding individual results of erythrocytes and 
haematocrit) 
• CNALV for neutrophils or leucocytes (including corresponding individual results of 
basophils, eosinophils, lymphocytes and monocytes) 
• CNALV for platelets (including corresponding individual results of erythrocytes and 
leucocytes) 
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• CNALV for liver function parameters (including corresponding individual results of 
gamma-GT) 
• CNALV for serum creatinine  
13.8.3. Global Physical Examination 
Recorded data of the global physical examination performed will not be tabulated as any 
abnormal findings post-randomisation should be reported as AEs (if clinically significant). 
Physical examination assessments will be provided in the listings of individual data. 
13.8.4. Vital Signs, Physical Findings and Other Observations Related to Safety 
13.8.4.1. 
Vital Sign Measurements Over Time 
For each parameter (systolic blood pressure, diastolic blood pressure and HR in supine and 
standing positions), descriptive statistics over time of values and changes from baseline will be 
tabulated by treatment group and assessment time. 
13.8.4.2. 
Body weight 
Descriptive statistics over time of values and changes from baseline will be tabulated by treatment 
group and assessment time. 
13.8.4.3. 
Individual Patient Changes 
The number and percentage of patient with at least one Predefined Potentially Clinically 
Significant Change (PSC) and with at least one PSC Leading to Clinically Significant Value 
(PSCV) will be tabulated by treatment group (see Table 1 in Appendix 17.3).  
According to the pharmacological drug profile mentioned previously in this Protocol, the changes 
from baseline to the maximum and/or minimum post-baseline value could be categorized and 
tabulated by treatment group with frequencies and decreasing cumulative percentages. 
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If there is a signal of a drug effect toward one direction rather than the other, additionally shift 
tables of variations from baseline to the maximum or minimum post-baseline value could be also 
provided (see Table 2 to 4 in Appendix 17.3). 
An individual data listing of patients with symptomatic or asymptomatic orthostatic hypotension 
will be provided by treatment group (see Table 5 in Appendix 17.3). 
13.8.5. ECG 
Frequencies on the clinical interpretation (normal, abnormal CS or NCS) will be presented by 
treatment group and assessment time. Individual tabulated data for ECG abnormalities will be also 
displayed. 
13.8.6. Coagulation parameters 
Scatter plots highlighting individual results for coagulation parameters (prothrombin time/INR, 
activated partial thromboplastin time and thrombin clotting time) before and after study treatment 
administration will be produced. 
13.9. CONCOMITANT TREATMENTS 
Concomitant treatments will be tabulated by treatment group within a descriptive perspective. 
They will be classified by therapeutic area according to the WHO-DRUG dictionary using the 
"anatomical therapeutic chemical" classification on the safety set. 
13.10. 
COMPLIANCE 
 
The percentage of compliance will be described by treatment group using the quantity 
 
100
_
_
_
(%)
×
=
n
consumptio
l
Theoretica
n
consumptio
actual
Estimated
Compliance
 
 
 
with: Estimated actual consumption = number of tablets provided at the start of study (Visit 2) 
minus number of tablets returned at the end of study (Visit 9) 
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Theoretical consumption = number of days of treatment intake planned between the start and the 
end of study (168 days ± 7days) 
 
13.11. 
INTERIM ANALYSIS AND DATA MONITORING 
No interim analysis is planned. 
14. GENERAL ETHICAL CONSIDERATIONS  
14.1. 
ETHICAL CONDITIONS 
This study is performed in accordance with the principles stated in the Declaration of Helsinki 
(1964) and subsequent amendments and in accordance with the Good Clinical Practice Guideline 
(CPMP/ICH/135/95). 
14.2. 
ETHICS COMMITTEE AND LEGAL REQUIREMENTS 
All the documents required by National Regulations and any other informative documents that 
may be requested are submitted for review to an Ethics Committee whose procedures and 
operations meet the GCP and National Legal Requirements. 
Depending on National Regulations, the application is submitted to the Ethics Committee by the 
Sponsor (or representative) or by the Investigator. 
A copy of the formal written approval from the Ethics Committee is provided to the Sponsor 
(directly by the Ethics Committee or via the Investigator) with a list of names and qualifications 
of its members. 
The request for authorisation by the Competent Authority or its notification if required (depending 
on National Regulations) is carried out by the Sponsor. 
The screening of patients does not start before the approval of the Ethics Committee has been 
obtained and the study authorised by the Competent Authority or notified to the Competent 
Authority (depending on National Regulations). 
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14.3. 
PATIENT'S INFORMATION LEAFLET AND INFORMED CONSENT 
 
FORM 
An information must be given to the patients before their decision to participate or abstain from 
participation. 
This information is based on the elements set out in the Declaration of Helsinki and the ICH GCP 
Guidelines. It must also describe the measures taken to safeguard patient’s privacy and protection 
of personal data, according to European Directive 95/46 EC or other local regulation. 
Restraints and risks must be explained, as well as the right to discontinue participation in the 
study at any stage, without affecting their further relationship with the Investigator and/or their 
future care. 
The written information and consent form must be submitted to the patient with an oral 
explanation. It must be agreed and signed by the patient before any study-related procedure starts. 
This information and consent procedure is under the Investigator’s responsibility. 
The information and consent document are made in triplicate: the original copy is kept by the 
Investigator, one copy is given to the patient and the last copy is kept by the Clinical Quality 
Assurance Unit of the Sponsor in a sealed envelope at the end of study (except in case of specific 
country requirement). 
Specific areas of the Sponsor’s copy are not triplicated to avoid the reading of the patient’s 
surname (except the first 3 letters), first name, address and signature.  
If any information becomes available during the trial that may be relevant to the patient’s 
willingness to keep on participating in the trial, an updated written informed consent must be 
submitted to the patient to confirm  agreement to continue participating. 
14.4. 
PERSONAL DATA PROTECTION 
All information from this study (excluding data from the informed consent) is entered into a 
computer under the Sponsor’s responsibility in accordance with the French law, "Loi 
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Informatique et Libertés" (January 6, 1978, and subsequent amendments) and with the European 
Directive 95/46/CE. 
14.5. 
INSURANCE POLICY 
In accordance with the provisions of the law and the GCP, the Sponsor Pierre Fabre Médicament, 
has an insurance policy intended to guarantee against possible damage resulting from the research. 
The studies and/or experiments performed on behalf of the Sponsor Pierre Fabre Médicament are 
specifically and expressly guaranteed. 
It is advisable to underline that non compliance with the Research Legal Conditions is a cause for 
guarantee exclusion. 
15. ADMINISTRATIVE PROCEDURES 
15.1. 
PROTOCOL AMENDMENT 
Neither the Investigator nor the Sponsor may alter the protocol without the authorisation of the 
other party.  
All changes to the protocol are subject to an amendment which must be dated and signed by both 
parties and must appear as an amendment to the protocol. 
Substantial amendments are submitted for approval / authorisation to the Ethics Committees and 
Competent Authorities 
Urgent amendments are submitted for approval / authorisation to the Ethics Committees and 
Competent Authorities, but could be implemented immediately under specific conditions defined 
with the Sponsor. 
15.2. 
SOURCE DOCUMENTS, INVESTIGATOR'S FILE STORAGE 
The Investigator: 
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• Keeps all trial-related documents in appropriate file folders. Records of patient, original 
informed consent forms, source documents, a CD Rom containing a pdf copy of e-CRF, 
drug inventory, Ethics Committees and Sponsor correspondence pertaining to the study 
must be kept on file. 
• Retains all documents relating to the screening (consent and investigation results) of all 
patients included in the trial or not. 
• Retains a list of the patient’s names, addresses (and/or number of medical file), code 
numbers to allow checking of data reported on e-CRFs with those from source documents. 
• Authorises direct access to source documents for monitoring, audits and inspections. 
• The trial-related documents must be retained as strictly confidential at the Investigator’s 
site for at least 15 years or according to local requirements, whatever is the longest after 
the completion or discontinuation of the trial (European Directive 2003/63/EC). 
15.3. 
END OF THE STUDY 
15.3.1. Definition of the End of Study 
The end of study is the last visit of the last patient undergoing the trial. 
Any change to this definition during the study, for whatever reason, must be notified as a 
substantial amendment. 
15.3.2. Early Study Termination 
15.3.2.1. 
Early Study Termination Decided by the Sponsor 
The Sponsor may discontinue the study at any time for any of the following reasons: 
• Lack of recruitment 
• Deviations from good clinical practice and/or regulations 
• Poor product safety 
• New information that could jeopardise the patient’s safety 
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• Stopping of the development … 
15.3.2.2. 
Early Study Termination Decided by the Competent Authorities 
The Competent Authorities may suspend or prohibit a study if they consider that either the 
conditions of authorisation are not being met or has doubt about the safety or scientific validity of 
the study. 
15.4. 
AUDIT 
The Sponsor is responsible for making sure that both its representatives (Study Manager, CRA...) 
and the Investigator fulfil the requirements as specified by the GCP Guideline.  
An audit can be organised internally at Pierre Fabre Médicament and at the investigational site 
where the e-CRFs are matched against source documents. 
All study documentation must be directly accessible to auditors. 
The practical conditions for the audit are discussed between the Investigator and the Clinical 
Quality Assurance Department. 
Oral information about the audit results are given to the Investigator. 
15.5. INSPECTION 
The Health Authorities may inspect any investigation site or the Sponsor in the course of the study 
or after its completion, to verify the conduct of the study and quality of the data. The Investigator 
must provide to the inspectors direct access to study documents. 
15.6. CONFIDENTIALITY 
The present materials (protocol and related documentation, e-CRF, Investigator's Brochure) 
contain confidential information.  
Except if agreed in writing with the Study Manager, the Investigators must hold such information 
confidential, and must not disclose it to others (except where required by Applicable Law). 
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15.7. CLINICAL STUDY REPORT 
Data analysis and clinical study report writing are under the Sponsor’s responsibility.  
Upon data analysis completion, a final report including a review of the objectives and methods, a 
presentation and a discussion of the results is drawn up according to ICH Guidelines (Structure 
and Content of Clinical Study Reports, ICH-E3, CPMP/ICH/137/95). 
The report is a clinical and statistical integrated report. It must be signed by the Sponsor's 
representative(s) and the Coordinating Investigator. 
15.8. STUDY RESULTS COMMUNICATION 
Upon completion of the study, the global results of the Research are communicated to the 
Investigator. According to the Local Regulation, the patient can ask the Investigator for the 
results. 
15.9. STUDY RESULTS PUBLICATION 
The information and data collected during the conduct of this clinical study are considered 
confidential and are used by the Sponsor in connection with the development of the study drug. 
This information may be disclosed if deemed necessary by the Sponsor. 
To allow the use of the information derived from this clinical study and to insure compliance with 
Current Regulations, the Investigator must provide the Sponsor with complete test results and all 
data collected during the study.  
Only the Sponsor may make study information available to physicians and to Regulatory 
Agencies, except as required by Current Regulations. 
All the results of this study including data, reports, discoveries and inventions resulting from the 
study, are the property of the Sponsor. 
In the event the Sponsor chooses to publish study data, the manuscript must be provided to the 
author(s) at least 30 days prior to the expected date of submission to the intended publisher. 
The Investigator(s) can reserve the right to publish or present study data; if so, the manuscript or 
abstract must be provided to the Sponsor for review at least 30 days prior to the expected date of 
submission to the intended publisher or of planned presentation. 
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In addition, if necessary, (the) Investigator(s) shall withhold publication for an additional 60 days, 
to allow the filing of a patent application, or to allow the Sponsor to take any measures he deems 
appropriate to establish and preserve his proprietary rights. 
It is agreed that publication of study results by each site shall be made only as part of a 
publication of the study results obtained by all sites performing the protocol, once the study is 
completed and finalised.  
The authors list is agreed by all Investigators prior to publication. The names of the authors are 
provided according to their participation in the design of the protocol as well as their recruitment 
of eligible and analysable patients. 
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16. REFERENCES 
 
[1] 
F373280 INVESTIGATOR'S BROCHURE, version October 2013 
 
[2] 
NODARI S., TRIGGIONAI M., CAMPIA U., MANERBA A., MILESI G., CESANA 
M.B., GHEORGHIADE M., DEI CAS L. 
n-3 Polyunsaturated Fatty Acids in the prevention of atrial Fibrillation Recurrences after 
electrical cardioversion. A prospective, Randomised study 
Circulation, 2011; 124:1100-1106 
 
[3] 
NODARI S., TRIGGIANI M., CAMPIA U., MANERBA A., MILESI G., CESANA 
M B., GHEORGHIADE M., DEI CAS L. 
Effects of n-3 polyunsaturated fatty acids on left ventricular function and functional 
capacity in patients with dilated cardiomyopathy 
J. Am. Coll. Cardiol. 2011;57;870-879 
 
[4] 
MOERTL D., HAMMER A., STEINER S., HUTULEAC R., VONBANK K., 
BERGER R. 
Dose-dependant effects of omega-3-polyunsaturated fatty acids on systolic left ventricular 
function, endothelial function, and markers of inflammation in chronic heart failure of non 
ischemic origin: A double-blind, placebo-controlled, 3-arm study  
American Heart Journal 2011; 161:915.e1-915.e9 - volume 161, number 5 
 
[5] 
GISSI-HF INVESTIGATORS 
Effects of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GSSI-
HF Trial): a randomised, double-blind, placebo-controlled trial 
The lancet on line - August 2008 
 
[6] 
CAMM A.J., KIRCHHOF P., LIP G.Y., SCHOTTEN U., SAVELIEVA I., ERNST S., 
VAN GELDER I.C., AL-ATTAR N., HINDRICKS G., PRENDERGAST B., 
HEIDBUCHEL H., ALFIERI O., ANGELINI A., ATAR D., COLONNA P., DE 
CATERINA R., DE SUTTER J., GOETTE A., GORENEK B., HELDAL M., 
HOHLOSER S.H., KOLH P., LE HEUZEY J.Y., PONIKOWSKI P., RUTTEN F.H. 
Guidelines for the management of atrial fibrillation: the Task Force for the Management of 
Atrial Fibrillation of the European Society of Cardiology (ESC). 
European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery,  
Eur Heart J. 2010 Oct;31(19):2369-429 
 
 
[7] 
KOWEY PR, REIFFEL JA, ELLENBOGEN KA, NACCARELLI GV, PRATT CM. 
Efficacy and safety of prescription omega-3 fatty acids for the prevention of recurrent 
symptomatic atrial fibrillation: a randomised controlled trial. 
JAMA. 2010;304:2363–2372. 
 
 
 
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[8] 
BIANCONI L., CALO L., MENNUNI M., SANTINI L., MOROSETTI P., 
AZZOLINI P., BARBATO G., BISCIONE F., ROMANO P., SANTINI M.  
N-3 polyunsaturated fatty acids for the prevention of arrhythmia recurrence after electrical 
cardioversion of chronic persistent atrial fibrillation: a randomised, double-blind, 
multicentre study  
Europace (2011) 13, 174-181 
 
[9] 
OMACOR® SUMMARY PRODUCT CARACTERISTICS (SPC) dated 17/02/2012 
 
[10] 
BEPANTHENE ® SUMMARY PRODUCT CARACTERISTICS (SPC) 
 
[11] 
TOUBOUL P, BRUGADA J, CAPUCCI A, CRIJNS HJ, EDVARDSSON N, 
 
HOHNLOSER SH.  
Dronedarone for prevention of atrial fibrillation: a dose-ranging study.  
Eur Heart J 2003;24(16):1481-7. 
 
[12] LE HEUZEY JY AND ALL.  
A Short-Term, Randomised, Double-Blind, Parallel-Group Study to Evaluate the Efficacy 
and Safety of Dronedarone versus Amiodarone in Patients with Persistent Atrial 
Fibrillation: The DIONYSOS Study. 
J Cardiovasc Electrophysiol. 
 
[13] METCALF G.R., JAMES J.M., GIBSON A.R., EDWARDS J., STUBBERFIELD J., 
STUKLIS R., YOUNG D.G., ROBERTS-THOMSON K. & CLELAND G.L.M.L. & 
OKEN H. 
Effects of fish-oil supplementation on myocardial fatty acids in humans.  
Am J Clin Nutr (2007); 85 : 1225. 
 
[14] ARTERBURN M.L. & OKEN H. 
Distribution, interconversion and dose response of n-3 fatty acids in humans.  
Am J Clin Nutr (2006);83 : 1469-1473S. 
 
[15] TIELEMAN RG, VAN GELDER IC, CRIJNS HJ, DE KAM PJ, VAN DEN BERG 
MP, HAAKSMA J, VAN DER WOUDE HJ, AND ALLESSIE MA. 
Early recurrences of atrial fibrillation after electrical cardioversion: a result of 
fibrillation-induced electrical remodelling of the atria? 
J. Am. Coll. Cardiol. 1998;31;167-173 
 
[16] 
SALM P, TAYLOR PJ, KOSTNER K 
Simultaneous quantification of total eicosapentaenoic acid, docosahexaenoic acid and 
arachidonic acid in plasma by high-performance liquid chromatography-tandem mass 
spectrometry.  
Biomed Chromatogr 2011 Jun;25(6):652-9. 
 
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[17] LEGRAND P., SCHMITT B., MOUROT J., CATHELINE D., CHESNEAU G., 
MIREAUX M., KERHOAS N., WEILL P. 
The consumption of food products from linseed-fed animals maintains erythrocyte omega-3 
fatty acids in obese human 
Lipids, 2010, 45, 11-19. 
 
[18] HARRIS WS, VON SCHACKY C. 
The Omega-3 Index: a new risk factor for death from coronary heart disease? 
Prev Med. 2004 Jul; 39(1):212-20 
 
[19] ABSTRACT: P5161 . 
NODARI S, MANERBA A., MADURERI A., BERLINGHIERI N., PULCINI E., 
FRATTINI S., METRA M, DEI CAS L. 
Effects of Polyunsaturated Fatty Acids n-3 (PUFA n-3) in the prophylaxis of atrial 
fibrillation relapses after external electric cardioversion 
World Congress of Cardiology 2006, 2-6 September, Barcelona – Spain 
 
[20] 
KIRCHHOF P., AURICCHIO A., BAX J., CRIJNS H., CAMM J., DIENER HC., 
 
GOETTE A., HINDRICKS G., HOHNLOSER S., KAPPENBERGER L., KUCK 
 
KH., LIP HYG., OLSSON B., MEINERTZ T., PRIORI S., RAVENS U., 
 
STEINBECK G., SVERHAGE E., TIJSSEN J., VINCENT A., BREITHARDT G. 
 
Outcome parameters from a consensus conference organized by the German Atrial 
 
Fibrillation Competence NETwork and the European Heart Rhythm Association. 
 
Europace 2007, 9, 1006-1023 
 
[21] 
EUROPEAN MEDICINES AGENCY 
 
Addendum to the guideline on antiarrhythmics on atrial fibrillation and atrial flutter. 
 
EMA/CHMA/EWP/213056/2010 
 
[22] 
OWEN AJ, PETER-PRZYBOROWSKA BA, HOY AJ, MCLENNAN PL. 
Dietary fish oil dose- and time-response effects on cardiac phospholipid fatty acid 
composition. 
Lipids. 2004;39:955–961 
 
[23] 
ROBERTO M. LANG, MICHELLE BIERIG, RICHARD B. DEVEREUX, FRANK 
A. FLACHSKAMPF*, ELYSE FOSTER, PATRICIA A. PELLIKKA, MICHAEL H. 
PICARD, MARY J. ROMAN, JAMES SEWARD, JACK SHANEWISE, SCOTT 
SOLOMON, KIRK T. SPENCER, MARTIN ST. JOHN SUTTON, WILLIAM 
STEWART. 
 
Recommendations for chamber quantification 
 
Eur J Echocardiography (2006) 7, 79-108 
 
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17. APPENDICES 
 
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17.1. DECLARATION OF HELSINKI 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
ETHICAL PRINCIPLES FOR MEDICAL RESEARCH INVOLVING 
HUMAN SUBJECTS 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 29th WMA 
General Assembly, Tokyo, Japan, October 1975 35th WMA General Assembly, Venice, Italy, October 1983 41st 
WMA General Assembly, Hong Kong, September 1989 48th WMA General Assembly, Somerset West, Republic of 
South Africa, October 1996 52nd WMA General Assembly, Edinburgh, Scotland, October 2000 53th WMA General 
Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 55th WMA General Assembly, Tokyo 
2004 (Note of Clarification on Paragraph 30 added) 59th WMA General Assembly, Seoul, October 2008 
 
A. INTRODUCTION  
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of 
ethical principles for medical research involving human subjects, including research on identifiable 
human material and data. The Declaration is intended to be read as a whole and each of its constituent 
paragraphs should not be applied without consideration of all other relevant paragraphs.  
2. Although the Declaration is addressed primarily to physicians, the WMA encourages other participants 
in medical research involving human subjects to adopt these principles.  
3. It is the duty of the physician to promote and safeguard the health of patients, including those who are 
involved in medical research. The physician's knowledge and conscience are dedicated to the fulfilment 
of this duty.   
4. The Declaration of Geneva of the WMA binds the physician with the words, “The health of my patient 
will be my first consideration,” and the International Code of Medical Ethics declares that, “A physician 
shall act in the patient's best interest when providing medical care.”  
5. Medical progress is based on research that ultimately must include studies involving human subjects. 
Populations that are underrepresented in medical research should be provided appropriate access to 
participation in research.  
6. In medical research involving human subjects, the well-being of the individual research subject must 
take precedence over all other interests.  
7. The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic interventions 
(methods, procedures and treatments). Even the best current interventions must be evaluated continually 
through research for their safety, effectiveness, efficiency, accessibility and quality.  
8. In medical practice and in medical research, most interventions involve risks and burdens.  
9. Medical research is subject to ethical standards that promote respect for all human subjects and protect 
their health and rights. Some research populations are particularly vulnerable and need special 
protection. These include those who cannot give or refuse consent for themselves and those who may be 
vulnerable to coercion or undue influence.  
10. Physicians should consider the ethical, legal and regulatory norms and standards for research involving 
human subjects in their own countries as well as applicable international norms and standards. No 
national or international ethical, legal or regulatory requirement should reduce or eliminate any of the 
protections for research subjects set forth in this Declaration.  
 
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B. PRINCIPLES FOR ALL MEDICAL RESEARCH  
11. It is the duty of physicians who participate in medical research to protect the life, health, dignity, 
integrity, right to self-determination, privacy, and confidentiality of personal information of research 
subjects.  
12. Medical research involving human subjects must conform to generally accepted scientific principles, be 
based on a thorough knowledge of the scientific literature, other relevant sources of information, and 
adequate laboratory and, as appropriate, animal experimentation. The welfare of animals used for 
research must be respected.   
13. Appropriate caution must be exercised in the conduct of medical research that may harm the 
environment.  
14. The design and performance of each research study involving human subjects must be clearly described 
in a research protocol. The protocol should contain a statement of the ethical considerations involved 
and should indicate how the principles in this Declaration have been addressed. The protocol should 
include information regarding funding, sponsors, institutional affiliations, other potential conflicts of 
interest, incentives for subjects and provisions for treating and/or compensating subjects who are 
harmed as a consequence of participation in the research study. The protocol should describe 
arrangements for post-study access by study subjects to interventions identified as beneficial in the 
study or access to other appropriate care or benefits.   
15. The research protocol must be submitted for consideration, comment, guidance and approval to a 
research ethics committee before the study begins. This committee must be independent of the 
researcher, the sponsor and any other undue influence. It must take into consideration the laws and 
regulations of the country or countries in which the research is to be performed as well as applicable 
international norms and standards but these must not be allowed to reduce or eliminate any of the 
protections for research subjects set forth in this Declaration. The committee must have the right to 
monitor ongoing studies. The researcher must provide monitoring information to the committee, 
especially information about any serious adverse events. No change to the protocol may be made 
without consideration and approval by the committee.  
16. Medical research involving human subjects must be conducted only by individuals with the appropriate 
scientific training and qualifications. Research on patients or healthy volunteers requires the 
supervision of a competent and appropriately qualified physician or other health care professional. The 
responsibility for the protection of research subjects must always rest with the physician or other health 
care professional and never the research subjects, even though they have given consent.  
17. Medical research involving a disadvantaged or vulnerable population or community is only justified if 
the research is responsive to the health needs and priorities of this population or community and if 
there is a reasonable likelihood that this population or community stands to benefit from the results of 
the research.   
18. Every medical research study involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and communities involved in the research in 
comparison with foreseeable benefits to them and to other individuals or communities affected by the 
condition under investigation.  
19. Every clinical trial must be registered in a publicly accessible database before recruitment of the first 
subject.  
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20. Physicians may not participate in a research study involving human subjects unless they are confident 
that the risks involved have been adequately assessed and can be satisfactorily managed. Physicians 
must immediately stop a study when the risks are found to outweigh the potential benefits or when 
there is conclusive proof of positive and beneficial results.  
21. Medical research involving human subjects may only be conducted if the importance of the objective 
outweighs the inherent risks and burdens to the research subjects.  
22. Participation by competent individuals as subjects in medical research must be voluntary. Although it 
may be appropriate to consult family members or community leaders, no competent individual may be 
enrolled in a research study unless he or she freely agrees.  
23. Every precaution must be taken to protect the privacy of research subjects and the confidentiality of 
their personal information and to minimize the impact of the study on their physical, mental and social 
integrity.   
24. In medical research involving competent human subjects, each potential subject must be adequately 
informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional 
affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort 
it may entail, and any other relevant aspects of the study. The potential subject must be informed of the 
right to refuse to participate in the study or to withdraw consent to participate at any time without 
reprisal. Special attention should be given to the specific information needs of individual potential 
subjects as well as to the methods used to deliver the information. After ensuring that the potential 
subject has understood the information, the physician or another appropriately qualified individual 
must then seek the potential subject’s freely-given informed consent, preferably in writing. If the 
consent cannot be expressed in writing, the non-written consent must be formally documented and 
witnessed.  
25. For medical research using identifiable human material or data, physicians must normally seek consent 
for the collection, analysis, storage and/or reuse. There may be situations where consent would be 
impossible or impractical to obtain for such research or would pose a threat to the validity of the 
research. In such situations the research may be done only after consideration and approval of a 
research ethics committee.   
26. When seeking informed consent for participation in a research study the physician should be 
particularly cautious if the potential subject is in a dependent relationship with the physician or may 
consent under duress. In such situations the informed consent should be sought by an appropriately 
qualified individual who is completely independent of this relationship.  
27. For a potential research subject who is incompetent, the physician must seek informed consent from the 
legally authorized representative. These individuals must not be included in a research study that has 
no likelihood of benefit for them unless it is intended to promote the health of the population 
represented by the potential subject, the research cannot instead be performed with competent persons, 
and the research entails only minimal risk and minimal burden.   
28. When a potential research subject who is deemed incompetent is able to give assent to decisions about 
participation in research, the physician must seek that assent in addition to the consent of the legally 
authorized representative. The potential subject’s dissent should be respected.  
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29. Research involving subjects who are physically or mentally incapable of giving consent, for example, 
unconscious patients, may be done only if the physical or mental condition that prevents giving 
informed consent is a necessary characteristic of the research population. In such circumstances the 
physician should seek informed consent from the legally authorized representative. If no such 
representative is available and if the research cannot be delayed, the study may proceed without 
informed consent provided that the specific reasons for involving subjects with a condition that renders 
them unable to give informed consent have been stated in the research protocol and the study has been 
approved by a research ethics committee. Consent to remain in the research should be obtained as soon 
as possible from the subject or a legally authorized representative.  
30. Authors, editors and publishers all have ethical obligations with regard to the publication of the results 
of research. Authors have a duty to make publicly available the results of their research on human 
subjects and are accountable for the completeness and accuracy of their reports. They should adhere to 
accepted guidelines for ethical reporting. Negative and inconclusive as well as positive results should 
be published or otherwise made publicly available. Sources of funding, institutional affiliations and 
conflicts of interest should be declared in the publication. Reports of research not in accordance with 
the principles of this Declaration should not be accepted for publication.  
 
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE  
31. The physician may combine medical research with medical care only to the extent that the research is 
justified by its potential preventive, diagnostic or therapeutic value and if the physician has good 
reason to believe that participation in the research study will not adversely affect the health of the 
patients who serve as research subjects.   
32. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the 
best current proven intervention, except in the following circumstances:  
• 
The use of placebo, or no treatment, is acceptable in studies where no current proven intervention 
exists; or  
• 
Where for compelling and scientifically sound methodological reasons the use of placebo is 
necessary to determine the efficacy or safety of an intervention and the patients who receive 
placebo or no treatment will not be subject to any risk of serious or irreversible harm.  Extreme 
care must be taken to avoid abuse of this option.  
33. At the conclusion of the study, patients entered into the study are entitled to be informed about the 
outcome of the study and to share any benefits that result from it, for example, access to interventions 
identified as beneficial in the study or to other appropriate care or benefits.  
34. The physician must fully inform the patient which aspects of the care are related to the research. The 
refusal of a patient to participate in a study or the patient’s decision to withdraw from the study must 
never interfere with the patient-physician relationship.  
35. In the treatment of a patient, where proven interventions do not exist or have been ineffective, the 
physician, after seeking expert advice, with informed consent from the patient or a legally authorized 
representative, may use an unproven intervention if in the physician's judgement it offers hope of 
saving life, re-establishing health or alleviating suffering. Where possible, this intervention should be 
made the object of research, designed to evaluate its safety and efficacy. In all cases, new information 
should be recorded and, where appropriate, made publicly available.  
 
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17.2. SAE REPORT FORM 
 
 
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N O T I F I C A T I O N  O F  S E R I O U S  A D V E R S E  E V E N T  ( S A E )  O R  P R E G N A N C Y   
T O  P I E R R E  F A B R E  C O R P O R A T E  V I G I L A N C E S  D I V I S I O N   
 
TO 
BE 
TRANSMITTED 
TO 
THE 
CORPORATE 
VIGILANCES 
DIVISION 
BY 
E-MAIL 
WITHIN 
24H 
TO 
HQ.pharmacovigilance@pierre-fabre.com OR BY FAX WITHIN 24H – Fax N°: 33 (0) 1.49.10.80.90 
Transmission date  
 
 
  
 
  
 
 
 
(ddmmyyyy) 
Country :  
........................................
 
 
 
   SAE N° 
 
 
 
                      FIRST NOTIFICATION           FOLLOW-UP   N° 
 
 SUBJECT CHARACTERISTICS  
 
 
 
 
 
 
 
 
Birth date  
 
 
 
 
 
 
 
 
  
 
 
Gender 
 
1=M,    2=F 
   Height 
 
 
 
cm 
 Weight 
 
 
 
 
 
kg 
 
 
 DESCRIPTION OF THE EVENT 
The serious adverse event resulted in : 
 Death (whatever may be the cause) 
 Hospitalisation (*) or extension thereof 
 Life threatening 
 Invalidity or disability 
 
 Congenital abnormality or abnormal pregnancy outcome 
 Cancer 
 Other  (any other serious clinical or laboratory event 
     according to the investigator or the protocol, overdosage 
      meeting seriousness criteria, suicide attempts) 
Other fact to be notified : 
 Pregnancy exposure 
Nature of the event (if clinical nature, indicate the diagnosis or the major symptom) : 
........................................................................................................................................................................................................... 
........................................................................................................................................................................................................... 
........................................................................................................................................................................................................... 
AE onset date  |__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
 
Seriousness onset date  |__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
 
Summary description (if clinical cause, significant history, progression of event, available laboratory results, etc...) : 
 
 
 
 
 
 
(*) Except hospitalisations with durations and goals planned in the protocol 
 
 THE SAE IN RELATION TO THE TRIAL 
                                                      TREATMENT NUMBER         |___|___|___|___|___|___| 
• Time of occurrence of SAE 
 
 During the selection or run-in period 
 
 During the administration phase of the study treatment 
 
 After the administration phase of the study treatment 
• Date of first study treatment administration 
• Date of last study treatment administration 
   before the occurence of SAE 
|__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
 
|__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
• Was the blind broken ?       Yes         No          Not applicable 
   If yes, or if this is an open study, drug(s) administered : 
 
 
 
 
 
  Conditions of administration (cycles(s), daily dose(s), route(s) of administration, etc..) :  
 
 
 
 
 
 
 
 
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Transmission date 
 
 
  
 
  
 
 
 
  (ddmmyyyy) 
Country : ............................................ 
 
 
 
  SAE N° 
 
 
 
                     FIRST NOTIFICATION           FOLLOW-UP   N° 
 
 CONCOMITANT MEDICATION SINCE TRIAL INITIATION and UP UNTIL THE OCCURRENCE OF THE SAE 
     (EXCEPT THE TREATMENTS GIVEN FOR THE SAE)  
 
Trade name  
(or INN) 
 
 
Daily dose 
 
Start date 
(dd/mm/yy) 
Ongoing at 
occurence of the 
event 
 
Stop date 
(dd/mm/yy) 
Route of 
admin. 
 
Indication 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 MEASURES TAKEN FOLLOWING THE SAE 
• Study treatment 
 
 No change 
 
 Dosage modification, specify :……………………………..….      Modification Date : 
 
 Temporarily discontinued                                                       Readministration date : 
 
 Withdrawn                                                                                                  End date : 
 
 Not applicable 
 
 
 
 
 ____/____/_____ 
 ____/____/_____ 
 ____/____/_____ 
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• The event led to : 
 
 Prescription of corrective or symptomatic treatments: 
 
 
Trade name  
(or INN) 
 
 
Daily dose 
 
Start date 
(dd/mm/yy) 
Ongoing at 
occurence of the 
event 
 
Stop date 
(dd/mm/yy) 
Route of 
admin. 
 
Indication 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
 Discontinuation of concomitant treatments: 
 
 
Trade name  
(or INN) 
 
 
Daily dose 
 
Start date 
(dd/mm/yy) 
Ongoing at 
occurence of the 
event 
 
Stop date 
(dd/mm/yy) 
Route of 
admin. 
 
Indication 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
 Others, specify : 
 
 
 OUTCOME 
         Not recovered/Not resolved                  Recovering/Resolving               Recovered/Resolved 
         Recovered/Resolved with sequelae     Fatal                                          Unknown 
 
                In case of death, has an autopsy been conducted ?       Yes         No 
 
 INVESTIGATOR CAUSALITY ASSESSMENT (investigator’s assessment to be done as soon as possible) 
Study drug:                                                                         Related to study protocol: 
 Not Suspected                 Suspected                             Not Suspected                          Suspected                   
Comments: ............................................................................................................................................................. 
 
Enclose in the notification the results of carried out examinations, reports of hospitalisation, etc... 
 
 
 
 
 
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17.3. PREDEFINED LIMITS OF LABORATORY AND VITAL SIGN 
POTENTIALLY CLINICALLY SIGNIFICANT CHANGES AND VALUES  
 
List of Predefined Potentially Clinically Significant Change For Laboratory Values(¤) 
 
 
PARAMETERS 
UNIT 
PSC 
 
 
 
Decrease 
Increase 
MUSCLE 
Creatine  Phosphokinase 
U / l 
- 
236 
KIDNEY 
Creatinine 
Urea 
Uric acid 
Phosphate 
Calcium 
µmol/l 
mmol/l 
µmol/l 
mmol/l 
mmol/l 
- 
- 
- 
0.39 
0.30 
35 
3.2 
119 
0.39 
0.30 
ELECTROLYTES 
Sodium 
Potassium 
Chloride 
Bicarbonate 
mmol/l 
mmol/l 
mmol/l 
mmol/l 
8 
1.1 
8 
7 
8 
1.1 
7 
8 
METABOLISM/ 
NUTRITIONAL 
Glucose (random) 
Albumin 
Protein 
Cholesterol 
HDL cholesterol 
LDL cholesterol 
Triglycerides 
mmol/l 
g/l 
g/l 
mmol/l 
mmol/l 
mmol/l 
mmol/l 
3 
6 
11 
- 
0.91 
2.17 
- 
3.7 
6 
10 
1.97 
0.85 
2.04 
2.91 
ERYTHROCYTES 
Erythrocyte count 
Haemoglobin 
Haematocrit 
MCV  
MCH (Fe) 
MCHC (Fe) 
T/l 
g/l 
1 
fl 
fmol 
mmol/l 
0.7 
20 
0.06 
7 
0.19 
2 
0.7 
- 
0.06 
7 
0.19 
2 
LEUKOCYTES 
Leukocyte count 
G/l 
4.2 
3.8 
DIFFERENTIAL 
COUNT 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
G/l 
G/l 
G/l 
G/l 
G/l 
3.47 
1.76 
- 
- 
- 
3.19 
1.63 
0.49 
0.41 
0.14 
URINE 
Specific gravity 
pH 
- 
- 
0.017 
2 
0.015 
2 
LIVER 
Total bilirubin 
ASAT (SGOT) 
ALAT (SGPT) 
Gamma GT 
Alkaline phosphatase 
µmol/l 
U/l 
U/l 
U/l 
U/l 
- 
- 
- 
- 
-- 
10 
N x (23/36) 
N x (28/45) 
N x (25/38) 
N x (30/95) 
 
N = upper limit of normal range 
 
(¤) Delta-limits from « Routine Laboratory Tests in Clinical Trials » W. Leigh Thompson, Rocco 
L. Brunelle, Gregory G. Enas, Patrick J. Simpson and Randy L. Walker Lilly Research 
Laboratories, Lilly Corporate Centre, Indianapolis, Indiana in « Clinical Trials and Tribulations » 
1988. 
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Definition of Clinically Noteworthy Abnormal Laboratory Values (CNALV) 
 
 
PARAMETERS 
CNALV 
HAEMOGLOBIN 
 
• Decrease of at least 2g/dl and value < 10 g/dl whatever the baseline 
value 
• If missing baseline : value <10g/dl 
NEUTROPHILS 
• < 1 500/mm3 whatever the baseline value 
WBC 
(if missing value for neutrophils) 
• < 3 000/mm3 whatever the baseline value 
PLATELETS 
• < 100 000/mm3 whatever the baseline value 
SERUM CREATININE 
• Increase of at least 30 % as compared to baseline value and 
value > 150 µmol/l whatever the baseline value 
• If missing baseline : value > 150 µmol/l 
LIVER FUNCTION TESTS 
 
 
ALAT 
 
 If normal baseline :  
 
 
•ALAT > 2 N 
 If abnormal baseline : 
→if baseline value ≤ 2.5 N : 
  
• increase of at least 100 % as compared to baseline value 
→ if baseline value > 2.5 N :  
 
 
• value > 5 N 
and/or 
ASAT 
 
  If normal baseline :  
 
 
• ASAT > 2 N 
  If abnormal baseline : 
→ if baseline value ≤ 2.5 N : 
  
• increase of at least 100 % as compared to baseline value 
→ if baseline value > 2.5 N :  
 
 
• value > 5 N 
and/or 
Alkaline phosphatase (AP) 
 
  If normal baseline :  
 
 
• AP > 1.25 N 
  If abnormal baseline :  
 
 
• AP > 2 N 
and/or 
Total bilirubin (TB) 
  If normal baseline :  
 
 
• TB > 1.5 N 
  If abnormal baseline :  
 
 
• TB > 2 N 
N=upper limit of normal range 
International consensus Meeting. International Journal of Clinical Pharmacology, Therapy and Toxicology, 1990;28:317-322 
Standardisation of definitions and criteria of causality assessment of adverse drug reactions: drugs-induced liver disorders: report 
of an Standardisation of definitions and criteria of causality assessment of adverse drug reactions: drugs-induced cytopenia. 
International Journal of Clinical Pharmacology, Therapy and Toxicology, 1991;29:75-81 
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Cardiovascular Safety 
 
Table 1: Predefined Limits for Potentially Clinically Significant Changes (PSC) and PSC 
Leading to Clinically Significant Values (PSCV) 
 
Parameter 
PSC 
PSCV 
SBP 
Increase ≥ 20 mmHg 
Decrease ≥ 20 mmHg 
SBP ≥ 160 mmHg and increase ≥ 20 mmHg 
SBP ≤ 90 mmHg and decrease ≥ 20 mmHg 
DBP 
Increase ≥ 10 mmHg 
Decrease ≥ 10 mmHg 
DBP ≥ 100 mmHg and increase ≥ 10 mmHg 
DBP ≤ 50 mmHg and decrease ≥ 10 mmHg 
HR 
Increase ≥ 10 bpm 
Decrease ≥ 10 bpm 
HR ≥ 110 bpm and increase ≥ 10 bpm 
HR ≤ 50 bpm and decrease ≥ 10 bpm 
 
Table 2: Predefined Classes for changes from Baseline to the Maximum (and/ or Minimum) 
Post-baseline Value 
Classes of Change from Baseline to the Maximum 
Post-baseline Value 
Classes of Change from Baseline to the 
Minimum Post-baseline Value 
SBP  mmHg 
DBP  mmHg 
HR bpm 
SBP  mmHg 
DBP  mmHg 
HR bpm 
All 
All 
All 
All 
All 
All 
≥  0 
≥  0 
≥  0 
≤  0 
≤  0 
≤  0 
>  0 
>  0 
>  0 
<  0 
<  0 
<  0 
≥ 10 
≥  5 
≥ 10 
≤ -10 
≤ - 5 
≤ -10 
≥ 20 
≥ 10 
≥ 20 
≤ -20 
≤ -10 
≤ -20 
≥ 30 
≥ 15 
≥ 30 
≤ -30 
≤ -15 
≤ -30 
≥ 40 
≥ 20 
 
≤ -40 
≤ -20 
 
 
≥ 25 
 
 
≤ -25 
 
 
≥ 30 
 
 
≤ -30 
 
 
Table 3: Classes for Vital Signs Maximum or Minimum Values 
Classes  for  the Maximum Post-baseline Value 
for each parameter 
Classes  for  the Minimum Post-baseline Value 
for each parameter 
SBP  mmHg 
DBP  mmHg 
HR bpm 
SBP  mmHg 
DBP  mmHg 
HR bpm 
< 120 
< 80 
≤ 50 
≤ 90 
≤ 50 
≤ 50 
[120 ;140[ 
[80;90[ 
]50 ;75[ 
[90 ;120[ 
[50;80[ 
]50 ;75[ 
[140;160[ 
 [90;100[ 
[75;100[ 
[120;140[ 
 [80;90[ 
[75;100[ 
≥ 160 
≥ 100 
≥ 100 
≥ 140 
≥ 90 
≥ 100 
 
Table 4: Classes for Maximum or Minimum of BP in its entirety 
Classification of Maximum Values for Blood 
Pressure (mmHg) 
Classification of Minimum Values Blood 
Pressure (mmHg) 
SBP < 140 and DBP < 90 
SBP > 90 and DBP > 50 
SBP [140;160[ and DBP < 100 
or DBP [90;100[ and SBP < 160 
SBP ≤  90 or DBP ≤  50 
SBP ≥ 160 or DBP ≥ 100 
 
 
Table 5: Definition of orthostatic hypotension 
Orthostatic Hypotension * 
SBP Decrease ≥ 20 mmHg or DBP Decrease ≥ 10 mmHg between supine and standing positions 
* Consensus Committee of the American Autonomic Society and the American Academy of Neurolog :Consensus statement on the definition of 
orthostatic hypotension, pure autonomic failure and multiple system atrophy. Neurology 1996;46:1470-3. 
 
 
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16.1.1.7. 
Protocol amendment n° PA04  
General and non-substantial dated on 03 June 
2014 linked to Protocol and appendices 
(version 7: 03 June 2014) 
 
 
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CLINICAL STUDY PROTOCOL AMENDMENT n° PA04 Version 1 
(General – Non Substantial) 
 
 
 
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Pierre Fabre Médicament 
Represented by: Institut de Recherche Pierre Fabre 
45, Place Abel Gance 
F-92100 Boulogne, France 
 
 
CLINICAL STUDY PROTOCOL AMENDMENT n° PA04 Version 1 
 
(General – Non Substantial) 
 
 
Efficacy and safety study of F373280 for maintenance of sinus rhythm after electrical 
cardioversion in patients with persistent Atrial Fibrillation and Chronic Heart Failure. 
 
International, multicentric, randomised, double-blind, placebo controlled study 
 
Pierre Fabre Study Code: 
F373280 CA 2 01  
EudraCT Number or equivalent : 2012-003487-48 
Sponsor’s Representative: 
Gaëlle ALCARAZ 
INSTITUT DE RECHERCHE PIERRE FABRE   
Centre de R&D Pierre Fabre - BP 13562  
3 avenue Hubert Curien  
31035 TOULOUSE Cedex 1 
 
Study Coordinating Investigator: 
Pr Savina NODARI 
Department of Clinical and Surgical Specialities, Radiological Science and 
Public Health 
Section of Cardiovascular Diseases 
University Medical School and Spedali Civili Hospital of Brescia 
c/o Spedali Civili di Brescia 
Piazzale Spedali Civili, 1 
25123 - BRESCIA, ITALY 
 
Date of amendment PA04: 
03 Jun 2014 
 
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COUNTRY COORDINATING INVESTIGATOR SIGNATURE FORM 
STUDY: Efficacy and safety study of F373280 for maintenance of sinus rhythm after 
electrical cardioversion in patients with persistent Atrial Fibrillation and Chronic Heart 
Failure. 
 
International, multicentric, randomised, double-blind, placebo controlled study 
 
Clinical Study Protocol Amendment n° PA04 Version 1 
(General – Non Substantial) 
Dated: 03JUN2014 
 
 
Country Coordinating Investigator: 
Date:  
Signature: 
 
 
 
 
 
 
 
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INVESTIGATOR SIGNATURE FORM  
STUDY: Efficacy and safety study of F373280 for maintenance of sinus rhythm after 
electrical cardioversion in patients with persistent Atrial Fibrillation and Chronic Heart 
Failure. 
 
International, multicentric, randomised, double-blind, placebo controlled study 
 
Clinical Study Protocol Amendment n° PA04 Version 1 
(General – Non Substantial) 
Dated: 03JUN2014 
 
 
By my signature below, I, Dr _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _, hereby confirm that I have read, taken 
note of (and will apply) the modifications brought by the protocol amendment n° PA04 and I will 
conduct the trial according to these new modalities. 
 
 
Date: 
Signature: 
 
 
 
Final version
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HISTORY OF AMENDMENTS 
 
N° 
TYPE 
APPLICATION 
AREA 
DATE 
MODIFICATIONS 
NA 
NA 
General 
NA 
Following French CA request (ANSM) and leading 
to protocol version 2: 
- Add of a non inclusion criteria: “Breast-feeding 
female patient” 
- Add of haematology examination at visit 3 and 6 
 
PA01 
Substantial 
Local (Italy) 
01MAR2013 
Corresponding to Protocol Version 3: 
- Integration of the modification included in the 
protocol version 2 
- Harmonisation of the protocol and the Informed 
Consent Form: 
* adjustment of the selection criteria n°10 related to 
the contraception method  
* addition of a letter that is given by the patient to 
his/her general practitioner (GP) 
* precision that the sponsor can not collect a copy 
of the Informed Consent Form  
* precision that the patient card is in Italian 
language only (without any English mention)     
 
PA02 
Non 
Substantial 
General 
28MAR2013 
Corresponding to Protocol Version 4 : 
- change of Sponsor’s Representative (Clinical 
Study Manager),  
- modification of the technical handling of the blood 
samples for determination of red blood cells 
concentration of DHA: the centrifugation is no more 
needed, 
- precision on the function and address of the 
International Study Coordinator Pr Nodari,  
- add of address and contacts details of two CRO 
newly involved in the study: Theradis (in charge of 
transportation of blood samples to the Analytical 
centre and material supply) and “Clinact” (in charge 
of refund of patients expenses linked to the study), 
 - adjustment of the wording, in agreement with the 
commitment to the French Ethics Committee. In the 
paragraphe 8.3.2.1, the wording "hematology 
examination” is replaced by "standard hematologic 
dosage", 
  - precision of the full title in the study synopsis (in 
agreement with the commitment to the Spanish 
Ethics Committee),  
- correction of a mistake in section 8.1.1.3 (related 
to TTEM transmission) and sections 3, 9 and study 
synopsis (related to the definition of INR not 
stabilized). 
- addition of the changes included in the local italian 
substantial protocol amendment (i.e: contraception 
method, letter to General Practionner, patient card 
in Italian and no collection of the consent form by 
the sponsor in Italy). 
 
 
 
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PA03 
Substantial 
General 
23OCT2013 
Corresponding to Protocol Version 5:  
- Fax modification of the sponsor’s representatives 
- Planned end of study postponed to January 
2015. 
- The authorized history of the first 
documented persistent atrial fibrillation is less 
than 3 years. 
- 
At 
selection 
a 
hyperkalemia 
or 
a 
hypokalemia is better defined by the standards 
of the local laboratories.  
- 
Regarding 
previous 
treatments 
by 
amiodarone the non inclusion criteria of the 
protocol are adapted as follow: 
• 
Previous treatment with oral 
amiodarone within 4 months prior to 
inclusion 
• 
Intake of oral amiodarone for more 
than 1 month within 4 to 12 months 
before inclusion 
• 
Previous treatment with intravenous 
amiodarone within 4 weeks prior to 
inclusion. 
- For male with a child-bearing potential 
partner (in Italy only): taking into account the 
duration of spermatogenesis the absolute 
abstention from sexual intercourse or the use 
of double barrier contraception method are 
extended to 3 months after the end of the 
study. 
- Ranolazine is an antiarrhythmic treatment 
added to the prohibited treatments. 
- Update of Serious Adverse Events (SAEs) 
form: Main change is the SAE sending: SAEs 
have to be reported to the Corporate Vigilance 
Department, and not anymore to the clinical 
study manager. Also SAEs can be sent by e-
mail and by fax. 
- Addition of Alpha Bioresearch as CRO 
involved for Feasibility, Monitoring and 
Regulatory issues in Spain. 
- Correction of some minor typographic errors  
 
 
 
 
1. AMENDMENT RATIONALE 
 
The purpose of this non-substantial amendment is to clarify or specify some points of the 
protocol. Theses changes do not affect the balance of the risk and benefits in the study nor change 
the specific aims or design of the study. 
 
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2. CHANGES DESCRIPTION 
 
PREVIOUS VERSION 
MODIFIED VERSION 
SYNOPSIS 
Study Schedule: 
[…] 
- V2/ D1: Inclusion visit (start of treatment) 
 
SYNOPSIS 
Study Schedule: 
[…] 
- V2/ D1: Inclusion visit (start of study treatment) 
Evaluation Criteria: 
 
Efficacy evaluation variables: 
[…] 
Cardioversion: 
• 
Assessment of spontaneous cardioversion 
• 
Assessment of successful cardioversion 
• 
Number of patients needing an other cardioversion 
after the initial ECV 
 
[…] 
Evaluation Criteria: 
 
Efficacy evaluation variables: 
[…] 
Cardioversion: 
• 
Assessment of spontaneous cardioversion 
• 
Assessment of successful cardioversion 
• 
Shocks distribution (1, 2 or 3 shocks) 
• 
Number of patients needing an other cardioversion 
after the initial ECV 
[…] 
 
Other: 
• 
Evolution of echocardiographic parameters (from V4 
to V6 and V9) (Left atrial diameter (mm), Left atrial 
area (cm²), Left atrial volume (mL), Left atrial 
volume/BSA (mL/m2), Left ventricular ejection 
fraction (%), Left ventricular end diastolic 
volume/BSA (mL/m2), Left ventricular end systolic 
volume/BSA(mL/m2), Left ventricular end diastolic 
diameter (mm), Left ventricular end diastolic volume 
(mL) Left ventricular end systolic diameter (mm), 
Left ventricular end systolic volume (mL)) 
[…] 
 
Other: 
Evolution of echocardiographic parameters (at V4,  V6 and V9) 
(Left atrial diameter (mm), Left atrial area (cm²), Left atrial 
volume (mL), Left atrial volume/BSA (mL/m2), Left ventricular 
ejection fraction (%), Left ventricular end diastolic 
volume/BSA (mL/m2), Left ventricular end systolic 
volume/BSA(mL/m2), Left ventricular end diastolic diameter 
(mm), Left ventricular end diastolic volume (mL) Left 
ventricular end systolic diameter (mm), Left ventricular end 
systolic volume (mL)) 
 
[…] 
 
Safety criteria: 
- Adverse events (observed and / or spontaneously reported) 
- Vital signs (Blood pressure (supine and standing), heart rate) 
- Physical examination (body weight)  
- Standard 12-lead ECG: heart rate (bpm), PR (ms), QRS (ms), 
QT (ms), repolarisation patterns (ECG not centralized) 
 
Safety criteria: 
- Adverse events (observed and / or spontaneously reported) 
- Vital signs (Blood pressure (supine and standing), heart rate) 
- Physical examination (body weight, body surface area)  
- Standard 12-lead ECG: heart rate (bpm), PR (ms), QRS (ms), 
QT (ms), QTcB (ms), QTcF (ms), repolarisation patterns 
(ECG not centralized) 
 
 
Concomitant treatments 
 
 
Compliance 
 
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4.  STUDY DESIGN 
4.1     OVERALL DESCRIPTION 
[…] 
After a 1 to 4-week of run-in period without treatment, patients 
will be randomised into one of the following treatment groups: 
F373280 1 g or placebo for 24 weeks. 
 Nine visits are planned for the study: 
- 
Visit 1 (V1): W-4 to W-1: Selection visit (7 to 28 days 
before the Inclusion Visit) 
- 
Visit 2 (V2): D1: Inclusion visit (start of treatment)  
 
4. STUDY DESIGN 
 
OVERALL DESCRIPTION 
[…] 
After a 1 to 4-week of run-in period without study treatment, 
patients will be randomised into one of the following treatment 
groups: F373280 1 g or placebo for 24 weeks.  
Nine visits are planned for the study: 
- 
Visit 1 (V1): W-4 to W-1: Selection visit (7 to 28 days 
before the Inclusion Visit) 
- 
Visit 2 (V2): D1: Inclusion visit (start of study treatment)  
 
8. EVALUATION CRITERIA 
 
   PRIMARY EFFICACY CRITERION  
 
Time to the first Atrial Fibrillation 
Recurrence 
8.1.1.3. 
Evaluation Methods 
[…] 
• 
Trans Telephonic ECG Monitoring: 
The ECG follow up will be documented using the TTEM: daily 
transmission from visit 4 (week 5) to visit 5 (week 8). Then 
every two days from visit 5 (week 8) to visit 9 (week 24 – End 
of study). 
[…] 
The cardiologist interpretation will be faxed to the site. 
8.   EVALUATION CRITERIA 
8.1    PRIMARY EFFICACY CRITERION  
8.1.1 
Time to the first Atrial Fibrillation 
Recurrence 
8.1.1.3    Evaluation Methods 
[…] 
• 
Trans Telephonic ECG Monitoring: 
The ECG follow up will be documented using the TTEM: daily 
transmission from the day after visit 4 (week 6) to visit 5 
(week 8). Then every two days from the day after visit 5 
(week 9) to visit 9 (week 24 – End of study). 
[…] 
The cardiologist interpretation will be emailed to the site (or 
per fax on request of the site).  
 
8.1.2.4. Cardioversion assessment 
[…] 
• 
Shock distribution (1, 2 or 3 shocks) 
 
 
8.1.2.4. Cardioversion assessment 
[…] 
• 
Shocks distribution (1, 2 or 3 shocks) 
 
 
 
 
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8.2. 
BIOMARKER ASSESSMENT: RED BLOOD 
CELL CONCENTRATIONS OF DHA 
8.2.2 
Blood samples 
8.2.2.2. 
Technical handling 
Two blood samples (4 ml) will be collected in EDTA tubes. 
They will be gently shaken, stored at +4°C (no freezing will be 
allowed) and sent to Analytical Centre in refrigerated 
conditions (between +2°C and +8°C). Analysis will be 
performed within 2 weeks following reception at the Analytical 
Centre. 
 
8.2. BIOMARKER ASSESSMENT: RED BLOOD 
CELL CONCENTRATIONS OF DHA 
8.2.2 
Blood samples 
8.2.2.2 
Technical handling 
Two blood samples (4 ml) will be collected in EDTA tubes. 
They will be gently shaken, stored between +2°C/+8°C in a 
fridge (no freezing will be allowed) and sent to Analytical 
Centre in refrigerated conditions (between +2°C and +8°C). 
Analysis will be performed within 2 weeks following reception 
at the Analytical Centre. 
 
8.3. SAFETY ASSESSMENT 
8.3.3 
Global physical examination  
A global physical examination including the measurement of 
body weight will be carried out on each body system at visit 1, 
visit 2, visit 3, visit 5, visit 6, visit 7, visit 8 and visit 9. 
The physical examination will be globally evaluated as 
“normal/abnormal”. 
Further 
target 
inspection 
will 
be 
undertaken for any abnormal finding. 
8.3. 
SAFETY ASSESSMENT 
8.3.3 
Global physical examination  
A global physical examination including the measurement of 
body weight will be carried out on each body system at visit 1, 
visit 2, visit 3, visit 5, visit 6, visit 7, visit 8 and visit 9. 
The Body surface area (BSA) will be calculated at the same 
visits using Mostellers’ formula: 
BSA = [(Weight x Height)/3600]1/2 
(Weight in kg, height in cm) 
The physical examination will be globally evaluated as 
“normal/abnormal”. 
Further 
target 
inspection 
will 
be 
undertaken for any abnormal finding. 
 
8.3.5. Electrocardiogram (ECG)  
8.3.5.1.  Schedule 
An ECG will be recorded at visit 1, visit 2, visit 3, visit 5, visit 
6, visit 7, visit 8 and visit 9 using an usual standardised 12-lead 
cardiograph. 
8.3.5.2. Technical Procedure and Parameters 
• 
Electrocardiogram: 
The global interpretation from manual reading (normality, 
clinical relevance) and HR (bpm), PR (ms), QRS (ms), QT 
(ms), repolarisation patterns will be reported in the e-CRF. 
8.3.5.   Electrocardiogram (ECG)  
8.3.5.1. Schedule 
An ECG will be recorded after at least 10 minutes of rest at 
visit 1, visit 2, visit 3, visit 5, visit 6, visit 7, visit 8 and visit 9 
using an usual standardised 12-lead cardiograph. 
8.3.5.2. Technical Procedure and Parameters 
• 
Electrocardiogram: 
The global interpretation from manual reading (normality, 
clinical relevance) and HR (bpm), PR (ms), QRS (ms), QT 
(ms), QTcB (ms), QTcF (ms), repolarisation patterns will be 
reported in the e-CRF. 
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8.3.7. Concomitant Treatments 
 
8.4.     CONCOMITANT TREATMENTS 
8.4.    COMPLIANCE 
The patient will be reminded at each visit to bring back at the 
following visit any used or unused remaining soft capsule, 
blister and case. 
At each visit, the Investigator will record the number of 
supplied and remaining soft capsules in the e-CRF. 
 
8.5.     COMPLIANCE 
The patient will be reminded at each visit to bring back at the 
following visit any used or unused remaining soft capsule, 
blister and case. 
At each visit (except at visit 4), the Investigator will record the 
number of supplied and remaining soft capsules in the e-CRF. 
 
9. 
STUDY PROCEDURES 
Visit 4 (Week 5: D35 -2/+7 days) 
[…] 
The patient will be requested to performed daily transmission 
from week 6 to week 8, then every 2 days from week 9 to week 
24. 
9.  STUDY PROCEDURES 
Visit 4 (Week 5: D35 -2/+7 days) 
[…] 
The patient will be requested to perform daily transmission 
from the day after visit 4 (week 6) to visit 5 (week 8), then 
every two days from the day after visit 5 (week 9) to visit 9 
(week 24 – End of study). 
Visit 5 (Week 8: D56 ± 7 days) – Visit 6 (Week 
12: D84 ± 7 days) - Visit 7 (Week 16: D112 ± 7 
days) - Visit 8 (Week 20: D140 ± 7 days) 
[…] 
The cardiac monitoring will be continued using a TTEM 
device. The device will be given to the patient who will be 
requested to perform daily transmission from week 6 to week 8, 
then every 2 days from week 9 to week 24. 
Visit 5 (Week 8: D56 ± 7 days) – Visit 6 (Week 
12: D84 ± 7 days) - Visit 7 (Week 16: D112 ± 7 
days) - Visit 8 (Week 20: D140 ± 7 days) 
[…] 
The cardiac monitoring will be continued using a TTEM 
device. The device will be given to the patient who will be 
requested to perform daily transmission from the day after 
visit 4 (week 6) to visit 5 (week 8), then every two days from 
the day after visit 5 (week 9) to visit 9 (week 24 – End of 
study). 
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13. STATISTICAL ANALYSIS 
13.11. INTERIM ANALYSIS AND DATA 
MONITORING 
No interim analysis is planned. 
 
13. STATISTICAL ANALYSIS 
13.11. INTERIM ANALYSIS AND DATA 
MONITORING 
No analyses of efficacy data are planned for IDMC that ensures 
that the overall probability of type I error is controlled. No 
Type I error and sample size adjustments are necessary. Any 
recommendations of the IDMC to alter study conduct will be 
based on safety, so IDMC monitoring of the study will not 
affect the statistical operating characteristics of the final 
analysis. The IDMC will review, three times during the study 
period (after the first 30 subjects will have been randomized, 
when the first 80 subjects will have terminated their study 
participation and when 130 subjects will have terminated their 
study participation), safety data results across treatment groups 
and judges whether the overall safety and feasibility (not 
futility) of the trial remain acceptable. 
 
 
 
 
 
 
 
 
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F 373280 CA 2 01 
 
 
 
 
 
 
 
Final version
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Pierre Fabre Médicament 
Represented by: Institut de Recherche Pierre Fabre 
45, Place Abel Gance 
F-92100 Boulogne 
CLINICAL STUDY PROTOCOL 
 
Efficacy and safety study of F373280 for maintenance of sinus rhythm after 
electrical cardioversion in patients with persistent Atrial Fibrillation and 
Chronic Heart Failure. 
International, multicentric, randomised, double-blind, placebo controlled study 
F373280 / Soft Capsules / 1g  
Pierre Fabre Study Code: 
EudraCT Number: 
 
Sponsor's Representative: 
 
 
 
 
 
 
 
 
Study Coordinating Investigator 
F 373280 CA 2 01  
2012 – 003487 - 48 
 
Gaëlle ALCARAZ 
INSTITUT DE RECHERCHE PIERRE FABRE - 
Centre de R&D Pierre Fabre - BP 13562  
3 avenue Hubert Curien  
31035 TOULOUSE Cédex 1, FRANCE 
Phone: +33 5 34 50 62 16  
Fax:+33 5 34 50 69 69  
E-mail:gaelle.alcaraz@pierre-fabre.com  
 
Pr Savina NODARI 
Associate Professor of Cardiology 
Department of Clinical and Surgical Specialities, 
Radiological Science and Public Health 
Section of Cardiovascular Diseases 
University Medical School and Spedali Civili Hospital of 
Brescia 
c/o Spedali Civili di Brescia 
Piazzale Spedali Civili, 1 
25123 - BRESCIA, ITALY 
Phone: +39 030 3996 587 – +39 030 393849 
Fax: +39 030 3700 359 
E-mail: savinanodari@gmail.com; nodari@med.unibs.it 
 
Version 7 – 03JUN2014 
The information contained in this document is confidential and is the property of the Sponsor, Pierre Fabre 
Medicament. This information is given for the needs of the study and must not be disclosed without prior written 
consent of the Sponsor Pierre Fabre Medicament. Persons to whom this information is given for the needs of the 
study must be informed that it is confidential and must not be disclosed. 
Final version
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SPONSOR PERSONNEL 
PIERRE FABRE MEDICAMENT 
represented by 
Institut de Recherche Pierre Fabre 
 
Clinical Study Manager (Monitor) 
Gaëlle ALCARAZ 
Phone: +33 5 34 50 62 16  
Fax: + 33 5 34 50 69 69 
E-mail: gaelle.alcaraz@pierre-
fabre.com 
Institut de Recherche Pierre Fabre 
Centre de R&D Pierre Fabre 
BP 13 562 
3, Avenue Hubert Curien 
31035 TOULOUSE Cedex 1, FRANCE 
 
 
Medical Director 
Richard ROCHE, MD 
Phone: +33 5 34 50 61 94 
Fax: +33 5 34 50 69 69 
E-mail: richard.roche@pierre-
fabre.com 
Institut de Recherche Pierre Fabre 
Centre de R&D Pierre Fabre 
BP 13 562 
3, Avenue Hubert Curien 
31035 TOULOUSE Cedex 1, FRANCE 
 
 
 
 
 
 
 
Final version
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CONTRACT RESEARCH ORGANISATIONS 
 
For Feasibility, Monitoring and Regulatory issues: 
Pharmaceutical Service Network (PSN) 
Rufino Gonzalez 
28 037 Madrid - SPAIN 
Phone: +34 91 375 6930 - Fax: +34 91 375 6931 
E-mail: www.psnglobal.org 
 
For Feasibility, Monitoring and Regulatory issues (in Spain): 
Alpha Bioresearch 
Paseo de la Castellana, 163 - 2º Izquierda 
28 046 Madrid - SPAIN 
Phone: +34 91 745 2520 - Fax: +34 91 745 0653 
E-mail: teresa.bricio@alphabioresearch.com 
 
For Centralised Randomisation and Electronic Case Report Form 
S-Clinica 
6, Chaussée de Boondael 
B-1050 Brussels - BELGIUM 
Phone: +32 2 645 0567 - Fax: +32 2 645 0569 
E-mail: irena.seredina@s-clinica.com 
 
For Centralised Reading of Holder ECG and TTEM and equipment supply: 
Biomedical System 
1945 Chaussée de Wavre 
B-1160 Brussels - BELGIUM 
Phone: +32 2 661 20 70 - Fax: +32 2 661 20 71 
E-mail: sjacobs@biomedsys.com 
 
For intra erythrocyte DHA dosage: 
Agrocampus Ouest 
Laboratoire de Biochimie 
65 rue de Saint Brieuc – CS 84215 
35042 RENNES Cedex - FRANCE 
Phone: +33 2 23 48 55 49 - Fax: +33 2 23 48 55 50 
E-mail: daniel.catheline@agrocampus-ouest.fr 
 
For transportation of blood sample to the Analytical centre (Agrocampus) and material 
supply: 
Theradis Pharma 
41, chemin des Presses 
06800 CAGNES-SUR-MER – FRANCE 
Phone: +33 (0)4 97 02 07 07 - Fax: +33 (0)4 97 10 08 78 
E-mail: chantal.raffy@theradis.pharma.com 
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For refund of patients expenses linked to the study (in France): 
CLINACT 
6-10 rue TROYON 
92310 SEVRES – FRANCE 
Phone: +33 1 46 90 27 27 - Fax: +33 1 46 23 01 56 
Email: sebastien.beaumont@clinact.com 
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Final version
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Protocol F 373280 CA 2 01 
COUNTRY COORDINATING INVESTIGATOR  
SIGNATURE FORM 
Protocol Version 7 – 03 JUN 2014 
 
 
Country: …………………….. 
 
Country Coordinating Investigator:  
"Name"  
Date:   
 
 
 
 
 
 
Signature:  
 
 
 
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Protocol F 373280 CA 2 01 
INVESTIGATOR SIGNATURE FORM 
Protocol Version 7 – 03 JUN 2014 
 
 
 
By my signature below, I, Dr / Pr "                                         ", hereby confirm that I agree: 
♦ to conduct the trial described in the protocol F 373280 CA 2 01, dated 03 June 2014 in 
compliance with GCP, with applicable regulatory requirements and with the protocol 
agreed upon by the Sponsor Pierre Fabre Médicament and given approval / favourable* 
opinion by the Ethics Committee; 
♦ to document the delegation of significant study-related tasks and to notify the Sponsor of 
changes in site personnel involved in the study; 
♦ to comply with the procedure for data recording and reporting; 
♦ to allow monitoring, auditing and inspection; 
♦ to retain the trial-related essential documents until the Sponsor informs that these documents 
are no longer needed. 
Furthermore, I hereby confirm that I will have and will use the available adequate resources, 
personnel and facilities for conduct this trial. 
 
I have been informed that certain regulatory authorities require the Sponsor Pierre Fabre 
Médicament to obtain and supply details about the investigator’s ownership interest in the 
Sponsor or the study drug, and more generally about his/her financial relationships with the 
Sponsor. The Sponsor will use and disclose the information solely for the purpose of complying 
with regulatory requirements. 
Hence I agree: 
♦ to supply the Sponsor with any information regarding ownership interest and financial 
relationships with the Sponsor (including those of my spouse and dependent children); 
♦ to promptly update this information if any relevant changes occur during the course of the 
study and for 1 year following completion of the study; 
♦ that the Sponsor may disclose this information about such ownership interests and financial 
relationships to regulatory authorities. 
* To be adapted  
 
Date:  
Signature:  
 
 
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TABLE OF CONTENTS OF CLINICAL STUDY PROTOCOL 
 
1. 
INTRODUCTION AND STUDY RATIONALE ................................................................ 22 
1.1. 
TARGET PATHOLOGY AND THERAPY ........................................................................ 22 
1.2. 
INFORMATION ON THE TEST PRODUCT .................................................................... 24 
1.2.1. 
Chemical and pharmaceutical characteristics .................................................................... 25 
1.2.1.1. 
Nomenclature and structure ............................................................................................ 25 
1.2.1.2. 
Physical and chemical general properties ...................................................................... 25 
1.2.2. 
Non-clinical Data .............................................................................................................. 26 
1.2.2.1. 
Pharmacological profile ................................................................................................. 26 
1.2.2.2. 
Safety pharmacology ...................................................................................................... 27 
1.2.2.3. 
Toxicology profile .......................................................................................................... 27 
1.2.2.4. 
Pharmacokinetic data ..................................................................................................... 27 
1.2.3. 
Clinical data ....................................................................................................................... 27 
1.3. 
STUDY RATIONALE ......................................................................................................... 30 
1.4. 
OVERALL RISK AND BENEFIT ASSESSMENT ............................................................ 30 
2. 
STUDY OBJECTIVES ......................................................................................................... 33 
2.1. 
PRIMARY OBJECTIVE ..................................................................................................... 33 
2.2. 
SECONDARY OBJECTIVES ............................................................................................. 33 
3. 
ETHICAL CONSIDERATIONS RELATING TO THE STUDY .................................... 33 
4. 
STUDY DESIGN ................................................................................................................... 35 
4.1. 
OVERALL DESCRIPTION ................................................................................................ 35 
4.2. 
DISCUSSION OF THE STUDY DESIGN .......................................................................... 35 
4.2.1. 
Choice of the Study Population ......................................................................................... 35 
4.2.2. 
Choice of the Study Design ............................................................................................... 36 
4.2.3. 
Choice of the Dose ............................................................................................................ 38 
4.2.4. 
Choice of the Sample Size ................................................................................................. 38 
5. 
STUDY POPULATION ........................................................................................................ 38 
5.1. 
INCLUSION CRITERIA ..................................................................................................... 38 
5.2. 
NON INCLUSION CRITERIA ........................................................................................... 39 
5.3. 
NUMBER OF PATIENTS ................................................................................................... 40 
5.4. 
RECRUITMENT MODALITIES ........................................................................................ 41 
5.5. 
PATIENT IDENTIFICATION ............................................................................................ 41 
5.6. 
WITHDRAWAL CRITERIA ............................................................................................... 41 
5.7. 
REPLACEMENT OF PATIENTS ....................................................................................... 42 
5.8. 
POST-STUDY EXCLUSION PERIOD .............................................................................. 42 
5.9. 
STUDY CARD AND LETTER FOR GENERAL PRACTITIONER(S) ............................ 42 
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6. 
STUDY TREATMENT ......................................................................................................... 43 
6.1. 
SOURCE, PRESENTATION AND COMPOSITION OF  INVESTIGATIONAL 
PRODUCT ........................................................................................................................... 43 
6.2. 
PACKAGING AND LABELLING ..................................................................................... 43 
6.2.1. 
Packaging .......................................................................................................................... 44 
6.2.2. 
Labelling ............................................................................................................................ 44 
6.3. 
DISTRIBUTION TO CENTRE AND STORAGE .............................................................. 45 
6.4. 
ALLOCATION OF TREATMENTS AND DISPENSATION TO PATIENT ................... 46 
6.5. 
DRUG ADMINISTRATION ............................................................................................... 47 
6.5.1. 
Duration of Treatment ....................................................................................................... 47 
6.5.2. 
Dose Schedule ................................................................................................................... 47 
6.5.3. 
Route and Conditions of Administration ........................................................................... 47 
6.6. 
ACCOUNTABILITY ON SITE AND RETURN/DESTRUCTION OF  
INVESTIGATIONAL PRODUCT ...................................................................................... 47 
6.7. 
RECALL OF INVESTIGATIONAL PRODUCTS ............................................................. 48 
7. 
CONCOMITANT TREATMENTS ..................................................................................... 48 
7.1. 
ANTI-VITAMIN K TREATMENT ..................................................................................... 49 
7.2. 
PROHIBITED TREATMENTS ........................................................................................... 49 
7.3. 
AUTHORISED TREATMENTS ......................................................................................... 49 
8. 
EVALUATION CRITERIA ................................................................................................. 50 
8.1. 
PRIMARY EFFICACY CRITERION ................................................................................. 50 
8.1.1. 
Time to the first Atrial Fibrillation Recurrence ................................................................. 50 
8.1.1.1. 
Definition ........................................................................................................................ 50 
8.1.1.2. 
Schedule ......................................................................................................................... 50 
8.1.1.3. 
Evaluation Methods ........................................................................................................ 50 
8.1.2. 
Secondary Efficacy Criteria .............................................................................................. 51 
8.1.2.1. 
Numbers of AF episodes in the first week following visit 3 (ECV visit) ...................... 51 
8.1.2.2. 
Duration of AF episodes in the first week following visit 3 (ECV visit) ....................... 52 
8.1.2.3. 
Clinical parameters evaluation ....................................................................................... 52 
8.1.2.4. 
Cardioversion assessment ............................................................................................... 53 
8.1.2.5. 
Evolution of echocardiographic parameters ................................................................... 53 
8.2. 
BIOMARKER ASSESSMENT: RED BLOOD CELL  CONCENTRATIONS OF 
DHA ..................................................................................................................................... 54 
8.2.1. 
Definition ........................................................................................................................... 54 
8.2.2. 
Blood samples ................................................................................................................... 54 
8.2.2.1. 
Collection schedule ........................................................................................................ 54 
8.2.2.2. 
Technical handling ......................................................................................................... 55 
8.2.3. 
DHA concentration measurement ..................................................................................... 55 
8.3. 
SAFETY ASSESSMENT .................................................................................................... 55 
8.3.1. 
Adverse Events .................................................................................................................. 55 
8.3.2. 
Laboratory Investigations .................................................................................................. 56 
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8.3.2.1. 
Schedule ......................................................................................................................... 56 
8.3.2.2. 
Technical Procedures and Parameters ............................................................................ 56 
8.3.3. 
Global Physical Examination ............................................................................................ 57 
8.3.4. 
Vital Signs ......................................................................................................................... 57 
8.3.4.1. 
Schedule ......................................................................................................................... 57 
8.3.4.2. 
Technical Procedure and Parameters.............................................................................. 57 
8.3.5. 
Electrocardiogram (ECG) .................................................................................................. 58 
8.3.5.1. 
Schedule ......................................................................................................................... 58 
8.3.5.2. 
Technical Procedure and Parameters.............................................................................. 58 
8.3.6. 
Coagulation parameters ..................................................................................................... 58 
8.4. 
CONCOMITANT TREATMENTS ..................................................................................... 59 
8.5. 
COMPLIANCE .................................................................................................................... 59 
9. 
STUDY PROCEDURES ....................................................................................................... 59 
10. ADVERSE EVENTS: DEFINITION AND REPORTING ............................................... 65 
10.1. ADVERSE EVENTS ........................................................................................................... 65 
10.1.1. Definition of Adverse Events ............................................................................................ 65 
10.1.2. Grading of Adverse Events ............................................................................................... 66 
10.1.3. Reporting of Adverse Events ............................................................................................ 66 
10.2. SERIOUS ADVERSE EVENTS (SAE) .............................................................................. 66 
10.2.1. Definition ........................................................................................................................... 66 
10.2.2. Reporting of SAE .............................................................................................................. 67 
10.2.3. Follow-up of SAE ............................................................................................................. 68 
10.2.4. SAE Occurring After the Study ......................................................................................... 68 
10.3. REPORTING OF OVERDOSAGE TO THE SPONSOR ................................................... 68 
10.4. REPORTING OF PREGNANCY TO THE SPONSOR ...................................................... 68 
10.5. SPONSOR'S RESPONSIBILITIES FOR SAFETY REPORTING  PURPOSES ............... 69 
11. DATA COLLECTION AND STUDY MONITORING ..................................................... 69 
11.1. DATA COLLECTION ......................................................................................................... 69 
11.1.1. Case Report Form .............................................................................................................. 69 
11.1.2. Source Documents ............................................................................................................. 70 
11.2. STUDY MONITORING ...................................................................................................... 71 
11.2.1. Monitoring visits ............................................................................................................... 71 
11.2.1.1. Site Preselection Visit .................................................................................................... 71 
11.2.1.2. Initiation Visit ................................................................................................................. 71 
11.2.1.3. Follow-up Visits ............................................................................................................. 72 
11.2.1.4. Closing Visit ................................................................................................................... 72 
11.2.2. Direct Access to Source Documents ................................................................................. 72 
11.3. INDEPENDENT DATA MONITORING COMMITTEE ................................................... 73 
12. DATA MANAGEMENT ...................................................................................................... 73 
12.1. DATA ENTRY ..................................................................................................................... 73 
12.2. DATA CLEANING ............................................................................................................. 73 
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12.3. DATA CODING .................................................................................................................. 74 
12.4. DATA STORAGE ............................................................................................................... 74 
12.5. DATABASE LOCK ............................................................................................................. 74 
13. STATISTICAL ANALYSIS ................................................................................................. 74 
13.1. GENERAL CONSIDERATIONS ........................................................................................ 75 
13.2. SAMPLE SIZE ..................................................................................................................... 75 
13.3. PROTOCOL DEVIATIONS ................................................................................................ 75 
13.4. DATA SETS ANALYSED .................................................................................................. 76 
13.5. HANDLING OF DROPOUTS AND MISSING DATA ..................................................... 76 
13.5.1. Dropouts ............................................................................................................................ 76 
13.5.2. Repositioning of Visits ...................................................................................................... 76 
13.5.3. Missing Data ...................................................................................................................... 76 
13.6. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ............................... 77 
13.7. EFFICACY ANALYSIS ...................................................................................................... 77 
13.7.1. Primary Criterion ............................................................................................................... 77 
13.7.1.1. Primary Analysis ............................................................................................................ 77 
13.7.1.2. Supportive Analysis ....................................................................................................... 77 
13.7.2. Secondary Criteria ............................................................................................................. 78 
13.7.2.1. Numbers of Atrial Fibrillation Episodes ........................................................................ 78 
13.7.2.2. Duration of Atrial Fibrillation Episodes ......................................................................... 78 
13.7.2.3. Time to first AF recurrence less than 10 minutes or symtomatic .................................. 78 
13.7.2.4. Clinical parameters evaluation ....................................................................................... 78 
13.7.2.5. Biomarker analysis: red blood cell concentrations of DHA ........................................... 79 
13.8. SAFETY ANALYSIS .......................................................................................................... 79 
13.8.1. Adverse Events .................................................................................................................. 79 
13.8.2. Clinical Laboratory Evaluation ......................................................................................... 81 
13.8.3. Global Physical Examination ............................................................................................ 82 
13.8.4. Vital Signs, Physical Findings and Other Observations Related to Safety ....................... 82 
13.8.4.1. Vital Sign Measurements Over Time ............................................................................. 82 
13.8.4.2. Body weight ................................................................................................................... 82 
13.8.4.3. Individual Patient Changes ............................................................................................. 83 
13.8.5. ECG ................................................................................................................................... 83 
13.8.6. Coagulation parameters ..................................................................................................... 83 
13.9. CONCOMITANT TREATMENTS ..................................................................................... 83 
13.10. COMPLIANCE .................................................................................................................... 84 
13.11. INTERIM ANALYSIS AND DATA MONITORING ........................................................ 84 
14. GENERAL ETHICAL CONSIDERATIONS .................................................................... 84 
14.1. ETHICAL CONDITIONS ................................................................................................... 84 
14.2. ETHICS COMMITTEE AND LEGAL REQUIREMENTS ................................................ 85 
14.3. PATIENT'S INFORMATION LEAFLET AND INFORMED CONSENT  FORM ........... 85 
14.4. PERSONAL DATA PROTECTION ................................................................................... 86 
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14.5. INSURANCE POLICY ........................................................................................................ 86 
15. ADMINISTRATIVE PROCEDURES ................................................................................ 87 
15.1. PROTOCOL AMENDMENT .............................................................................................. 87 
15.2. SOURCE DOCUMENTS, INVESTIGATOR'S FILE STORAGE ..................................... 87 
15.3. END OF THE STUDY ......................................................................................................... 88 
15.3.1. Definition of the End of Study .......................................................................................... 88 
15.3.2. Early Study Termination ................................................................................................... 88 
15.3.2.1. Early Study Termination Decided by the Sponsor ......................................................... 88 
15.3.2.2. Early Study Termination Decided by the Competent Authorities.................................. 88 
15.4. AUDIT .................................................................................................................................. 88 
15.5. INSPECTION ....................................................................................................................... 89 
15.6. CONFIDENTIALITY .......................................................................................................... 89 
15.7. CLINICAL STUDY REPORT ............................................................................................. 89 
15.8. STUDY RESULTS COMMUNICATION .......................................................................... 89 
15.9. STUDY RESULTS PUBLICATION ................................................................................... 90 
16. REFERENCES ...................................................................................................................... 91 
17. APPENDICES ....................................................................................................................... 94 
17.1. DECLARATION OF HELSINKI ........................................................................................ 95 
17.2. SAE REPORT FORM .......................................................................................................... 99 
17.3. PREDEFINED LIMITS OF LABORATORY AND VITAL SIGN POTENTIALLY 
CLINICALLY SIGNIFICANT CHANGES AND VALUES ............................................ 102 
 
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SYNOPSIS 
 
Name of Sponsor: 
Pierre Fabre Médicament represented by the Institut de Recherche Pierre Fabre (IRPF) 
Name of Finished Product: 
Not applicable 
Name of Active Substance:  
F373280 (Panthenyl-Ester of DHA) 
Title of the Study: 
Efficacy and safety study of F373280 for maintenance of sinus rhythm after electrical 
cardioversion in patients with persistent Atrial Fibrillation and Chronic Heart Failure. 
International, multicentric, randomised, double-blind, placebo controlled study 
Abbreviated Title: 
Not applicable 
Study Coordinating Investigator: 
Pr Savina NODARI 
 
Study Centres: 
International, multicentric 
Publication / Rationale: 
F373280 is a new therapy based on DHA delivery (pro-drug) developed for the maintenance 
of sinus rhythm after electrical cardioversion in persistent atrial fibrillation (AF) patients with 
chronic heart failure. 
The results of a pharmacological study performed in animals evidenced that DHA reduces the 
duration of AF induced by burst pacing.[1] 
Moreover, the effectiveness of PolyUnsaturated Fatty Acid (PUFA) has been proven in the 
following conditions: 
− 
prevention of AF recurrence in patients with persistent AF, in co-administration 
with amiodarone (add on therapy) [2]  
− 
Improvement of ventricular functional parameters, morbi-mortality and duration of 
hospitalisation in patients with heart failure [3, 4, 5] 
Taking into account these studies, it seems that DHA might be of therapeutic interest in the 
treatment of patients with both persistent atrial fibrillation and chronic heart failure. 
This phase IIa study is designed to assess the efficacy and the safety of the investigational 
product (F373280) for maintenance of sinus rhythm after electrical cardioversion (ECV) in 
patients with persistent atrial fibrillation and chronic heart failure. 
Planned Study Period: 
January 2013 –  January 2015 
Clinical Phase: IIa 
 
Objectives: 
Primary: 
- Efficacy of F373280 on the maintenance of sinus rhythm after direct electrical 
cardioversion in patients with persistent atrial fibrillation and chronic heart failure 
Secondary: 
- Efficacy of F373280 on the efficiency of direct electrical  cardioversion 
- Effect of F373280 on echocardiographic parameters 
- Safety and tolerability of F373280 
Methodology: 
- International, multicentre, randomised, double-blind, placebo-controlled 
- Selection period 
- Start of treatment 4 weeks before ECV 
• 
Condition to ECV:  
− 
INR 2-3 anti-vitamin K should be given at least 3 weeks before ECV) 
− 
No spontaneous cardioversion before ECV 
- Follow-up 20 weeks after visit 3 (ECV visit) 
• 
Condition: successful ECV or spontaneous CV 
- Cardiac monitoring: 
• 
7-days continuous ECG ambulatory recording (Holter ECG) between visit 3 (ECV 
visit) and visit 4 (week 5) in patients with sinusal rhythm 
• 
TTEM: daily transmission from week 6 to week 8; then every two days from week 
9 to week 24, and in case of AF symptoms 
- Treatment duration: 24 weeks 
Study Schedule: 
9 visits will be scheduled: 
- V1/ W-4 to W-1: selection visit (7 to 28 days before the inclusion visit)  
- V2/ D1: Inclusion visit (start of study treatment) 
- V3/ W4 (D28 -2/+7 days): cardioversion visit (outpatient or hospitalization according to 
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clinical practice of the centre) (installation of the Holter device) 
- V4/ W5 (D35 -2/+7 days): follow-up visit (removing of the Holter device and installation 
of the TTEM) 
- V5/ W8 (D56± 7 days): follow-up visit 
- V6/ W12 (D84 ± 7 days): follow-up visit 
- V7/ W16 (D112 ± 7 days): follow-up visit 
- V8/ W20 (D140 ± 7 days): follow-up visit 
- V9/ W24 (D168 ± 7 days): final study visit 
 
Number of  Patients: 
76 x 2 patients  
Diagnosis and Criteria for Inclusion: 
Inclusion Criteria: 
Demographic Characteristics and Other Baseline Characteristics: 
1. 
Men or women aged more than 18 years (inclusive) 
2. 
Patients with current episode of persistent AF between 7 days and 6 months duration for 
whom electrical cardioversion is warranted 
3. 
History of first documented persistent AF less than 3 years. 
4. 
History of ischemic or non ischemic heart failure  
5. 
NYHA class I or II chronic heart failure at selection and at inclusion 
6. 
Reduced left ventricular ejection fraction between 30% and 45% inclusive (using the 
two-dimensional echocardiography biplane Simpson’s rule) at selection and at inclusion 
7. 
On appropriate, stable medical treatments for heart failure, including a diuretic and/or 
angiotensin-converting enzyme, and/or angiotensin-receptor blocker and/or 
mineralocorticoid receptor (MR) antagonists, and/or betablockers 
8. 
Left atrial area ≤ 40 cm² at selection and at inclusion 
9. 
Patients treated or having to be treated by anti-vitamin K 
10. For female patient of child-bearing potential:  
• 
in all the countries except Italy:  
- 
use of an effective method of contraception (hormonal contraception or intra-
uterine device) assessed by the investigator, for at least 2 months before the 
selection in the study, and agreement to go on using it during the whole duration of 
the study and up to 1 month after the last dose of the study treatment 
- 
documented as surgically sterilized 
 
• 
in Italy only:  
- 
absolute abstention from sexual intercourse during the whole duration of the study 
and for a month after the end of the study or 
- 
use of double barrier contraception method (use of effective medical contraception 
method) from at least 2 months before the start of the study to the entire duration of 
the study and for a month after the end of the study or 
- 
documented as surgically sterilized 
 
11. For female patient of child-bearing potential: negative urine pregnancy test at inclusion 
12. For male with a child-bearing potential partner (In Italy only): 
- 
Absolute abstention from sexual intercourse during the whole duration of the study 
and for 3 months after the end of the study or 
- 
 use of double barrier contraception method (use of condom for male and effective 
contraception method for the partner) from the entire duration of the study to 3 
months after the end of the study. 
 
 
Ethical /legal considerations: 
13. Having signed his/her written informed consent, 
14. Affiliated to a social security system, or is beneficiary (if applicable in the national 
regulation) 
 
Non-Inclusion Criteria: 
Criteria related to pathologies: 
1. 
History of first documented episode of persistent AF more than 3 years 
2. 
More than two successful cardioversions (electrical or pharmacological) in the last 6 
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months 
3. 
Secondary Atrial Fibrillation due to alcohol or severe valvular heart disease (grade III to 
IV) 
4. 
NYHA class III or IV heart failure at selection or at inclusion 
5. 
Thyroid disease uncontrolled by treatment: TSH ± T4L ± T3L to be checked in case of 
treatment for thyroid disease 
6. 
Myocardial infarction or unstable angina or presence of unstable ischemic 
coronaropathy assessed by coronarography or cardiac stress test (Echo stress, exercise 
stress test, nuclear or MR perfusion evaluation methods) within 6 months before 
selection 
7. 
Severe chronic kidney disease (creatinine ≥ 25 mg/L or estimated glomerular filtration 
rate < 30 mL/min) at selection 
8. 
Bradycardia (HR ≤ 50 bpm) 
9. 
Hyperkalemia or hypokalemia (according to the standards of local laboratories) at 
selection  
10. Cardiac surgery within 3 months before selection or planned during the study duration 
 
 
Criteria related to treatments: 
11. Previously ineffective pharmacological or electrical cardioversion 
12. Concomitant treatment with ranolazine or any antiarrhythmic drug (within 7 days prior 
to selection), except stable dose of digoxin, betablockers, calcium-blockers 
13. Oral amiodarone: 
              13a  Previous treatment with oral amiodarone within 4 months prior to inclusion 
              13b  Intake of oral amiodarone for more than 1 month within 4 to 12 months before 
inclusion 
14. Previous treatment with intravenous amiodarone within 4 weeks prior to inclusion 
15. Patient requiring a cardiac resynchronization therapy (CRT) or having undergone CRT 
implantation within the last 6 months  
16. Treatment with any Polyunsaturated Fatty Acid (PUFA) within the last 3 months 
17. Dietary supplement with ω 3 or ω 6 according to investigator’s judgement 
18. Having undergone any form of ablation therapy for AF 
19. Patient treated with other anticoagulant treatment than antivitamin K: thrombin inhibitor 
such as Dabigatran or treated with antiaggregant P2Y12 inhibitors such as Clopidogrel 
or Prasugrel 
 
Other criteria: 
20. Patient liable not to comply with protocol instructions and/or with treatment, in the 
investigator’s opinion 
21. Patient having taken part in a clinical trial in the preceding 2 months or taking part 
in a trial at the time of selection 
22. Patient linguistically or mentally unable to understand the nature, objectives and 
possible consequences of the trial, or refusing to patient himself/herself to its 
constraints 
23. Patient family member or work associate (secretary, nurse, technician,..) of the 
Investigator 
24. Patient having forfeited his / her freedom by administrative or legal award or being 
under guardianship 
25. Breastfeeding female patient 
 
Exclusion criteria before V3: 
Patients not stabilized for INR (i.e. values not between 2 and 3) on at least 3 consecutive 
weekly tests performed before ECV will be excluded from the study, unless the presence of 
atrial thrombosis may be excluded with ECHO –TE (trans-esophageal echocardiograph) 
performed  in the same day (before ECV) 
ECV will be performed in patients without dyskalemia 
If necessary for obtaining stabilized INR between 2 and 3, the ECV (and following visits) 
could be postponed by 7 days. 
Test Product:  
F373280  
Soft Capsules  
Dose: 
Arm with 1g of F373280 
Mode of Administration: 
Oral, one capsule each evening with dinner. 
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Duration of Treatment: 
24 weeks of treatment exposure with F373280 (25 weeks if ECV postponed by 1 week) 
Reference Therapy 
Placebo soft capsules 
Placebo will be administered in the same conditions as the tested product. 
Mode of Administration: 
Oral, one capsule each evening with dinner 
Evaluation Criteria: 
Efficacy evaluation variables: 
 
Primary evaluation variable: 
- Time to first Atrial Fibrillation recurrence defined by the first episode of AF lasting for at 
least 10 minutes (Follow up of 20 weeks after visit 3 (ECV visit). 
Handling of AF recurrences: 7-day continuous ECG (5-leads/2 or 3 channels) ambulatory 
recording (holter ECG) between visit 3 (ECV visit) and visit 4 (week 5). Then, the follow 
up will be documented using the TTEM: daily transmission from week 6 to week 8. Then, 
every two days from week 9 to week 24. 
For randomised patients with spontaneous cardioversion before ECV, the recurrence of AF 
will be assessed after visit 3 (week 5).  
Moreover, during this TTEM period, if patient experiences any AF symptoms, it should be 
recorded and documented using the TTEM.  
All ECG traces will be evaluated by a Central Reading Laboratory. 
 
Secondary evaluation variables: 
During the 7-day continuous ECG monitoring, 
• 
Numbers of AF episodes 
• 
Duration of AF episodes 
 
Clinical parameters: 
During the whole study: 
• 
Number of recurrence of symptomatic AF episodes 
• 
EHRA score 
• 
Hospitalization for cardiovascular events 
• 
Hospitalization for thromboembolic stroke 
• 
All causes of hospitalization 
 
Cardioversion: 
• 
Assessment of spontaneous cardioversion 
• 
Assessment of successful cardioversion 
• 
Shocks distribution (1, 2 or 3 shocks) 
• 
Number of patients needing an other cardioversion after the initial ECV 
 
Other: 
• 
Evolution of echocardiographic parameters (at V4,  V6 and V9) (Left atrial 
diameter (mm), Left atrial area (cm²), Left atrial volume (mL), Left atrial 
volume/BSA (mL/m2), Left ventricular ejection fraction (%), Left ventricular end 
diastolic volume/BSA (mL/m2), Left ventricular end systolic volume/BSA(mL/m2), 
Left ventricular end diastolic diameter (mm), Left ventricular end diastolic volume 
(mL) Left ventricular end systolic diameter (mm), Left ventricular end systolic 
volume (mL)) 
• 
Evolution of omega 3 index and intra erythrocyte DHA (For this assessment 
samples will be centralized). 
 
Safety criteria: 
- Adverse events (observed and / or spontaneously reported) 
- Vital signs (Blood pressure (supine and standing), heart rate) 
- Physical examination (body weight, body surface area)  
- Standard 12-lead ECG: heart rate (bpm), PR (ms), QRS (ms), QT (ms), QTcB. (ms), 
QTcF. (ms), repolarisation patterns (ECG not centralized) 
- Haematology: haematocrit, haemoglobin, red blood cell (RBC) count, white blood cell 
(WBC) count, WBC differential count, reticulocytes, platelets 
- Biochemistry: sodium, potassium, bicarbonate, chloride, alkaline phosphatase, gamma 
GT, albumin, total bilirubin, conjugated bilirubin, creatinin, aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), fasting glucose, total cholesterol, cholesterol 
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(HDL, LDL), triglycerides, creatin phosphokinase (CPK) fibrinogen (local laboratory) 
- Coagulation parameters: Activated partial thromboplastin time (aPTT), thrombin clotting 
time (TCT), INR (local laboratory), Prothrombine Time (PT) 
 
Concomitant treatments 
 
Compliance 
 
Statistical Methods: 
Sample Size: 
Assuming an AF recurrence rate under placebo of 85%, a power of 80%, an alpha risk of 5% 
and a rate of not assessable patients of 15%, 76 randomised patients per group will be 
necessary, using a log-rank test of survival curves, a difference between groups of 20%.  
Primary Efficacy Analysis 
The primary analysis, performed on the Full Analysis Set (FAS: all randomised patients with 
at least one dose of treatment and with a successful cardioversion observed at visit 3), will be 
a survival analysis using the Kaplan Meier method and Cox regression model. 
Secondary Analyses  
All secondary efficacy criteria will be described and compared using appropriate tests on the 
FAS. 
Safety Analyses 
Descriptive statistics will be performed on the Safety Set (all randomised patients with at 
least one dose of treatment).  
 
 
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STUDY FLOW-CHART 
F373280 CA 201 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
Weeks 
W-4 to W-1 
D1 
W4 
(28 -2D/+7 D) 
W5 
(35 -2D/+7 D) 
W8 
(56+/-7D) 
W12 
(84+/-7D) 
W16 
(112+/-7D) 
W20 
(140+/-7D)  
W24 
(168+/-7D) 
  
  
  
  
  
  
  
  
  
  
Outpatient or Hospitalization (1) 
  
  
X 
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
  
  
  
  
  
  
  
  
Demographic characteristics 
X 
  
  
  
  
  
  
  
  
Medico-surgical history 
X 
  
  
  
  
  
  
  
  
Concomitant disease 
X 
  
  
  
  
  
  
  
  
Concomitant treatment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Habits 
X 
  
  
  
  
  
  
  
  
Global physical examination (body weight) 
X 
X 
X 
 
X 
X 
X 
X 
X 
Echocardiography 
X 
X 
  
X 
  
X 
  
  
X 
Eligibility criteria check 
X 
X 
  
  
  
  
  
  
  
Blood pressure, heart rate  
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead  ECG Recording 
X 
X 
X 
  
X 
X 
X 
X 
X 
INR  
 
 
                     (2) 
  
X 
X 
X 
X 
X 
aPTT, TCT  
X 
X 
X 
  
X 
X 
X 
X 
X 
Biochemistry 
X 
  
  
  
  
  
  
  
X 
Hematology 
X 
  
X 
  
  
X 
  
  
X 
Urinary pregnancy test 
  
X 
  
  
  
  
  
  
X 
Red Blood Cell concentrations of DHA  
  
X 
X 
  
  
X 
  
  
X 
Treatment allocation 
  
X 
  
  
  
X 
  
  
  
IVRS/IWRS 
X 
X 
  
  
 
X 
  
  
  
ECV (3) 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Drug administration  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Adverse events recording 
  
X 
X 
X 
X 
X 
X 
X 
X 
Holter ECG 
                (4) 
  
 
                (5) 
 
 
 
 
 
TTEM (6) 
  
  
 
 
 
  
  
  
  
(1) Outpatient or hospitalization according to clinical practice of the centre (less or more than 24 hours) 
(2) In case of AVK introduction: INR 2 to 3 times a week, then weekly until the ECV, then every 4 weeks after ECV 
(3) In patients with AF 
(4) 24-hour Holter ECG 
(5) 7-day Holter ECG 
(6) TTEM: everyday from week 6 to week 8;. then every 2 days from week 9 to week 24; at any time in case of AF symptoms. 
In case of AF recurrence for at least 10 minutes and if the patient does not stop the study treatment, then TTEM once a week 
 
 
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LIST OF ABBREVIATIONS 
 
aPTT 
: 
Activated partial thromboplastin time 
AE 
: 
Adverse event 
AF 
: 
Atrial fibrillation 
ALA 
: 
Alpha-linoleic acid 
ALT 
: 
Alanine aminotransferase 
AST 
: 
Aspartate aminotransferase 
AUC 
: 
Area under the plasma concentration versus time curve 
AUCinf 
: 
Total area under the curve extrapolated to infinity 
AVK 
: 
Anti-vitamin K 
βHCG 
: 
beta human chorionic gonadotrophin 
BLQ 
: 
Below the limit of quantification 
BMI 
: 
Body mass index 
BP 
: 
Blood pressure 
BSA 
: 
Body Surface Area 
CEP 
: 
Protocol evaluation committee 
CHMP 
: 
Committee for medicinal products for human use 
Cmax 
: 
Maximum concentration 
Cmin 
: 
Minimum concentration 
CNALV 
: 
Clinically noteworthy abnormal laboratory value 
CPK 
: 
Creatin phosphokinase 
CPP 
: 
Comité de protection des personnes  
CRA 
: 
Clinical research associate 
CRT 
: 
Cardiac resynchronization therapy 
CSC 
: 
“Clinically Significant Change”, i.e., Predefined potentially clinically significant 
change leading to a potentially clinically significant value (vital signs) 
CV 
: 
Coefficient of variation 
DBP 
: 
Diastolic blood pressure 
DHA 
: 
Docosahexaenoic acid 
EC 
: 
Ethics committee 
ECG 
: 
Electrocardiogram 
ECHO –TE : 
Trans-esophageal echocardiograph 
ECV 
: 
Electrical cardioversion 
EHRA 
: 
European heart rhythm association 
EPA 
: 
Eicosapentaenoic acid 
e-CRF 
: 
Electronic case report form 
FAS 
: 
Full analysis set 
Fe 
: 
Fraction of the administered drug excreted in urine 
GCP 
: 
Good clinical practice 
GFR 
:  Glomerular Filtration Rate 
HBs 
: 
Hepatitis B antigen 
HCV 
: 
Hepatitis C virus 
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HDL 
: 
High density lipoprotein 
HF 
: 
Heart failure 
HIV 
: 
Human immunodeficiency virus 
HR 
: 
Heart rate 
ICH 
: 
International conference on harmonisation of technical requirements for 
registration of pharmaceuticals for human use 
IDMC 
: 
Independent data monitoring committee 
INR 
: 
International normalized ratio 
IRPF 
: 
Institut de Recherche Pierre Fabre 
IVRS 
: 
Interactive voice response system 
LAA 
: 
Left atrial area 
LC/MS-MS : 
Liquid chromatography with tandem mass spectrometry 
LDL 
: 
Low density lipoprotein 
LOQ 
: 
Limit of quantification 
LVEF 
: 
Left ventricular ejection fraction 
MedDRA 
: 
Medical dictionary for regulatory activities 
MR 
: 
Mineralocorticoid receptor 
MR perfusion : 
Magnetic Resonance perfusion 
MTD 
: 
Maximum tolerated dose 
N 
: 
Number of determinations or replicates 
NOAEL 
: 
No observed adverse effect level 
NYHA 
: 
New York heart association 
od 
: 
Once a day 
PC 
: 
“Predefined Change”, i.e., Predefined potentially clinically significant change (lab 
or vital signs) 
PCA 
: 
PC leading to an out-of-range value (lab values) 
PFB 
: 
Pierre Fabre Biométrie 
PSC 
: 
Potentially Clinically Significant Change 
PSCV 
: 
Potentially Clinically Significant Value 
PUFA 
: 
PolyUnsaturated fatty acid 
p.o. 
: 
Per os 
PP 
: 
Per protocol data set 
QTcB 
QT interval using Bazett’s correction formula 
QTcF 
QT interval using Fridericia’s correction formula 
RBC 
: 
Red blood cells 
SAE 
: 
Serious adverse event 
SBP 
: 
Systolic blood pressure 
SD 
: 
Standard deviation 
T1/2 
: 
Terminal half-life 
T0 
: 
Time of drug administration 
Tmax 
: 
Time to reach the maximal concentration 
TCT 
: 
Thrombin clotting time 
TEAEs 
: 
Treatment emergent adverse events 
TTEM 
: 
TransTelephonic ECG monitoring 
WBC 
: 
White blood cells 
WHO-DRUG : 
World health organization drug reference list 
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1. INTRODUCTION AND STUDY RATIONALE 
1.1. 
TARGET PATHOLOGY AND THERAPY 
Atrial Fibrillation (AF) is a supraventricular arrhythmia characterized by uncoordinated atrial 
electric activity with consequent deterioration of atrial mechanical function. It is the most 
common sustained cardiac rhythm disorder, increasing in prevalence with age. Haemodynamic 
impairment and thromboembolic events related to AF result in significant morbidity and mortality 
[7]. 
In 2009, Decision Resources estimated that there were 7.8 million diagnosed prevalent cases of 
AF in US, Europe and Japan. This age-related pathology should increase to 9.4 million cases in 
2019.  
Except for the conventional class I and class III anti-arrhythmic agents, the Polyunsaturated Fatty 
Acids (PUFAs) constitute one emerging antiarrhythmic therapy. These compounds potently 
address the AF substrate by directly targeting both the electrical and the structural remodelling of 
the deficient atria. The n-3 PUFAs, essential for human, are alpha-linoleic acid (ALA), 
eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). First, PUFAs specifically 
modulate ionic channels by fastening their inactivating mode which renders these compounds 
selective for pathological situations (such as AF) without any major effect in normal conditions. 
PUFAs are “open Kv1.5 channel blockers” leading to a lengthening of atrial action potential 
duration and are “persistent Nav1.5 channel blockers” leading to hyperpolarization of diastolic 
resting potential. Second, PUFAs influence structural remodelling through their anti-inflammatory 
effects as they directly compete with arachidonic acid in the production of inflammatory 
eicosanoids. In summary, PUFAs share unique, well-tolerated antiarrhythmic potential by 
interacting with the electrical and structural remodelling during sustained AF. In animal studies, it 
was recently demonstrated that DHA is particularly effective in pathologic conditions such as 
ischemia and/or AF. 
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The potential anti-arrythmic effects of a PUFA were previously developed in AF: nicotinyl ester 
of DHA (pro-drug based on DHA delivery) was assessed in a two-week ventricular tachypaced 
canine model. Dogs were subjected to 4 weeks of medication prior to undergoing an 
electrophysiology study, and received either placebo or nicotinyl ester of DHA. Dogs were 
tachypaced at 240 beats per min for the final two weeks of the treatment plan. The results showed 
that the tested PUFA reduced the duration of AF induced by burst pacing, and the incidence of 
sustained AF, compared to dogs treated with the placebo [1]. 
In clinical practice, Nodari and coll [2] assessed n-3 PUFAs in the prevention of AF recurrences 
after electrical cardioversion (ECV). All included patients were treated with amiodarone and a 
renin-angiotensin-aldosterone system inhibitor. The 199 patients were assigned either to placebo 
or n-3 PUFAs 2 g/d and then underwent direct ECV 4 weeks later. The primary end point was the 
maintenance of sinus rhythm at 1 year after cardioversion. At the 1-year follow up, the 
maintenance of sinus rhythm was significantly higher in the n-3 PUFAs treated patients compared 
with the placebo group (hazard ratio, 0.62 [95% confidence interval, 0.52 to 0.72] and 0.36 [95% 
confidence interval, 0.26 to 0.46], respectively; p = 0.0001). The study concludes that in patients 
with persistent AF on amiodarone and a renin-angiotensin-aldosterone system inhibitor, the 
addition of n-3 PUFAs 2 g/d improves the probability of the maintenance of sinus rhythm after 
direct current cardioversion. Previously, during the World Congress of Cardiology in 2006, an 
abstract reported the effectiveness of PUFAs on top of traditional treatment (amiodarone, beta 
blockers, renin-angiotensin-aldosterone system inhibitor) in the prevention of AF relapses in 
patients having undergone ECV. In the PUFA group, AF relapses were significantly lower than in 
the placebo group at 1 month (3.3% vs 10%; p = 0.043), at 3 months (10% vs 25%; p = 0.004) and 
at 6 months (13.3% vs 40%; p < 0.0001) [19]. 
In contrast, in the general AF population (paroxystic atrial fibrillation and persistent atrial 
fibrillation), PUFAs failed to prove their efficacy [7] because of the absence of cardiac 
remodelling or because of a short pre-treatment duration before ECV (1 week) [8]. The effects of 
PUFAs were only observed in patients with persistent AF on add on therapy and after a sufficient 
pre-treatment before ECV. Persistent AF is commonly associated to heart failure. Previous studies 
performed in heart failure population demonstrated the benefit of PUFAs on the improvement of 
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functional ventricular parameters and morbi-mortality, and on the reduction of hospitalisation [3, 
4, 5]. 
Nodari and coll [3] performed a trial in patients with chronic heart failure (NYHA I to III and 
LVEF< 45%). After a treatment of 133 patients with PUFAs (n=67) or placebo (n=66) at a dosage 
of 5 g/day for 1 month, then 2 g/day for 11 months, the n-3 PUFAs group and the placebo group 
differed significantly (p <0.001) in regard to:  
− LVEF (increased by 10.4% and decreased by 5.0%, respectively) 
− peak VO2 (increased by 6.2% and decreased by 4.5%, respectively) 
− exercise duration (increased by 7.5% and decreased by 4.8%, respectively) 
− mean New York Heart Association functional class (decreased from 1.88+/- 0.33 to 1.61 
+/- 0.49 and increased from 1.83+/- 0.38 to 2.14 +/- 0.65, respectively).  
The hospitalization rates for patients with HF were 6% in the n-3 PUFAs and 30% in the placebo 
group (p <0.0002). 
Moertl and coll [4] performed a dose-ranging study in patients with a more severe chronic heart 
failure (NYHA III and IV and LVEF < 35%). It was a double-blind, randomised, controlled pilot 
trial in 43 patients treated with PUFAs or placebo for 3 months (1 g/d n3-PUFA (n = 14), 4 g/d 
n3-PUFA (n = 13), or placebo (n = 16)). After treatment, left ventricular ejection fraction 
increased in a dose-dependent manner (p = 0.01 for linear trend) in the 4 g/d (baseline vs 3 
months [mean ± SD]: 24% ± 7% vs 29% ± 8%, p = 0.005) and 1 g/d treatment groups (24% ± 8% 
vs 27% ± 8%, p = 0.02). 
No changes in any investigated parameters were noted with placebo. 
Taking into account these studies performed with PUFAs, it seems that the best target for DHA is 
persistent AF in patients with heart failure. The aim of this proof of concept study is to assess in 
stand alone therapy (without association of other anti-arrhythmic treatments), the effect of 
F373280 in patients with persistent AF and heart failure in the maintenance of sinus rhythm after 
ECV. 
1.2. 
INFORMATION ON THE TEST PRODUCT 
F373280 or panthenyl ester of DHA is the mono-ester of panthotenic alcohol and DHA, selected 
to be developed for the management of AF.  
F373280 is a prodrug of DHA. 
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A brief summary of F373280 known characteristics is presented in this section. For further details, 
please refer to the F373280 Investigator’s Brochure. [1] 
1.2.1. 
Chemical and pharmaceutical characteristics 
1.2.1.1. 
Nomenclature and structure 
Chemical name (IUPAC):  
(4Z,7Z,10Z,13Z,16Z,19Z)-3-((R)-2,4-dihydroxy-3,3-diméthylbutanamido) 
propyl 
docosa-
4,7,10,13,16,19-hexaenoate 
Structural formula: 
O
O
O
O
NNHH
O
O
OHH
O
OHH
 
Laboratory code: F373280 
Molecular formula: C31H49NO5 
Molecular mass: 515.7 
1.2.1.2. 
Physical and chemical general properties 
Appearance: Clear oily viscous liquid 
Solubilities:  
− Water: Practically insoluble 
− Alcohol: Very soluble  
− Trimethylpentane: Slightly soluble  
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1.2.2. 
Non-clinical Data 
Non-clinical data are exhaustively detailed in the Investigator’s brochure [1]. A brief summary is 
provided below. 
1.2.2.1. 
Pharmacological profile 
F373280 (mono-ester of panthotenic alcohol and DHA) is a novel pro-drug of DHA which exerts 
antiarrhythmic properties by interacting with the electrical and structural remodelling of the atria.  
Experimental investigations were conducted in HEK293 cell line transfected with human Kv1.5 
channel using the whole cell patch clamp technique to evaluate whether F373280 could block the 
sustained component of IKv1.5. F373280 concentration-dependently reduced Kv1.5 channel activity 
with an IC50 value of 13.7 µM. 
The effects of F373280 on atrial effective refractory period were investigated in anesthetized pig 
using a conventional pacing protocol through epicardial electrodes placed on the left atrium. 
F373280 administered as a bolus and an infusion (10 mg/kg) significantly increased atrial 
effective refractory period (23.8 ± 2.2 ms versus -7.3 ± 11.5 ms in the presence of vehicle, p < 
0.05). In addition, F373280 was devoid of significant effect on the hemodynamic and the 
electrocardiogram (ECG) intervals.  
Proof of the pharmacological concept was performed with a different DHA derivative named: 
Nicotinyl ester of DHA (pro-drug based on DHA delivery). Ventricular tachypacing-induced 
congestive heart failure provides a clinically-relevant animal model of AF associated with 
structural remodelling, as is often seen clinically. It has been shown that sustained oral PUFA 
administration suppresses congestive heart failure-induced AF-promotion and fibrosis in the 
ventricular tachypacing canine model. Nicotinyl ester of DHA was tested in this model, at 1 g/day 
and 5 g/day, during 4 weeks, to prevent congestive heart failure-related atrial structural 
remodelling and AF promotion in dogs. Nicotinyl ester of DHA dose dependently reduced heart 
failure-induced increases in AF duration (989 ± 111 sec, n=5 in the presence of placebo versus 
637 ± 196 sec, n=5 in the presence of 1 g/kg/d Nicotinyl ester of DHA and 79 ± 51 sec, n=5, in 
the presence of 5 g/kg/d Nicotinyl ester of DHA). The protective effect of Nicotinyl ester of DHA 
was associated with a marked increase of plasma level of DHA and important incorporation of 
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DHA in the left atrial tissue. Because F373280 similarly to Nicotinyl ester of DHA increases 
plasma level of DHA, it could be estimated that the compound may exert a similar protective 
effect [1]. 
1.2.2.2. 
Safety pharmacology 
A battery of safety pharmacology studies was performed to evaluate the effects of F373280 on the 
central nervous, cardiovascular and respiratory systems. Data of these studies are exhaustively 
detailed in the Investigator’s brochure [1]. 
No particular alerts were evidenced with F373280. 
1.2.2.3. 
Toxicology profile 
 
Concerning the toxicological data, 4-week and 26-week repeat-dose studies in rat and dog were 
performed. Compared to the high administered doses of F373280 (500 to 2000 mg/kg/day), low 
circulating concentrations of F373280 were measured.  
During these toxicity studies, no toxicity was observed in rat after 4 and 26 weeks of dosing and 
in dog after 4 weeks of dosing. A NOAEL of 2000 mg/kg/day was established in these repeat 
toxicity studies.  
During the 26-week toxicity study in dogs, the NOAEL was set at 1000 mg/kg/day based on 
changes observed on red blood cell parameters. 
Based on toxicological profiles, F373280 is considered to support the proposed clinical trial. 
 
1.2.2.4. 
Pharmacokinetic data  
According to animal studies described in the Investigator’s brochure [1], the non-clinical 
pharmacokinetic profile of F373280 is not associated with particular alerts concerning the 
proposed clinical phase IIa study. 
1.2.3. 
Clinical data 
Part A: single dose 
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Six consecutive single ascending doses were tested (0.5 g, 1 g, 2 g, 4 g, 8 g and 16 g) on 6 
independent cohorts of 8 subjects (6 verum + 2 placebo). 49 subjects were treated and 48 
completed the study. 
No Serious Adverse Events (SAE) occurred in the course of the study. 
Regarding the reported Treatment Emergent Adverse Events (TEAEs) that were judged by the 
Investigator as having a causal relationship with the study drug administration in the absence of 
an alternative explanation, 3 TEAEs were observed in the placebo group (palpitation, dizziness in 
standing position, symptomatic orthostatic hypotension without loss of consciousness) and 4 in 
the group of F373280 at the dosage of 16 g (meteorism, liquid stool, symptomatic orthostatic 
hypotension and dizziness in standing position). None of these adverse events (AE) were reported 
in the groups of F373280 at the dosages of 0.5 g, 1 g, 2 g, 4 g and 8 g. 
After a single administration of the different tested doses no difference between the tested product 
and placebo has been reported, regarding vital signs (heart rate, systolic blood pressure and 
diastolic blood pressure), biological parameters (related to coagulation: platelets and fibrinogen) 
and coagulation parameters (bleeding time, prothrombin time/INR, activated partial 
thromboplastin time, thrombin clotting time). Variations of these parameters were within the 
physiological ranges. 
After single oral administration of F373280 from 0.5 g to 16 g in 36 young healthy male subjects 
(6 per dose level), the following was observed: 
 
- F373280: Whatever the tested dose there is no circulating F373280 in plasma: only few, 
sparse and non consecutive samples with quantifiable level of F373280 close to LOQ were 
observed. This confirms that F373280 is a prodrug. 
- Panthenol: Cmax and AUC increased with the administered dose between 0.5 and 16 g. 
Panthenol concentrations were rapidly cleared from plasma with a mean terminal half-life 
around 2 hours. 
- DHA: after 0.5 and 1 g, low increased in DHA plasma concentrations compared to the 
baseline levels led to a high inter-individual variability of the corresponding 
Pharmacokinetics parameters. Plasma exposure in DHA increased with the administered dose 
between 2 and 16 g with no departure from proportionality (baseline corrected parameters). 
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Part B: Multiple doses  
Three consecutive repeated ascending doses (1, 2 and 4 g) were tested on 3 independent cohorts of 
12 subjects (9 verum + 3 placebo, double blind). 36 subjects completed the study. Each treatment 
was administered over a period of 28 days. Pharmacokinetic parameters were assessed over a 
period of 14 days.  
Among the TEAE judged by the investigator as suspected to F373280, 5/9 TEAEs were classified 
according the System Organ Class in vascular system disorder with orthostatic hypotension (2 in 
the 1 g group, 1 in the 2 g group and 2 in the 4 g group) and 4/9 were classified in nervous system 
disorder with 3 dizziness (2 in the 2 g group and 1 in the 4 g group) and 1 migraine (in the 1 g 
group). These TEAEs have already been reported with PUFAs and are commonly observed in 
phase I studies. 
After a repeated administration of the different tested doses, no difference between the tested 
products and placebo was reported regarding vital signs (heart rate, systolic blood pressure and 
diastolic blood pressure), biological parameters. The assessment of coagulation parameters and 
platelet function after administration of repeated dose of F373280 did not report any bleeding 
issue. The reported changes in coagulation parameters and platelet function were within 
physiological ranges. 
After a 14-day repeated oral administration of F373280 from 1 g to 4 g, the following was 
observed: 
 Panthenol: Cmax and AUC increased with the administered dose between 1 and 4 g. No 
accumulation of panthenol in plasma was observed. 
 
 DHA: Plasma exposure increased with dose. A 2-fold accumulation in total plasma exposure 
of DHA was observed after 14 days of administration, whatever the administered dose. 
 
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1.3. 
STUDY RATIONALE 
F373280 is a new therapy based on DHA delivery (pro-drug) developed for the maintenance of 
sinus rhythm after ECV in persistent AF patients with chronic heart failure. 
The results of a pharmacological study performed in animals evidenced that DHA reduces the 
duration of AF induced by burst pacing [1]. 
Moreover, the effectiveness of PUFAs has been proven in the following conditions: 
- 
Prevention of AF recurrence in patients with persistent AF in co-administration with 
amiodarone (add on therapy) [2], 
- 
Improvement of ventricular functional parameters, morbi-mortality and duration of 
hospitalisation in patients with heart failure [3, 4, 5]. 
Taking into account these studies, it seems that DHA might be of therapeutic interest in the 
treatment of patients with both persistent AF and chronic heart failure. 
This phase IIa study is designed to assess the efficacy and the safety of the investigational product 
(F373280) for maintenance of sinus rhythm after ECV in patients with persistent AF and chronic 
heart failure. 
1.4. 
OVERALL RISK AND BENEFIT ASSESSMENT 
F373280 is a new pro-drug of DHA.  
DHA is a well-known long chain PUFAs with a long-term clinical experience in cardiovascular 
diseases. DHA is contained in several medicinal products such as Omacor, (1 g of Omacor 
contains about 320 mg of DHA acid) marketed by Laboratoires Pierre Fabre for 
hypertriglyceridemia and as an adjuvant treatment for secondary prevention after myocardial 
infarction. According to the summary product characteristics of Omacor [9]: 
 
- The frequencies of adverse reactions are ranked according to the following: common 
(>1/100, <1/10); uncommon (>1/1000, <1/100); rare (>1/10000, <1/1000); very rare (<1/10000), 
not known (cannot be estimated from the available data). 
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- The reported adverse events are: 
• Infection and infestations: 
Uncommon: gastroenteritis 
• Immune system disorders: 
Uncommon: hypersensitivity 
• Metabolism and nutrition disorders: 
Rare: hyperglycaemia 
• Nervous system disorders: 
Uncommon: dizziness, dysgeusia 
Rare: headache 
• Vascular disorders: 
Very rare: hypotension 
• Respiratory thoracic and mediastinal disorders:  
Very rare: nasal dryness 
• Gastrointestinal disorders: 
Common: dyspepsia, nausea 
Uncommon: abdominal pain, gastrointestinal disorders, gastritis, abdominal pain upper 
Rare: gastrointestinal pain 
Very rare: lower gastrointestinal haemorrhage 
• Hepatobiliary disorders:  
Rare: hepatic disorders  
• Skin and subcutaneous tissue disorders:  
Rare: acne, rash pruritic 
Very rare: urticaria 
• General disorders and administration site conditions: 
Rare: malaise sensation 
• Investigations: 
Very rare: white blood count increased, blood lactate dehydrogenase increased 
Moderate elevation of transaminases has been reported in patients with hypertriglyceridaemia. 
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Panthenol is a well-known substance with a long-term experience in medical, nutraceutic and 
cosmetic uses. According to the summary product characteristics of a product such as 
Bépanthene (tablet indicated in alopecia) which contains panthenol (100 mg), adverse event 
observed are rare cases of urticaria and erythema [10]. Panthenol is metabolised in panthotenic 
acid, i.e. B5 vitamin. 
Concerning toxicological studies performed results can support the administration of F373280 in 
the proposed clinical phase II study without particular alert [1]. 
Any safety warning was reported during a phase I study performed with F373280 administered to 
84 healthy volunteers in single dose in a range between 500 mg and 16 g or in repeated dose 
during 28 days in a range between 1 g and 4 g. Adverse events reported and related to study 
treatment were minor to moderate. The adverse events were palpitations, orthostatic hypotension, 
dizziness, meteorism and liquid stool. Most were reported in both groups (placebo and F373280) 
without a dose relationship. The assessment of coagulation parameters and platelet function after 
administration of repeated dose of F373280 did not report any bleeding concern: the reported 
changes in coagulation parameters and platelet function were within physiological ranges. 
Moreover, DHA has been associated with anticoagulant products in AF studies [2, 8]. The range 
of PUFAs doses tested was between 2 g to 3 g (640 mg to 960 mg of DHA) and the range of study 
durations between 6 to 12 months. This association did not report a significant side effect of 
bleeding. 
DHA has already been used in HF patients in several studies without safety concern [3, 4, 5]. The 
range of PUFAs doses tested was between 1 g to 5 g (1 g of the tested PUFAs contains about 320 
mg of DHA acid) and the range of study durations was between 3 months to 3.9 years. 
Thus, inclusion of patients with no specific antiarrhythmic treatment is acceptable. They will 
receive an anticoagulant treatment to prevent the thrombo-embolic complications of AF 
(particularly stroke) and the adequate treatments to control the heart rate and heart failure.   
In conclusion, the overall available data allow in safe conditions the treatment of patients with 
persistent AF and chronic heart failure with F373280 in safe conditions. 
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2. STUDY OBJECTIVES 
2.1. 
PRIMARY OBJECTIVE 
The primary objective of the study is to assess the efficacy of F373280 on the maintenance of 
sinus rhythm after direct ECV in patients with persistent AF and chronic heart failure. 
2.2. 
SECONDARY OBJECTIVES 
The secondary objectives of the study are to assess: 
• the efficacy of F373280 on the efficiency of direct ECV 
• the effect of F373280 on echocardiographic parameters 
• the safety and tolerability of F373280 
3. ETHICAL CONSIDERATIONS RELATING TO THE STUDY 
The trial is conducted according to Good Clinical Practices (CPMP/ICH/135/95), the National 
regulations and the Declaration of Helsinki and its subsequent amendments (see Appendix 17.1). 
This protocol and the informed consent form will be submitted for approval to independent local 
or national Institutional Review Boards/Ethics Committees before the study set up, according to 
national regulation. 
All the protocol amendments or critical events liable to increase the risks incurred by the patients 
or to compromise the validity of the study or patients' rights will be submitted to the coordinator 
and to the Ethics Committees. 
After being informed orally and in writing of all potential risks and constraints of the trial, as well 
as their freedom to withdraw their participation at any time, patients will then sign a consent form.  
A time of reflection will be given to the patients, before giving a written consent and starting the 
study procedures. 
The use of a placebo is in accordance with EMA Addendum to the guideline on antiarrhythmics 
on AF and atrial flutter (EMA/CHMP/EWP/213056/2010) [21] and is acceptable because the 
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included patients will remain under the standard treatment of AF and chronic heart failure. Except 
antiarrythmics, they will receive anticoagulant (anti-vitamin K), rate control treatment, chronic 
heart failure treatment. During the study, in case of AF recurrence that would require 
cardioversion or the introduction of an anti-arrhythmic because of intolerable and/or 
uncomfortable clinical symptoms for instance, patients will be withdrawn and the tested product 
stopped. These patients will be considered as treatment failure. 
In this study, patients will be carefully screened, particularly for their cardiac condition, with 
ECG, 24-hour holter monitor and echocardiographic data, and their biologic and coagulation 
condition. 
The study will be addressed only to patients requiring an ECV due to their persistent AF, in the 
following conditions: 
- 
ECV in patients not presenting a contra-indication 
- 
Anticoagulation with anti-vitamin K (AVK) for at least 3 weeks before ECV 
- 
ECV in patients with stabilized INR (i.e. values between 2 and 3;sp to ) on at least 3 
consecutive weekly tests performed. Patients not stabilized for INR (i.e. values not 
between 2 and 3) on at least 3 consecutive weekly tests performed before ECV will be 
excluded from the study, unless the presence of atrial thrombosis may be excluded 
with ECHO –TE (trans-esophageal echocardiograph) performed in the same day 
(before ECV). Patients who do not revert to sinus rhythm or present an early relapse 
within the observation period after ECV will be withdrawn and the tested product 
stopped. 
During the whole study, patients will remain under medical control: visits in cardiology units will 
be scheduled at least every month. This follow up will include clinical signs, ECG, biological and 
coagulation parameters. Moreover, patient’s cardiac rhythm will be monitored between visits 
using daily, then every 2 days Trans Telephonic ECG Monitoring (TTEM) reviewed by a Central 
Reading Laboratory. 
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Patients may withdraw from the study at any time without having to give a reason and can expect 
to receive regular conventional therapy. 
4. STUDY DESIGN 
4.1. 
OVERALL DESCRIPTION 
This phase IIa trial will be conducted as an international, multicentric, 24 weeks, double-blind, 
placebo-controlled, randomised, parallel group design, trial in 152 patients suffering from 
persistent AF and chronic heart failure. 
After a 1 to 4-week of run-in period without study treatment, patients will be randomised into one 
of the following treatment groups: F373280 1 g or placebo for 24 weeks.  
Nine visits are planned for the study: 
- 
Visit 1 (V1): W-4 to W-1: Selection visit (7 to 28 days before the Inclusion Visit) 
- 
Visit 2 (V2): D1: Inclusion visit (start of study treatment)  
- 
Visit 3 (V3): W4 (D28 -2/+7D): cardioversion visit (outpatient or hospitalization 
according to clinical practice of the centre) (installation of the Holter ECG device) 
- 
Visit 4 (V4): W5 (D35 -2/+7D): follow-up visit (removing of Holter ECG device and 
installation of the TTEM) 
- 
Visit 5 (V5): W8 (D56 ± 7D): follow-up visit 
- 
Visit 6 (V6): W12 (D84 ± 7D): follow-up visit 
- 
Visit 7 (V7): W16 (D112 ± 7D) : follow-up visit 
- 
Visit 8 (V8): W20 (D140 ± 7D): follow-up visit 
- 
Visit 9 (V9): W24 (D168 ± 7D): final study visit 
4.2. 
DISCUSSION OF THE STUDY DESIGN 
4.2.1. 
Choice of the Study Population 
The target indication of F373280 will be the maintenance of sinus rhythm after cardioversion of 
patients with persistent AF and chronic heart failure. In the present proof of concept study, the 
evaluation will focus on patients within this indication. This target population is justified by: 
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− The proved efficacy of PUFAs in patients with persistent AF with or without heart failure 
in co-administration with amiodarone (add on therapy) [2] 
− The proved efficacy of PUFAs on the improvement of ventricular functional parameters, 
morbi-mortality and duration of hospitalisation in patients with heart failure [3, 4, 5] 
The study aim is to investigate the product effect in patients with: 
− Persistent AF history (less than three years) with a duration of the current episode from 7 
days to 6 months. 
− a moderately abnormal systolic heart failure (Left Ventricular Ejection Fraction (LVEF) 
between 30 to 45% as defined in the report from the American Society of 
Echocardiography’s Guideline). According to a sub-group analysis performed in patients 
with persistent AF associated to heart failure (Nodari S. personnal data), PUFAs would 
be effective to prevent recurrence of AF after cardioversion in patients with moderately 
abnormal LVEF. 
 
− a Left Atrial Area (LAA) not severely abnormal (less than 40 cm2 as defined in the report 
from the American Society of Echocardiography’s Guideline). According to a sub-group 
analysis performed in patients with persistent AF associated to heart failure (Nodari S. 
personnal data), PUFAs would not be effective to prevent recurrence of AF after 
cardioversion of patients with severely abnormal LAA. 
For the successful rate of ECV, patients should have a stable medical treatment of heart failure 
and should not have any myocardial infarction or unstable angina or unstable ischemic 
coronaropathy assessed by coronarography or cardiac stress test (Echo stress, exercise stress 
test, nuclear or MR perfusion evaluation methods) within 6 months before selection.  
4.2.2. 
Choice of the Study Design 
As the target indication would be the prevention of AF recurrence after ECV, the study design 
meets 
the 
requirements 
of 
EMA 
guideline 
on 
antiarrhythmics 
in 
AF 
(EMA/CHMP/EWP/213056/2010) [21]. 
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As F373280 aims to be a safe treatment for the prevention of AF recurrence, it will not be tested 
as an add-on therapy during the study. To avoid any interaction with the tested product, 
antiarrhythmic class I and III will be forbidden during the study. 
The study design is defined in order to avoid methodological bias. A double blind study is 
appropriate to assess the efficacy and safety of the use of F373280 to prevent recurrence of AF 
episodes. Moreover, this study design is similar to the design of almost all trials that have assessed 
intervention for rhythm control [2, 8, 11, 12].  
According to the target indication, only patients with persistent AF and requiring an ECV will be 
included in order to assess the time to first documented recurrence of AF since cardioversion. 
To confirm the persistent nature of AF, a 24-hour holter monitoring will be performed during the 
selection visit.  
Eligible participants will enter a selection phase in which anticoagulant treatment (AVK) will be 
adjusted to achieve an International Normalized Ratio (INR) of 2.0 to 3.0 before ECV. According 
to guidelines for the management of AF [6], AVK should be given at least 3 weeks before 
cardioversion because of risk of thrombo-embolism due to post-cardioversion.  
Experimental data suggest that the maximal incorporation of n-3 PUFAs in the myocardial cell 
membrane takes up to 28 days to occur [22]. In addition, as shown in Nodari’s study [2], the 
duration of pre-treatment with PUFAs before cardioversion appears to be a contributing factor in 
success. Therefore, before starting follow up for the assessment of AF recurrence, treatment with 
F373280 should be started 28 days before ECV.  
Detection of AF recurrence will be performed using systematic (scheduled) ECG recording, thus 
allowing detection of asymptomatic (about 50% of episodes) as well as symptomatic AF episodes. 
According to previous studies, most of AF recurrences occurred during the first days after 
cardioversion [11, 15]. So that, the heart rhythm will be closely monitored during the first week 
after successful cardioversion using an ambulatory continuous 7-day holter ECG recording in 
order to increase sensibility to detect asymptomatic AF episodes. Thereafter, to improve patient 
compliance, this follow up will be continued using an easier device  to carry and to use, i.e. a 
TTEM.  
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Finally, during the study, patients will be scheduled for a clinical visit every month (with an 
additional visit 7 days after visit 3 (ECV visit)) in order to ensure a close medical monitoring and 
to assess efficacy and safety parameters. 
4.2.3. 
Choice of the Dose  
According to a previous study in patients with AF [2], the tested PUFA product (Omacor) at the 
dose of 2 g (i.e. 640 mg of DHA acid) was effective in the prevention of AF after cardioversion. 
Moreover, PUFAs at dosage of 1 g and 2 g were also effective on the improvement of ventricular 
functional parameters, morbi-mortality and duration of hospitalisation in patients with heart 
failure [3, 4, 5].  
From the F373280 phase I study, after a 14-day repeated administration of F373280 (1 g/day), 
observed plasma concentrations of DHA measured before treatment (Cmin) were similar to that of 
an effective dose of Omacor at 2 g/day (60 to 95 mg/mL and 60 to 90 mg/mL, respectively) 
(phase I study of F373280 and [16]). With regard to the rhythm of administration, mean 
peak/trough fluctuation (baseline corrected) was around 0.3. This value supports an once-daily 
administration allowing a 24-hour plasma exposure in DHA. Therefore, a 1 g daily dose of 
F373280 is considered to be appropriate for this proof of concept study. 
4.2.4. 
Choice of the Sample Size 
See chapter 13. 
5. STUDY POPULATION 
Each patient fulfilling all the inclusion criteria and none of the non inclusion criteria will be 
eligible. 
5.1. 
INCLUSION CRITERIA 
Demographic Characteristics and Other Baseline Characteristics: 
1. Men or women aged more than 18 years (inclusive) 
2. Patient with current episode of persistent AF between 7 days and 6 months duration for 
whomelectrical cardioversion is warranted 
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3. History of first documented persistent AF less than 3 years 
4. History of ischemic or non ischemic heart failure 
5.  NYHA class I or II chronic heart failure at selection and at inclusion 
6. Reduced left ventricular ejection fraction between 30% and 45% inclusive (using the two-
dimensional echocardiography biplane Simpson’s rule) at selection and at inclusion 
7. On appropriate, stable medical treatments for heart failure, including a diuretic and/or 
angiotensin-converting enzyme, and/or angiotensin-receptor blocker and/or mineralocorticoid 
receptor (MR) antagonists, and/or betablockers 
8. Left atrial area ≤ 40 cm² at selection and at inclusion 
9. Patient treated or having to be treated by anti-vitamin K 
10. For female patient of child-bearing potential:  
• in all the countries except Italy: 
 
- 
use of an effective method of contraception (hormonal contraception or intra-uterine 
device) assessed by the investigator for at least 2 months before the selection in the 
study and agreement to go on using it during the whole duration of the study and up to 
1 month after the last dose of the study treatment or 
- 
documented as surgically sterilized 
 
• in Italy only: 
- 
absolute abstention from sexual intercourse during the whole duration of the study and 
for a month after the end of the study or 
- 
use of double barrier contraception method (use of effective medical contraception 
method) from at least 2 months before the start of the study to the entire duration of the 
study and for a month after the end of the study or 
- 
documented as surgically sterilized  
 
11. For female patient of child-bearing potential: negative urine pregnancy test at inclusion 
12. For male with a child-bearing potential partner (In Italy only): 
- 
absolute abstention from sexual intercourse during the whole duration of the study and 
for 3 months after the end of the study or 
- 
use of double barrier contraception method (use of condom for male and effective 
contraception method for the partner) from the entire duration of the study to 3 months 
after the end of the study. 
 
Ethical /legal considerations: 
13. Having signed his/her written informed consent, 
14. Affiliated to a social security system, or is a beneficiary (if applicable in the national 
regulation) 
5.2. 
NON INCLUSION CRITERIA 
Criteria related to pathologies: 
1. History of first documented episode of persistent AF more than 3 years, 
2. More than two successful cardioversions (electrical or pharmacological) in the last 6 months, 
3. Secondary Atrial Fibrillation due to alcohol or severe valvular heart disease (grade III to IV), 
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4. NYHA class III or IV heart failure at selection or at inclusion 
5. Thyroid disease uncontrolled by treatment: TSH ± T4L ± T3L to be checked in case of 
treatment for thyroid disease  
6. Myocardial infarction or unstable angina or presence of unstable ischemic coronaropathy 
assessed by coronarography or cardiac stress test (Echo stress, exercise stress test, nuclear or 
MR perfusion evaluation methods) within 6 months before selection 
7. Severe chronic kidney disease (creatinine ≥ 25 mg/L or estimated glomerular filtration rate < 
30 mL/min) at selection 
8. Bradycardia (HR ≤ 50 bpm) 
9. Hyperkalemia or hypokalemia (according to the standards of local laboratories) at selection 
10. Cardiac surgery within 3 months before selection or planned during the study duration 
Criteria related to treatments: 
11. Previously ineffective pharmacological or electrical cardioversion 
12. Concomitant treatment with ranolazine or any anti-arrhythmic drug (within 7 days prior to 
selection), except stable dose of digoxin, beta-blockers, calcium-blockers. 
13. Oral amiodarone: 
13a   Previous treatment with oral amiodarone within 4 months prior to inclusion 
      13b   Intake of oral amiodarone for more than 1 month within 4 to 12 months before inclusion 
14. Previous treatment with intravenous amiodarone within 4 weeks prior to inclusion 
15. Patient requiring a cardiac resynchronization therapy (CRT) or having undergone CRT 
implantation within the last 6 months 
16. Treatment with any Polyunsaturated Fatted Acid within the last 3 months 
Dietary supplement with ω3 or ω6 according to investigator’s judgment 
18. Having undergone any form of ablation therapy for AF 
19. Patient treated with other anticoagulant treatment than antivitamin K: thrombin inhibitor such 
as Dabigatran or treated with antiaggregant P2Y12 inhibitors such as Clopidogrel or Prasugrel 
Others criteria:  
20. Patient liable not to comply with protocol instructions and/or with treatment, in the 
investigator’s opinion, 
21. Patient having taken part in a clinical trial in the preceding 2 months or taking part in a trial at 
the time of selection, 
22. Patient linguistically or mentally unable to understand the nature, objectives and possible 
consequences of the trial, or refusing to patient himself / herself to its constraints, 
23. Patient family member or work associate (secretary, nurse, technician…) of the Investigator, 
24. Patient having forfeited his / her freedom by administrative or legal award or being under 
guardianship, 
25. Breastfeeding female patient. 
5.3. 
NUMBER OF PATIENTS 
76 x 2 patients (taking into account 15 % of non evaluable patients). 
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5.4. 
RECRUITMENT MODALITIES 
Patients will be recruited within the medical consultation of each centre involved in the study. If 
necessary and when authorized by local and national regulation, some specific supports or tools 
will be used to improve the recruitment (announcement, mailing to general practitioners, leaflet, 
website including ClinicalTrials.gov, CRO…). 
Before implementation, the documents will be submitted to and approved by the Ethics 
Committee. 
5.5. 
 PATIENT IDENTIFICATION 
Patient's code will contain 7 digits: the 2 first digits corresponding to the country number, the 
following 2 digits corresponding to the centre number and the last 3 digits corresponding to the 
patient's chronological order once having signed the written informed consent. 
5.6. 
WITHDRAWAL CRITERIA 
Reasons for a patient's premature withdrawal from the study may be the following: 
• Patient's decision. A patient who wishes to withdraw from the study for any reason may 
do so at any time but must inform the investigator. In all cases, the Investigator should 
attempt to contact the patient as soon as possible for a final assessment in order to: 
− have the patient's decision written on the consent form 
− obtain the reason(s) for withdrawal and report it/them in the case report form 
− evaluate the patient's clinical condition 
− if necessary, take appropriate therapeutic measures: management of an adverse effect or 
concomitant disease, prescription of another treatment. 
• Investigator's decision in the patient's interest, particularly if a serious adverse event 
occurs and is considered by the Investigator liable to threaten the health of the patient. The 
monitor will be informed by phone or fax and a letter or report explaining the withdrawal 
will be forwarded to the monitor as soon as possible. 
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• Erroneous inclusion according to the study protocol. Any inclusion not respecting 
inclusion/non inclusion criteria will immediately be withdrawn and an appropriate 
treatment will be given by the investigator under his/her responsibility. Erroneous 
inclusions will not be paid to the investigator. 
• Patients who could not be treated with AVK for at least 3 weeks before ECV. 
• Patients who will not have a stabilized INR between 2 and 3 on at least 3 consecutive 
weekly tests. 
• Patients with only 2 consecutives INR tests between 2 and 3 in the last 3 weeks for whom 
a trans-oesophagoal echocardiography can not be performed before ECV or for whom a 
trans-oesophagoal echocardiography shows a thrombus in the atria.  
• Patients who will not revert to sinus rhythm (i.e. unsuccessful ECV) or with early relapse 
within the observation period after ECV will be considered to have finished follow-up. 
• Occurrence of AF recurrence that would require, at the investigator’s judgement, a 
cardioversion or an introduction of an anti-arrhythmic because of intolerable and/or 
uncomfortable clinical symptoms for instance. 
5.7. 
REPLACEMENT OF PATIENTS 
Withdrawn patients will not be replaced. 
5.8. 
POST-STUDY EXCLUSION PERIOD  
Patients will not be allowed to participate to another clinical trial during 3 months following the 
study termination. 
5.9. 
STUDY CARD AND LETTER FOR GENERAL PRACTITIONER(S) 
The patient will receive from the Investigating Centre at Visit 1 - Selection Visit:  
- a personal card to be kept all along the study duration and providing the following information: 
patient's name, sponsor's name, study code, EUDRACT number, start date and expected end date 
of the study, complete address of the Investigating Centre with the name and phone number of the 
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Investigator and a sponsor 24H/24 phone contact number in case of emergency (French and 
English languages): 33 (0)5 63 35 25 83. For Italy, this card will be in Italian only, without any 
English mention. 
- in Italy, a letter to be given to his/her general practitioner. This letter intends to inform the 
general practitioner(s) (and any other doctors who take care of the patient) that the patient 
participates to the clinical study. It describes the study treatment and includes some information 
on the forbidden treatment during the study.  
 
6. STUDY TREATMENT 
The Clinical Pharmacy Department of the Institut de Recherche Pierre Fabre (IRPF) will supply 
the investigational centres with the treatment necessary for the conduct of the trial.  
6.1. 
SOURCE, PRESENTATION AND COMPOSITION OF 
 
INVESTIGATIONAL PRODUCT 
F373280 and placebo will be prepared in Soft Capsules similar presentation.  
• F373280 
Formulation of F373280, 1 g, Soft Capsules: oral administration, oblong size 20, off-white, Soft 
Capsules containing: Panthenyl ester of DHA, gelatine, glycerol, titanium, dioxide, purified water. 
• Placebo 
Formulation of placebo matching tested product, Soft Capsules: oral administration, oblong size 
20, off-white, Soft Capsules containing: paraffin liquid, fish flavour, gelatine, glycerol, titanium, 
dioxide, purified water. 
 
Placebo and F373280 capsules will be packaged in opaque blisters. 
6.2. 
PACKAGING AND LABELLING 
The treatment units will be packed and labelled by the Clinical Pharmacy Department of the IRPF 
according to European Directive and local requirements. 
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6.2.1. 
Packaging 
Each treatment unit will be composed of 3 cases for a 12-week treatment period. 
The Investigator will provide the patient with the treatment according to the following schedule: 
At Inclusion Visit (V2): a 12-week treatment unit will contain 3 cases, each case containing: 
− 10 blister packs of four 1 g F373280 soft capsules or placebo soft capsules each. 
At Visit 6 (V6): a 12-week treatment unit will contain 3 cases, each case containing: 
− 10 blister packs of four 1 g F373280 soft capsules or placebo soft capsules each. 
6.2.2. 
Labelling 
Investigational Products will be labelled according to the following rules: 
Labelling should comply with the local requirements for Investigational Medicinal Products. 
On the treatment units and cases, the labels will bear the following indications:  
a) name and address of the sponsor 
b) protocol number 
c) packaging batch number 
d) treatment number 
e) storage conditions 
f) expiry date 
g) pharmaceutical dose form 
h) route of administration 
i) quantity of dosage units 
j) direction for use 
k) legal statements:  
    -“for clinical trial only”, “keep out of the reach and the sight of children”, “please return to 
your doctor any unused product”, respect the prescribed dose” 
On the treatment unit, another label will be affixed with the mention of the Investigator’s name 
and patient’s code (completed by the Investigator). 
In addition, on each case will be mentioned the case number, and a detachable label will bear the 
following indications: 
− Protocol number 
− Packaging batch number 
− Expiry date 
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− Case number 
− Treatment number 
On the blister pack, the label will mention the protocol number, the packaging batch number, the 
case number and the treatment number. 
6.3. 
DISTRIBUTION TO CENTRE AND STORAGE 
The Clinical Pharmacy Department of the IRPF will supply the Investigational Centre with the 
treatment units along the study according to the need, upon request triggered by the patient’s 
selection.  
As soon as the Pharmacist or the Investigator receives the trial medication, he/she will check the 
contents and immediately acknowledges the receipt in the IVRS/IWRS. The copy of the 
acknowledgement will be kept in the Investigator’s or the Pharmacist’s file. The same procedure 
will be applied to all further supplies during the course of the trial. 
At the time of the delivery to the Centre, the following information will be provided: 
• Details of storage conditions that should be respected 
• And, upon request and for the 1st delivery only, a letter of release for the Investigational 
Medicinal Product from the Sponsor's Qualified Person 
The CRA will ensure during the monitoring visits that trial medications have been received in 
good conditions and the acknowledgment of receipt has been performed adequately. 
Treatment units should remain intact until dispensation to the patients. They should be kept at 
temperature below 30°C in an appropriate lockable room only accessible to the person authorised 
to dispense them, under the responsibility of the Pharmacist or the Investigator. 
In the case of undue delay in study execution, the Pharmacist or the Investigator should ensure 
that the expiry date has not been exceeded.  
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6.4. 
ALLOCATION OF TREATMENTS AND DISPENSATION TO PATIENT 
A randomisation list will be established by the Clinical Pharmacy Department of the IRPF. This 
list will be computer-generated with internal software. The randomisation methodology is 
validated by the Biometry Department before generation. 
Treatments F373280 or placebo will be balanced in a 1:1 ratio. 
As the treatment units are prepared for 12-week treatment periods, the Investigator will have to 
allocate a treatment number at inclusion visit (V2) and another one at visit 6.  
For each patient, the treatment number given at visit 6 will not be the same that the one given at 
inclusion visit (V2). 
The treatment numbers will be given through the IVRS/IWRS. 
Practically, once patient’s eligibility is confirmed at selection visit (V1):  
• The Investigator: 
− Contacts the IVRS/IWRS 
− Answers the questions relating to the patient  
− In return, the treatment number to be allocated for the first 12-week period to the patient is 
given by the IVRS/IWRS.  
• The IVRS/IWRS company: 
− Confirms this information by fax/email to the Investigator 
− Fills the “Request for Delivery of Investigational Product” form and sends it by email 
and/or fax to the Clinical Pharmacy Department of the IRPF.  
• The Clinical Pharmacy Department of the IRPF sends the corresponding treatment unit to 
the Investigator within 5 days from reception of the email request form. 
The Investigator will dispense to the patient the case which label indicates the treatment number 
and the administration period. 
At visit 6, the Investigator will contact again the IVRS/IWRS to obtain the treatment number for 
the last 12-week period of treatment according to the same process as described above. 
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6.5. 
DRUG ADMINISTRATION 
6.5.1. 
Duration of Treatment 
For a patient completing the study, the theoretical study treatment exposure to F373280 or 
placebo will be 24 weeks. 
If the ECV is postponed by 1 week to allow INR stabilization, the treatment duration will be 25 
weeks. 
6.5.2. 
Dose Schedule 
One soft capsule of 1g of F373280 or placebo to be taken each day during 24 weeks. 
6.5.3. 
Route and Conditions of Administration 
The soft capsules are to be taken orally. One soft capsule is to be taken each evening with the 
dinner during 24 weeks.  
6.6. 
ACCOUNTABILITY ON SITE AND RETURN/DESTRUCTION OF 
 
INVESTIGATIONAL PRODUCT 
The Investigator should maintain accurate written records of drug received, dispensed, returned 
and any remaining treatment units, on the drug accountability form. These records should be made 
available for Clinical Research Associate (CRA) monitoring. The packaging of the medication 
should remain intact until just before the dispensation. 
At each visit, the Investigator will record the number of soft capsules returned by each patient 
using the appropriate page of the e-CRF. 
At the end of the study, all used and unused treatments including packaging should be noted, and 
return is organised by the CRA to the Clinical Pharmacy Department of the IRPF for destruction. 
A copy of the drug accountability form should be provided by the Investigator to the CRA. 
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6.7. 
RECALL OF INVESTIGATIONAL PRODUCTS  
In case of recall of investigational products (decided by the Competent Authorities or the 
Sponsor), the Investigator will immediately be informed by the Sponsor. 
The Investigator in collaboration with the Sponsor’s representatives (Study Manager, CRA) must 
urgently: 
• Stop the delivery of the concerned investigational products to the patients. 
• Inform the concerned patients that they must immediately stop taking these investigational 
products and bring them back. 
The Study Manager/CRA organises the return of the recalled products to the Clinical Pharmacy 
Department of the IRPF according to the Sponsor’s procedures. 
7. CONCOMITANT TREATMENTS 
Any existing concomitant treatment (at selection visit), any new concomitant treatment or change 
in the dosage of an existing concomitant treatment during the course of the study must be noted 
on the electronic Case Report Forms (e-CRF). All treatments should be evaluated by the 
Investigator at patient’s selection, and treatment prolongation or stop during the study should be 
considered. 
For all concomitant treatments taken during the study, the following information must be noted in 
the relevant section(s) of the e-CRF: 
• The name of the treatment and its form 
• The reason for prescription 
• The route of administration 
• The daily dose 
• The duration of treatment. 
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7.1. 
ANTI-VITAMIN K TREATMENT 
AVK should be given for at least 3 weeks before ECV and continued for the whole study 
duration. The AVK used will be left to the decision of the each Investigator according to his/her 
local practice. 
7.2. 
PROHIBITED TREATMENTS 
- 
Class I and class III antiarrhythmic treatments: 
− Class I 
- 
Class IA: Disopyramide, Procainamide, Quinidine 
- 
Class IB: Lidocaine, Mexiletine 
- 
Class IC: Flecainide, Propafenone 
 
− Class III: Dofetilide, Ibutilide, Sotalol, Amiodarone, Dronedarone. 
 
- 
Ranolazine 
- 
Any PUFA 
- 
Any anticoagulant treatment other than AVK: thrombin inhibitor such as Dabigatran or 
antiaggregant P2Y12 inhibitors such as Clopidogrel or Prasugrel 
- 
Dietary supplement with Omega 3 or Omega 6 
Prohibited treatments at selection must not be prescribed for the duration of the study except in 
case of occurrence of an adverse event or AF episode that requires a corrective treatment in the 
interest of the patient’s health. 
7.3. 
AUTHORISED TREATMENTS 
Other treatments will be authorised during the study duration. 
However, if medication other than study drugs is administered at any time from the start of the 
study, details must be recorded in the e-CRF. During the study, patients must be asked whether 
they have been on a course of prescribed drug treatment or have taken any OTC or herbal drugs 
since the visit. 
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8. EVALUATION CRITERIA 
8.1. 
PRIMARY EFFICACY CRITERION  
8.1.1. 
Time to the first Atrial Fibrillation Recurrence 
8.1.1.1. 
Definition 
Time to first AF recurrence is defined by the first episode of AF (symptomatic or not) lasting for 
at least 10 minutes. 
8.1.1.2. 
Schedule 
The heart rhythm follow up will be performed from the end of ECV visit (visit 3) to the final 
study visit (visit 9).  
For randomised patients with spontaneous cardioversion before ECV, the recurrence of AF will be 
assessed after visit 3 (week 5). 
8.1.1.3. 
Evaluation Methods 
• 7-day holter monitor: 
The heart rhythm monitoring will be carried out from visit 3 to visit 4 using a 7-day continuous 
ECG (5-leads/2 or 3 channels) ambulatory recording (holter ECG) fixed after ECV visit. 
Following holter monitoring, the heart rhythm will be documented using Trans Telephonic ECG 
Monitoring (TTEM). 
• Trans Telephonic ECG Monitoring: 
The ECG follow up will be documented using the TTEM: daily transmission from the day after 
visit 4 (week 6) to visit 5 (week 8). Then every two days from the day after visit 5 (week 9) to 
visit 9 (week 24 – End of study). 
Moreover, if patient experiences AF symptoms during this TTEM period, it should be 
documented using the TTEM. 
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In case of AF recurrence and provided that the patient does not required a cardioversion or an 
introduction of an anti-arrhythmic at Investigator’s judgement, the patient could be maintained in 
the study with the treatment in order to assess a spontaneous cardioversion. For that purpose the 
patient will continue to transmit a TTEM once a week. 
The TTEM will be centralized by the Central Reading Laboratory. The patient will be requested 
to contact the Central Reading Laboratory for transmission of each stored TTEM. The TTEM will 
be validated by a trained technician, then analysed by a cardiologist. The cardiologist 
interpretation will be emailed to the site (or per fax on request of the site). The investigator will be 
asked to review and sign this document. 
The TTEM process will be fully described in a separate document. 
8.1.2. 
Secondary Efficacy Criteria 
8.1.2.1. 
Numbers of AF episodes in the first week following visit 3 (ECV visit) 
8.1.2.1.1. 
Definition 
Number of AF episodes will consist in the assessment of AF episodes with duration at least 10 
minutes (NSup10) and of less than 10 minutes (NInf10), respectively. 
8.1.2.1.2. 
Schedule 
The heart rhythm follow up will be performed from the end of successful ECV visit (visit 3) to the 
study visit 4.  
8.1.2.1.3. 
Evaluation Methods 
• 7-day holter monitor: 
The heart rhythm monitoring will start using a 7-day continuous ECG (5-leads/2 or 3 channels) 
ambulatory recording (holter ECG) after ECV visit from visit 3 to visit 4. 
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8.1.2.2. 
Duration of AF episodes in the first week following visit 3 (ECV visit) 
8.1.2.2.1. 
Definition 
Duration of AF episodes will consist in the sum of duration of each AF episode. 
8.1.2.2.2. 
Schedule 
The heart rhythm follow up will be performed from the end of successful ECV visit (visit 3) to the 
follow up study visit (visit 4).  
8.1.2.2.3. 
Evaluation Methods 
Duration of AF episodes will be assessed using the 7-day continuous ECG (5-leads/2 or 3 
channels) ambulatory recording. 
8.1.2.3. 
Clinical parameters evaluation 
8.1.2.3.1. 
EHRA score assessment 
8.1.2.3.1.1. Definition 
AF related symptoms will be evaluated by the EHRA (European Heart Rhythm Association) score 
[20]. The following items “during presumed arrhythmia episodes" are checked to determine the 
score: palpitation, fatigue, dizziness, dyspnea, chest pain and anxiety. 
Classification of AF-related symptoms (EHRA score) are as follows: 
• EHRA I          - ‘No symptoms’ 
• EHRA II         - ‘Mild symptoms’; normal daily activity not affected 
• EHRA III       - ‘Severe symptoms’; normal daily activity affected 
• EHRA IV       - ‘Disabling symptoms’; normal daily activity discontinued  
This classification relates exclusively to the patient-reported symptoms. 
In addition to this score, the frequency will be classified in three groups, namely occasionally 
(less than once per month), intermediate (1/month to almost daily) and frequent at least daily. 
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8.1.2.3.1.2. Schedule 
EHRA evaluation will be performed in case of evocative symptoms of arrhythmia. 
8.1.2.3.1.3. Evaluation Methods 
EHRA evaluation will be collected by Central Reading Laboratory during all the study period. 
8.1.2.3.2. 
Number of recurrence of symptomatic AF  
It consists of the number of AF recurrences associated with a symptom (palpitation, fatigue, 
dizziness, dyspnea, chest pain and anxiety) and confirmed by an ECG. 
8.1.2.3.3. 
Number and duration of hospitalizations 
• Number and duration of hospitalizations for cardiovascular events 
− Hospitalization for AF treatment 
− Hospitalization for worsening of heart failure 
− Hospitalization for myocardial infarction 
− All cause of hospitalization 
• Number and duration of hospitalizations for thromboembolic stroke  
8.1.2.4. 
Cardioversion assessment 
• Assessment of spontaneous cardioversion before visit 3 
• Assessment of successful cardioversion at visit 3 (i.e. return to sinus rhythm) 
• Shocks distribution (1, 2 or 3 shocks) 
• Number of patients needing another cardioversion after initial ECV 
8.1.2.5. 
Evolution of echocardiographic parameters 
8.1.2.5.1. 
Definition 
The following echocardiographic parameters will be assessed: Left atrial diameter (mm), LAA 
(cm2), Left atrial volume (mL), Left atrial volume/BSA (mL/m2), LVEF (%), Left ventricular end 
diastolic volume/BSA (mL/m2), Left ventricular end systolic volume/BSA (mL/m2), Left 
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ventricular end diastolic diameter (mm), Left ventricular end diastolic volume (mL), Left 
ventricular end systolic diameter (mm) and Left ventricular end systolic volume (mL). 
8.1.2.5.2. 
 Schedule 
Measurements will be performed at visit 1 and visit 2 to check the eligibility of the patient.  
Measurements performed at visit 4, visit 6 and visit 9 are done to follow the echocardiographic 
evolution of the patients in sinus rhythm. 
8.1.2.5.3. 
Evaluation method 
The echography evaluations will be carried out according to the recommendations for chamber 
quantification drawn up by the American Society of Echocardiography and the European 
Association of Echocardiography [23]. So, the recommended method for volume measurements is 
to use the biplane method of discs (modified Simpson’s rule) from 2-D measurement. 
8.2. 
BIOMARKER ASSESSMENT: RED BLOOD CELL 
 
CONCENTRATIONS OF DHA 
8.2.1. 
Definition 
Because of the limited human tissue accessibility for biopsy, red blood cell DHA contents is a 
marker of tissue DHA concentration [13], [14]. 
8.2.2. 
Blood samples 
8.2.2.1. 
Collection schedule 
Blood samples will be collected to determine the red blood cells (RBC) concentrations of DHA.  
Blood samples will be performed at visit 2 before treatment, visit 3, visit 6 and visit 9. 
Actual sampling times will be individually reported in the e-CRFs. 
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8.2.2.2. 
Technical handling 
Two blood samples (4 ml) will be collected in EDTA tubes. They will be gently shaken, stored 
between +2°C/+8°C in a fridge (no freezing will be allowed) and sent to Analytical Centre in 
refrigerated conditions (between +2°C and +8°C). Analysis will be performed within 2 weeks 
following reception at the Analytical Centre. 
8.2.3. 
DHA concentration measurement 
Analytical determination of RBC concentrations of DHA will be carried out by the Analytical 
Centre. 
Lipids will be extracted from red blood cells samples with a mixture of hexane/isopropanol after 
acidification [17]. Total lipid extracts will be saponified and methylated. The fatty acid methyl 
esters (FAME) will be extracted and analyzed by Gas Chromatography. 
Identification of FAME will be based on retention times obtained for FAME prepared from fatty 
acid standards. The area under peaks will be determined using ChemStation Software (Agilent) 
and results will be expressed as % of total fatty acids. DHA concentration will be calculated using 
the internal standard and expressed as µg/g for red blood cells samples. Thus, omega-3 index will 
be assessed. The omega-3 index represents the content of EPA plus DHA in red blood cells 
(expressed as a percent of total fatty acids). It is a biomarker considered as a new marker of risk 
for death from coronary disease [18]. 
Results of this analytical determination will be kept confidential by the dosing centre until the end 
of the study, and will be provided only at the end of the study (after database lock) in a separate 
file. 
8.3. 
SAFETY ASSESSMENT 
8.3.1. 
Adverse Events 
At selection, any concomitant disease will be reported on the e-CRF. At each further visit, the 
occurrence of AEs since the last visit will be based on the patient's spontaneous reporting, the 
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Investigator's non-leading questioning and his/her clinical evaluation. All AEs will be reported on 
the e-CRF (see section 10). 
8.3.2. 
Laboratory Investigations 
8.3.2.1. 
Schedule 
Laboratory investigations will be performed at visit 1 (before treatment) and visit 9 (end of 
treatment) or End of Treatment visit. 
At visit 3 and 6, only a standard haematologic dosage will be performed.  
Furthermore the kaliemia will be checked before electrical cardioversion at visit 3. 
The total volume of blood samples taken for haematology and biochemistry analysis should not 
exceed 30 mL. 
8.3.2.2. 
Technical Procedures and Parameters 
The following tests will be performed: 
 
Haematology: 
hematocrit, haemoglobin, RBC count, white blood cells (WBC) count, WBC 
differential counts (% and absolute), reticulocytes, platelets.  
 
Chemistry: 
sodium, potassium, bicarbonate, chloride, alkaline phosphatase, gamma GT, 
albumin, total bilirubin, conjugated bilirubin, creatinin, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), fasting glucose, 
total cholesterol, cholesterol (HDL, LDL), triglycerides, creatine 
phosphokinase (CPK), fibrinogen. 
Blood samples will be taken in the morning in fasting conditions.  
The estimation of GFR at selection relies on the measurement of serum creatinine and the 
Cockcroft- Gault formula: 
Cockcroft-Gault formula 
- with serum creatinine expressed as mg/L:  
in men: 
GFR (mL/min) = [(140-age) x weight / (7.2 x serum creatinine in mg/L)] 
 
in women: 
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GFR (mL/min) = [(140-age) x weight / (7.2 x serum creatinine in mg/L)] x 0.85 
 
- with serum creatinine expressed as μmol/l: 
GFR (mL/min) = [(140-age) x weight / serum creatinine in μmol/l] x k,where k = 1.23 for men, 
1.04 for women. 
 
(weight in kg, age in years) 
Additional tests may be done at the Investigator’s discretion, in the patient’s interest. In case of 
any abnormal or clinically significant results, the Investigator will order laboratory control tests. 
8.3.3. 
Global Physical Examination 
A global physical examination including the measurement of body weight will be carried out on 
each body system at visit 1, visit 2, visit 3, visit 5, visit 6, visit 7, visit 8 and visit 9. 
The Body surface area (BSA) will be calculated at the same visits using Mostellers’ formula: 
BSA = [(Weight x Height)/3600]1/2 
(Weight in kg, height in cm) 
The physical examination will be globally evaluated as “normal/abnormal”. Further target 
inspection will be undertaken for any abnormal finding. 
8.3.4. 
Vital Signs 
Vital signs will consist in blood pressure and heart rate at rest.  
8.3.4.1. 
Schedule 
Vital signs will be measured at each visit. 
8.3.4.2. 
Technical Procedure and Parameters 
Systolic blood pressure (SBP) and diastolic blood pressure (DBP), expressed in mmHg, will be 
measured after at least 5 minutes in supine position and after 2 minutes in standing position.  
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The heart rate (HR), expressed in beats per minute (bpm), will be measured by auscultation by 
counting the beats for at least 30 seconds, after at least 5 minutes in supine position and after 2 
minutes in standing position. 
Bodyweight will be measured with patient in underwear and with the same balance at each visit.  
8.3.5. 
Electrocardiogram (ECG)  
8.3.5.1. 
Schedule 
An ECG will be recorded after at least 10 minutes of rest at visit 1, visit 2, visit 3, visit 5, visit 6, 
visit 7, visit 8 and visit 9 using an usual standardised 12-lead cardiograph. 
8.3.5.2. 
Technical Procedure and Parameters 
• Electrocardiogram: 
The global interpretation from manual reading (normality, clinical relevance) and HR (bpm), PR 
(ms), QRS (ms), QT (ms), QTcB (ms), QTcF (ms), repolarisation patterns will be reported in the 
e-CRF. Each print-out will include the patient’s code, date, time, technician's initials and 
investigator's signature. 
In case of thermic paper ECG print out, a photocopy will be made by the centre to ensure safe 
filing. 
• 24 hour-Holter - ECG 
An ambulatory continuous 24-hour ECG (5-leads/2 or 3 channels) will be recorded at selection 
visit using a holter ECG, in order to confirm persistent AF.  
8.3.6. 
Coagulation parameters 
Coagulation assessment will be evaluated by the following parameters: 
− Prothrombin Time/INR (PT/INR) 
− Activated Partial Thromboplastin Time (aPTT) 
− Thrombin Clotting Time (TCT) 
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During the pre-cardioversion period, if the anticoagulation by AVK should be initiated, then the 
INR monitoring will be as follow:  
− INR 2-3 times a week for the first week of treatment 
− INR weekly up to ECV 
− INR every 4 weeks after ECV 
For patients already treated with AVK, INR monitoring will be as follow: 
− INR weekly up to ECV 
− INR every 4 weeks after ECV 
aPTT and TCT will be performed at visit 1, visit 2, visit 3, visit 5, visit 6, visit 7, visit 8 and visit 
9. 
Anti-coagulation by AVK should be given at least 3 weeks before ECV and continued for the 
whole study duration. 
The quantity of blood samples collected at each time for coagulation parameters will be 2 mL. 
8.4. 
CONCOMITANT TREATMENTS 
Concomitant treatments will be evaluated at each study visit. 
Requirements relating to patient's concomitant treatments started before screening visit and 
continued throughout the trial, or started during the trial, can be found in section 7.  
8.5. 
COMPLIANCE 
The patient will be reminded at each visit to bring back at the following visit any used or unused 
remaining soft capsule, blister and case. 
At each visit (except at visit 4), the Investigator will record the number of supplied and remaining 
soft capsules in the e-CRF. 
9. STUDY PROCEDURES 
Visit 1 - Selection Visit (Week -4 to Week -1) 
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The patient considered eligible for selection by the Investigator will be informed of the 
characteristics and the consequences of the trial both verbally and by reviewing the patient's 
information sheet and consent form (see section 14.3). If the patient accepts to participate in the 
study, he/she will sign the informed consent form and will keep a copy. 
The patient will be assessed for the following: 
• Demographic characteristics (gender, age, height, body surface area) 
• Personal and medico-surgical history 
• Habits (Tobacco, alcohol consumption, dietary habits including fish consumption…) 
• Cardiovascular diseases, mainly detailed history of Heart Failure and AF characteristics  
• Echocardiography using a two-dimensional echocardiography 
• 12-lead ECG 
• Concomitant diseases, adverse signs or symptoms (able to be used for treatment emergent 
AE determination) 
• Concomitant treatments (authorised, disallowed) 
• Global physical examination/bodyweight 
• Vital signs 
• Biology: haematology, biochemistry, assessment of coagulation parameters: Prothrombin 
Time/INR (PT/INR), Activated Partial Thromboplastin Time (aPTT), Thrombin Clotting 
Time (TCT) 
• Biology assessment of renal function: creatinine or estimated glomerular filtration rate 
If the results of the above assessments are compatible with the selection criteria 
• A 24-hour continuous ECG ambulatory recording (Holter ECG) device will be installed 
on the patient to monitor the patient heart rhythm. The patient will be requested to bring 
back the device after the termination of 24 hours recording. The recording will be 
transmitted from the Investigational site to the Central Reading Laboratory. The Central 
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Reading Laboratory will send his/her assessment regarding the confirmation of persistent 
AF within 2 working days to the Investigator. 
• The patient will enter the selection period in which anticoagulant (AVK) will be adjusted 
to achieve an International Normalized Ratio (INR) of 2 to 3 before ECV.  
At the end of the visit, the Investigator will contact the IVRS/IWRS to confirm the patient 
selection (which will automatically order the treatment delivery) and organise the appointment for 
the next visit.  
The patient will receive from the investigational centre the study card to be kept for the duration 
of the study. 
Visit 2 - Inclusion Visit (Day 1)  
If the patient's behaviour during the selection period and/or the result of complementary 
examinations particularly the confirmation of the presence of persistent AF by the Central 
Reading Laboratory during this period, the INR and laboratory tests, are compatible with the 
inclusion criteria, the patient will be assessed for the following: 
• Adverse events 
• Concomitant treatments (authorised, disallowed) 
• Laboratory examination: red blood cell concentrations of DHA and coagulation 
parameters Prothrombin Time/INR (PT/INR), Activated Partial Thromboplastin Time 
(aPTT), Thrombin Clotting Time (TCT) 
• Global Physical examination/bodyweight 
• Vital signs 
• Echocardiography using a two-dimensional echocardiography 
• 12-lead ECG 
• Urine pregnancy test for women of child bearing potential 
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If the results of the above assessments are compatible with the inclusion criteria, the patient will 
be included and allocated a treatment number using the IVRS/IWRS.  
Between this Inclusion visit and the next visit (V3), the INR will be closely monitored (refer to 
paragraph 8.3.6) in order to ensure that the INR is stable (between 2 to 3 before electrical 
cardioversion). 
At the end of the visit, the Investigator will organise the appointment for the next visit and will 
give the treatment for the next 4-week period. 
Visit 3 (Week 4: D28 -2/+7 days) cardioversion 
Patient will be assessed for the following criteria: 
• Adverse events 
• Concomitant treatments (authorised, disallowed) 
• Laboratory examination: Haematology, RBC concentrations of DHA, Prothrombin 
Time/INR (PT/INR), Activated Partial Thromboplastin Time (aPTT), Thrombin Clotting 
Time (TCT) 
• Global Physical examination /bodyweight 
• Vital signs  
• 12-lead ECG 
• Electrocardioversion (ECV): ECV has to be scheduled 4 weeks after randomization and 
after target international normalized ratio levels will be stabilized (between 2 and 3) on at 
least 3 consecutive weekly tests in patients with AF. Patients not stabilized for INR (i.e. 
values not between 2 and 3) on at least 3 consecutive weekly tests before ECV will be 
excluded from the study, unless the presence of atrial thrombosis may be excluded with 
ECHO –TE performed in the same day (and before ECV). ECV will be performed in the 
morning, with the patient in the fasting state and without dyskalemia. Anesthesia will be 
induced and patients will be cardioverted with administration of a synchronized, biphasic 
current. The initial shock will be set at 100 J if the body weight is less than 70 kg and at 
150 J for higher body weights. Successful cardioversion will be defined as recovery of 
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sinus rhythm lasting at least 1 minute after the shock. If unsuccessful, a second 200-J 
shock, and eventually a third 200-J shock, will be administered. Failure of ECV is defined 
as the persistence of AF after the third attempt at cardioversion. After the procedure, 
patients will be monitored on telemetry for at least 6 hours before discharge. Patients who 
will not revert to sinus rhythm or with early relapse within the observation period after 
ECV will be withdrawn from the study and will be considered to have finished their 
follow-up. 
At the end of the visit, a 7-day continuous ECG (5-leads/2 or 3 channels) ambulatory recording 
(holter ECG) will be installed on the patient in order to monitor the patient heart rhythm after 
ECV.  
At the end of the visit, the Investigator will organise the appointment for the next visit and give 
the treatment to be taken during the next 4-week period. 
Visit 4 (Week 5: D35 -2/+7 days) 
After removal of the continuous ECG ambulatory device, the patient will be assessed for the 
following criteria: 
• Assessment of AE 
• Concomitant treatments (authorised, disallowed) 
• Body weight (body weight measured at V3 to be used) 
• Vitals Signs 
• Echocardiography using a two-dimensional echocardiography 
At the end of the visit, the patient will be given the TTEM device for cardiac monitoring. The 
patient will be clearly instructed on the frequency and modalities of transmission. The patient will 
be requested to perform daily transmission from the day after visit 4 (week 6) to visit 5 (week 8), 
then every two days from the day after visit 5 (week 9) to visit 9 (week 24 – End of study). 
Moreover, in case of AF symptoms, additional transmissions may be performed.  
 
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Visit 5 (Week 8: D56 ± 7 days) – Visit 6 (Week 12: D84 ± 7 days) - Visit 7 (Week 16: D112 ± 
7 days) - Visit 8 (Week 20: D140 ± 7 days) 
Patient will be assessed for the following criteria: 
• Adverse events 
• Concomitant treatments (authorised, disallowed) 
• Laboratory 
examination: 
Prothrombin 
Time/INR 
(PT/INR), 
Activated 
Partial 
Thromboplastin Time (aPTT), Thrombin Clotting Time (TCT). However, in case of 
discontinuation of anticoagulation after ECV, the monitoring of INR, aPTT and TCT 
should be stopped. 
• Global Physical examination/bodyweight  
• Vital signs  
• 12-lead ECG 
• The cardiac monitoring will be continued using a TTEM device. The device will be given 
to the patient who will be requested to perform daily transmission from the day after visit 
4 (week 6) to visit 5 (week 8), then every two days from the day after visit 5 (week 9) to 
visit 9 (week 24 – End of study). Moreover, in case of AF symptoms, additional 
transmissions may be performed. 
The Investigator will collect all unused cases, blisters and soft capsules, and will count the unused 
capsules for each 4-week treatment period. 
At the end of the visit, the Investigator will organise the appointment for the next visit and give 
the treatment to be taken during the next 4-week treatment period. 
In addition: 
- at visit 6: 
• the investigator will contact the IVRS/IWRS to obtain the treatment unit number to 
be dispensed at visit 6 for the last 12-week period. 
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• an echocardiography will be performed, an haematology examination will be done 
and the RBC concentration of DHA will be measured.  
 
End-of-Study Visit - Visit 9 (Week 24: D168 ± 7 days) 
Patient will be assessed for the following: 
• Adverse events 
• Concomitant treatments (authorised, disallowed) 
• Global Physical examination/bodyweight 
• Vital signs 
• 12-lead ECG 
• Laboratory examination: haematology, biochemistry, assessment of coagulation 
parameters: Prothrombin Time/INR (PT/INR), Activated Partial Thromboplastin Time 
(aPTT), Thrombin Clotting Time (TCT), Red blood cell concentration of DHA. 
• Urine pregnancy test for women of childbearing potential 
• Echocardiography using a two-dimensional echocardiography 
The Investigator will collect all unused cases, blisters and soft capsules, and will count the unused 
soft capsules. 
10. ADVERSE EVENTS: DEFINITION AND REPORTING 
10.1. ADVERSE EVENTS 
10.1.1. Definition of Adverse Events 
An AE is any adverse change from the patient's baseline condition, i.e. any subjective signs and 
symptoms or change in a concomitant disease present at the Selection Visit considered or not 
related to the treatment. 
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AE includes intercurrent signs, symptoms, illnesses and significant deviations from baseline for 
vital signs and laboratory values which may occur during the course of the clinical study. 
All laboratory tests for which abnormal results are collected after study treatment initiation should 
be repeated until the values return to normal or to a stable status. Abnormal results are defined as 
those falling out of the laboratory normal ranges and that are clinically significant. The frequency 
of such checks should be defined by the Investigator according to the degree of abnormality. 
In all cases, the aetiology should, as much as possible, be identified and Pierre Fabre Médicament 
notified. 
10.1.2. Grading of Adverse Events 
Adverse or intercurrent events are graded as follows: 
• Mild: awareness of signs or symptoms, but easily tolerated 
• Moderate: uncomfortable enough to cause interference with usual activity 
• Severe: incapacity with inability to work or do usual activity 
10.1.3. Reporting of Adverse Events 
The records of AE in the e-CRF describe the nature (diagnosis, signs and symptoms), severity, 
onset date, stop date, outcome and actions taken, and relationship to study treatment (in the 
Investigator's opinion). It must be specified whether the event is serious or not. 
10.2. SERIOUS ADVERSE EVENTS (SAE) 
10.2.1. Definition 
A SAE includes, but is not necessarily restricted to, any event which: 
• Results in death (whatever may be the cause) 
• Is life-threatening 
• Results in persistent or significant disability/incapacity 
• Requires the patient's hospitalisation or prolongation of current hospitalisation * 
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• Is a congenital anomaly or birth defect 
Other events such as cancer and any additional adverse experience or abnormal laboratory values 
occurring during the study period, defined by the protocol as serious or which the Investigator 
considers significant enough or that suggest a significant hazard, contra-indications, side effect or 
precaution, must be handled as serious adverse events. 
Any overdosage meeting a seriousness criteria should be reported as a SAE (see section 10.3). 
Any pregnancy occurring during/after exposure to the study drug(s) should be reported on the 
SAE notification form (see section 10.4). 
* any hospitalisation, or prolongation of hospitalisation due to the circumstances listed below: 
− planned (as per protocol) medical/surgical procedure 
− preparation for routine health assessment/procedure (e.g. routine colonoscopy) 
− planned medical/surgical admission (planned prior to entry into study trial, appropriate 
documentation required) 
− administrative or social reasons (e.g. lack of housing, economic inadequacy, care-giver 
respite, family circumstances) 
will not be reported as a SAE. 
10.2.2. Reporting of SAE 
All Serious Adverse Events, according to the above-mentioned definitions and regardless of 
treatment or relationship to study drug, and occurring once the informed consent form has been 
signed, must be reported by the Investigator as soon as he/she is informed of the event. 
The Investigator must notify the Sponsor of this event by sending, within 24 hours, the 
"Notification of serious adverse event" form ("first notification") with all the available 
information about the event (see appendix 17.2), to the Sponsor's Corporate Vigilances e-mail 
dedicated box: 
HQ.pharmacovigilance@pierre-fabre.com 
 
 In case it is not possible to send the report by e-mail it can be sent by FAX at the 
following number: 
+ 33 1 49 10 80 90 
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In case of non-inclusion, the reporting period ends when the non-inclusion is documented. 
10.2.3. Follow-up of SAE 
The Investigator must draw-up a specific clinical report and use the "Notification of serious 
adverse event" form ("follow-up") (see appendix 17.2) and collect the results of the carried out 
examinations and the reports of hospitalisation. 
The serious adverse events must be followed up until resolution or stabilisation. 
10.2.4. SAE Occurring After the Study 
Any SAE occurring during 30 days following the end of the study for the patient should be 
notified to the Sponsor. 
Must also be notified to the Sponsor any event occurring at any time after the end of the study for 
the patient which may be related to the study treatment in the Investigator's opinion. 
10.3. REPORTING OF OVERDOSAGE TO THE SPONSOR 
For the purpose of this trial, an overdosage will be defined as any dose exceeding the planned 
prescribed dose of the study drug or the administration of any dose of an associated product that is 
considered both excessive and medically important. 
In the absence of seriousness criteria, the overdosage and associated adverse event if any, are 
reported only on the Adverse Event page of the e-CRF. If the definition of seriousness criteria is 
met, the SAE notification form must also be transmitted to the Sponsor. 
10.4. REPORTING OF PREGNANCY TO THE SPONSOR 
Pregnancies discovered in the period in between the informed consent form signed but before any 
study drug exposure are not to be reported to the Sponsor unless associated to a seriousness 
criteria (e.g. serious adverse event study-protocol related procedure). If pregnancy is confirmed, 
the women must not be administered the study drug and must be withdrawn immediately from the 
study.  
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If pregnancy is suspected while the patient is receiving study treatment, the study drug should be 
discontinued immediately until the result of the pregnancy testing is known. If pregnancy is 
confirmed, then the study treatment is permanently discontinued in an appropriate manner and the 
patient is withdrawn from the study.  
The Investigator must report to the Sponsor any pregnancy which occurs during or after the 
patient has been exposed to the study drug and until 30 days after the last study drug 
administration. The Investigator must immediately notify the Sponsor using the SAE notification 
form and also report the pregnancy on the AE page of the e-CRF. 
Women who become pregnant after exposure to the study drug must be followed by the 
Investigator until the completion/termination of the pregnancy. If the pregnancy goes to term, the 
outcome will have to be reported to the Sponsor (baby's healthy status). 
10.5. SPONSOR'S RESPONSIBILITIES FOR SAFETY REPORTING 
 
PURPOSES 
Sponsor will submit expedited and periodic reports to both Competent Authorities and Ethics 
Committees per corporate standard operating procedures as regards to the EU directive 
2001/20/EC taking into account local specific requirements. 
11. DATA COLLECTION AND STUDY MONITORING 
11.1. DATA COLLECTION 
11.1.1. Case Report Form 
An e-CRF will be used to record all patient data required by the protocol except the central ECG 
(Holter ECG, TTEM) and DHA data which will be transferred from vendors to the subcontractor 
as electronic data files that will be loaded into the study database.  
The e-CRF should be fully validated, compliant with ICH-GCP requirements and European 
regulations and should include a traceability system for data corrections and deletions (audit trail). 
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Prior to the start of the study, the Investigator will complete a "Delegation of significant study-
related duties" form. The signature and initials of all personal in charge of e-CRF completion 
should be recorded on this form. Each person involved in e-CRF completion, review, correction 
and / or validation will be trained and will have an individual login and access code to the e-CRF. 
Training sessions will be held by the subcontractor for all participants using this tool. An e-CRF 
user manual will be available for investigators and CRAs.  
All the information included into the e-CRF will be recorded from source documents onto the e-
CRF by an authorised person. 
The Investigator is responsible for the management and accuracy of the information on the e-
CRF. At each monitoring visit, the e-CRF(s) should be at the CRA's disposition for review and 
validation.  
At the end of the study, a CD-ROM containing the pdf version of all e-CRFs (including audit-
trail) will be sent by the subcontractor to the Sponsor and to the investigational sites for archiving. 
The subcontractor must store all study data for at least 15 years after the end of the study and 
ensure their legibility and accessibility during all the storage period. 
11.1.2. Source Documents 
A source document is an original record or certified copy of an original record of clinical findings, 
observations or any other medical or paramedical activities performed during the clinical trial, 
necessary for the transcription and the verification of the collected data. 
Source documents along with all other trial-related documents (copies of all "informed consent" 
forms, e-CRFs CD-ROM, drug inventories and any correspondence related to the study) must be 
kept in the investigator's file throughout the study, and then, must be stored in the study centre's 
archives for a period of at least 15 years or as per local legal requirements, whatever is the 
longest.  
For further details see section 15.2. 
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11.2. STUDY MONITORING 
11.2.1. Monitoring visits 
On-site visits will be carried out by a representative of the Sponsor's staff (Study Manager or 
CRA) prior to study initiation and at regular intervals (every 4 to 6 weeks) throughout the study. 
Additional visits and communication by telephone fax or meeting may be performed if necessary. 
Any site visit performed by the Sponsor's representatives will be recorded in the Investigator's 
study file. 
11.2.1.1. 
Site Preselection Visit 
Before selecting a centre for the study, a visit will be carried out by the CRA and/or the Study 
Manager to ensure that the Investigator has the necessary capacities (availability, patient's 
recruitment, environment), technical means and staff to carry out the study. 
11.2.1.2. 
Initiation Visit 
Before the start of the study at all investigational sites, an initiation visit will be carried out by the 
CRA to check at the latest that: 
• The Investigator: 
− has received the technical protocol, administrative and financial agreement signed by all 
parties 
− has received the written statement of the Ethics Committee approval and the list of its 
members and their functions 
• The original dated and signed curriculum vitae of the investigator(s) has been collected 
• Laboratory normal ranges have been collected  
• All study materials are available on the study site 
• All participants agree with the monitoring procedures and know the study procedures 
• All participants are aware of a possible audit or inspection 
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The CRA has also to provide training on the study protocol requirements and study specific 
procedures. 
11.2.1.3. 
Follow-up Visits 
Throughout the study, regular follow-up visits will be carried out by the CRA to check 
compliance with GCP, patient’s informed consents, strict application of the protocol, conformity 
of the data entered on the e-CRF with the source documents and ensure its correct completion, 
adverse events reporting, proper retention, storage and management of the study medication, as 
well as the source and other trial-related documents. 
11.2.1.4. 
Closing Visit 
At the end of the study, a final visit will be carried out by the CRA to: 
• Verify that the e-CRFs CD-ROM with pdf files are correctly stored 
• Control the accountability of intact and used treatment units and return them to the 
Clinical Pharmacy Department of the IRPF for destruction 
• Obtain the last data clarifications and/or solutions if any 
• Collect the patient's consent forms in sealed envelopes (except in case of specific country 
requirements),  
• Make an on-site review of all study documentation and complete it if necessary 
• And finally, remind the Investigator of his regulatory obligations, study document 
archiving process and duration. 
11.2.2. Direct Access to Source Documents 
In accordance to the requirements of the GCP, all Sponsor representatives (Study Manager, CRA 
and Auditors) have to be given a direct access to all source and study data to perform quality 
monitoring/audit, thus ensuring accuracy and completeness of data).  
Investigators are reminded that all Sponsor representatives keep professional confidentiality with 
regards to the patient data. 
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11.3. INDEPENDENT DATA MONITORING COMMITTEE 
An Independent Data Monitoring Committee (IDMC) will be established to assess at intervals the 
progress of the clinical trial, the compliance with the inclusion criteria, the quality of follow up, 
the quality of primary end point measures, the safety data. The IDMC will thereafter recommend 
to the Sponsor whether to continue, modify, or stop the study.  
The IDMC operating procedures will be described in an independent document.  
12. DATA MANAGEMENT  
All clinical data related to the study will be collected and saved in a computerised database by the 
Data Management Department of the subcontractor and under the supervision of the Data 
Manager of Pierre Fabre Biometry (PFB) according to the following procedures.  
12.1. DATA ENTRY 
All required data will be collected by the Investigator or authorised designee (duly identified into 
the delegation task list) on the e-CRFs.  
The e-CRFs used for this study will be developed and maintained by the Data Management 
Department of the subcontractor and approved by the Sponsor.  
Electronic data (Holter ECG, TTEM and DHA) will be transferred by the 3rd party vendor 
according to the specifications given by the Data Manager of the subcontractor. These data will be 
captured and handled in accordance with the European GCP ICH E6 guideline. 
12.2. DATA CLEANING 
The subcontractor will define in the Data Validation Plan for reviewing and querying data, 
descriptions of both manual and electronic edit checks. Upon Sponsor approval, the subcontractor 
will program the checks.  
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The subcontractor will review the data over the course of the study, working with the Sponsor to 
identify data inconsistencies. The Investigator will be asked to resolve queries by making changes 
directly into the e-CRF.  
12.3. DATA CODING 
Adverse events, concomitant diseases, medical/surgical histories will be coded by the 
subcontractor using the MedDRA dictionary (latest version in use). 
Concomitant medication will be coded by the subcontractor using the WHO-DRUG dictionary 
(latest version in use).  
The Sponsor Clinical Development Physician will validate the coding. 
12.4. DATA STORAGE 
Computer data files as well as their modifications will be archived by the subcontractor and kept 
available upon request of the Sponsor. 
12.5. DATABASE LOCK 
The validated database will be locked by the subcontractor upon request of the Data Manager of 
PFB following the completion of all steps required, i.e. data entry and check of all data, resolution 
of all queries, validation of the coding, Clinical and Products Safety databases reconciliation and 
validation committee.  
Then, the subcontractor will transfer the locked database in SAS format to the Data Manager of 
PFB who assume storage on the PFB secured server. 
13. STATISTICAL ANALYSIS 
After the database lock and the randomisation code release, the statistical analysis will be 
performed by PFB or under the supervision of the statistician of PFB using SAS® software, 
according to the Statistical Analysis Plan approved by the Validation Committee. 
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13.1. GENERAL CONSIDERATIONS 
The main objective of the study is to assess the efficacy of F373280 versus placebo on the 
maintenance of sinus rhythm after direct ECV in patients with persistent AF and chronic heart 
failure. 
Only the primary analysis of the primary efficacy criterion, on which is based the sample size 
justification, may lead to a causal interpretation. All other statistical results are to be regarded 
within a descriptive perspective. 
The statistical significance level of the various two sided tests of all analyses will be 5 %. 
13.2. SAMPLE SIZE 
Assuming an AF recurrence rate of 85% under placebo and 65% under active group, i.e. a 
clinically relevant difference ∆ of 20%, a sample size of 64 assessable patients per group is 
required, using a log-rank test of survival curves with a 80 % power and a 5 % two-sided 
significance level. 
According to the previous assumptions and assuming a rate of not assessable patients of 15%, a 
minimum of 76 patients will have to be randomised per group. 
13.3. PROTOCOL DEVIATIONS 
Prior to the database lock and the randomisation code release, the Validation Committee members 
will review the protocol deviations and will classify them as either minor or major. A protocol 
deviation will be considered major when it is likely to bias significantly the treatment effect 
estimate based on the primary efficacy criterion. 
Patients with major deviation(s) will be excluded from the Per Protocol data set (see section 13.4). 
A listing of all protocol deviations will be provided for all randomised patients, including the type 
(major/minor) of protocol deviations according to the decisions made by the members of the 
Validation Committee. 
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The number and percentage of patients with major protocol deviations will be tabulated by 
treatment group and type of major protocol deviations on the Full Analysis Set defined in section 
13.4. 
13.4. DATA SETS ANALYSED 
The following 3 data sets will be analysed (as defined by the Validation Committee):  
 
• The Safety Set composed of all randomised patients having received at least one dose of 
the study treatment. This data set will be used to perform analyses of Safety. 
• The Full Analysis Set (FAS) composed of all randomised patients having received at least 
one dose of the study treatment and with a successful cardioversion observed at visit 3. 
This data set will be used to perform analyses of Efficacy.  
• The Per Protocol Set (PP) which is the subset of the Full Analysis Set composed of all 
patients with a primary efficacy criteria available and without any major protocol 
deviation or other source of bias for primary criteria analyses. This data set will be used to 
perform the supportive analysis of the primary efficacy criterion. 
13.5. HANDLING OF DROPOUTS AND MISSING DATA 
13.5.1. Dropouts 
The number of patients who withdraw from the study after their randomisation will be provided 
by treatment group for all treated patients (Safety Set). All withdrawn patients will be further 
described regarding their time to dropout and reasons for withdrawal. 
13.5.2. Repositioning of Visits 
No repositioning of visits will be done. 
13.5.3. Missing Data 
Missing values will not be substituted by estimated values, but considered as missing in statistical 
analysis. 
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13.6. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Before the first trial drug intake, patient’s background, medical and surgical history, demographic 
data and disease characteristics will be described by treatment group on the Safety Set. 
- Quantitative parameters will be described by treatment group and overall using the 
following: number of patients, number of missing data, mean, standard deviation, 
minimum, median and maximum values. 
- Qualitative parameters will be described by treatment group and overall using 
frequencies. 
Concomitant diseases, as well as medical and surgical histories will be tabulated descriptively by 
treatment group and overall using the MedDRA codes of System Organ Classes and preferred 
terms. 
If more than 10% of patients are excluded from the FAS and PP set, the description of patients by 
treatment group at selection and inclusion will be repeated on the FAS and PP set for all 
parameters. 
No statistical test of comparability of treatment groups at baseline will be performed.  
13.7. EFFICACY ANALYSIS  
13.7.1. Primary Criterion  
13.7.1.1. 
Primary Analysis 
The primary criteria, time to first recurrence, will be analysed using the Kaplan Meier method and 
compared with the Log rank test. Hazard ratios and 95% confidence intervals will be estimated 
with the Cox regression model. 
The primary analysis will be performed on the FAS. 
13.7.1.2. 
Supportive Analysis 
The primary analysis will be repeated on the PP set. 
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13.7.2. Secondary Criteria 
All secondary analyses will be performed on the FAS. If more than 10% of patients are excluded 
from the PP set, the secondary analyses will be repeated on the PP set.  
13.7.2.1. Numbers of Atrial Fibrillation Episodes 
Both the numbers of AF episodes (symptomatic or not) lasting for at least 10 minutes and with 
duration less than 10 minutes (NSup10 and NInf10) will be described by treatment group and 
compared by the chi-square test (or CMH test adjusted for centre) or Fisher’s exact Test. 
13.7.2.2. Duration of Atrial Fibrillation Episodes 
The duration of all AF Episodes will be described by treatment group and compared using the 
Student t (or using an ANOVA with treatment and centres effects) or Wilcoxon test. 
13.7.2.3. Time to first AF recurrence less than 10 minutes or symtomatic 
The time to the first AF recurrence less than 10 minutes and the time to the first symptomatic AF 
recurrence will be analysed as the primary analysis.  
13.7.2.4. Clinical parameters evaluation 
The EHRA score will be described by treatment group and analysed using a chi-squared test (or 
CMH test adjusted for centre) or Fisher’s exact Test.  
The frequency of presumed arrhythmia will be described by treatment group. 
The number of recurrence of symptomatic AF, of hospitalizations (for cardiovascular events, for 
thromboembolic stroke and for all causes), of spontaneous cardioversion, of successful 
cardioversion (including number of shocks distribution) and the number of patients needing 
cardioversion after initial ECV will be described by treatment group and compared using a chi-
square test or a Fisher Test (if the numbers are relevant).  
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The duration of hospitalizations for cardiovascular events, for thromboembolic stroke and for any 
cause will be described by treatment group and compared using the Student t (or using an 
ANOVA with treatment and centre effects) or Wilcoxon test. 
The echocardiographic parameters values will be described at each time (V1, V2, V4, V6 and V9) 
and changes described from V4 to V9 and from V2 to V9. 
13.7.2.5. Biomarker analysis: red blood cell concentrations of DHA 
Values and changes from baseline for red blood cell concentration of DHA will be performed by 
treatment group and assessment time. 
13.8. SAFETY ANALYSIS 
The Safety Set will be used to perform all analyses of the safety criteria. 
13.8.1. Adverse Events 
Any adverse event having been reported during the study for a given patient will be classified by 
preferred term and corresponding system organ class using the MedDRA terminology. 
Adverse events will be classified as: 
• Treatment emergent adverse events, i.e., any adverse event which occurs or worsens on 
study treatment during the randomised period. 
• Or non treatment emergent adverse events, i.e., any adverse event which occurs during the 
run-in period (before V2) or is reported as concomitant disease with the same intensity. 
For each study period, any patient with at least one reported adverse event will be classified as a 
patient: 
• With at least one adverse event 
• With at least one treatment emergent adverse event 
• With one TEAE 
• With two TEAEs 
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• With at least three TEAEs 
• With at least one related TEAE 
• With an adverse event leading to the study treatment discontinuation (definitive or 
temporary) 
• With an adverse event leading to withdrawal 
• With at least one serious adverse event. 
Numbers and percentages of patient with at least one reported treatment emergent adverse event 
will be tabulated by treatment group: 
• By system organ class 
• By system organ class and preferred term 
• By system organ class and preferred term, taking into consideration its most severe 
intensity 
• And by system organ class and preferred term, taking into consideration the most severe 
relationship to the study treatment. 
Recurring adverse events (i.e., adverse events classified with the same preferred term) for a given 
patient will only be counted once and only their most severe intensity or most severe relationship 
to the study treatment will be tabulated. 
The number and percentage of patient with at least one most common (reported in 1% patients in 
any group) drug related TEAE ("not excluded or unassessable") will be tabulated by Preferred 
Term and Treatment group in decreasing order for the treatment group (for all patients). 
The number and percentage of patients with at least one reported most common treatment 
emergent adverse event will also be plotted by treatment group. This graphical representation will 
highlight the frequencies of the most severe intensities reported by system organ class and 
preferred term. 
SAE will also be described on an individual basis: treatment group, patient's code, sex and age, 
Investigator's reported term, preferred term, time of onset according to the time of the first study 
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treatment administration, duration, action taken regarding the study treatment administration, use 
of a corrective treatment, outcome and relationship to the study treatment in the Investigator’s 
opinion. 
13.8.2. Clinical Laboratory Evaluation  
For each laboratory parameter, data will be tabulated by treatment group and assessment time. 
The absolute changes post-trial drug administration - baseline (the baseline value being the value 
measured on the last blood sample collected before the first trial drug administration) will be 
calculated and tabulated by parameter, treatment group and post-trial drug administration 
assessment time. Results of retests performed post-trial drug administration will not be analysed 
and tabulated. They will only be displayed in individual data listings. 
For all biochemistry parameters, scatter plots highlighting individual results will display the 
baseline and week 24 of the laboratory measurements for each patient by locating the point 
defined by the baseline value on the abscissa and respectively week 24 value in the ordinate.  
For all haematology parameters, scatter plots highlighting individual results will display the 
baseline and week 4, week 12 and week 24 of the laboratory measurements for each patient by 
locating the point defined by the baseline value on the abscissa and respectively week 4, week 12 
and week 24 value in the ordinate.  
Each treatment group will be differently identified. The first bisecting line (45° line), the lines of 
lower and upper normal range, the lines of Potentially Clinically Significant Change (PSC) range 
and Clinically noteworthy abnormal laboratory value (CNALV) range added on the plots (see 
Appendix 17.3). 
For all blood laboratory parameters, shift tables will be provided to depict the numbers of  patients 
with post-trial drug administration variations at each assessment time as compared to the baseline 
values (measured on the last blood sample collected before the first trial drug administration) by 
treatment group. A 3-point scale (low, normal, high) will be used as defined by the normal ranges 
in use in the laboratory in charge of the assays. 
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CNALV (see in Appendix 17.3) will be identified and described on an individual basis. If 
relevant, five separate individual data listings by treatment group will be provided: 
• CNALV for haemoglobin (including corresponding individual results of erythrocytes and 
haematocrit) 
• CNALV for neutrophils or leucocytes (including corresponding individual results of 
basophils, eosinophils, lymphocytes and monocytes) 
• CNALV for platelets (including corresponding individual results of erythrocytes and 
leucocytes) 
• CNALV for liver function parameters (including corresponding individual results of 
gamma-GT) 
• CNALV for serum creatinine  
13.8.3. Global Physical Examination 
Recorded data of the global physical examination performed will not be tabulated as any 
abnormal findings post-randomisation should be reported as AEs (if clinically significant). 
Physical examination assessments will be provided in the listings of individual data. 
13.8.4. Vital Signs, Physical Findings and Other Observations Related to Safety 
13.8.4.1. 
Vital Sign Measurements Over Time 
For each parameter (systolic blood pressure, diastolic blood pressure and HR in supine and 
standing positions), descriptive statistics over time of values and changes from baseline will be 
tabulated by treatment group and assessment time. 
13.8.4.2. 
Body weight 
Descriptive statistics over time of values and changes from baseline will be tabulated by treatment 
group and assessment time. 
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13.8.4.3. 
Individual Patient Changes 
The number and percentage of patient with at least one Predefined Potentially Clinically 
Significant Change (PSC) and with at least one PSC Leading to Clinically Significant Value 
(PSCV) will be tabulated by treatment group (see Table 1 in Appendix 17.3).  
According to the pharmacological drug profile mentioned previously in this Protocol, the changes 
from baseline to the maximum and/or minimum post-baseline value could be categorized and 
tabulated by treatment group with frequencies and decreasing cumulative percentages. 
If there is a signal of a drug effect toward one direction rather than the other, additionally shift 
tables of variations from baseline to the maximum or minimum post-baseline value could be also 
provided (see Table 2 to 4 in Appendix 17.3). 
An individual data listing of patients with symptomatic or asymptomatic orthostatic hypotension 
will be provided by treatment group (see Table 5 in Appendix 17.3). 
13.8.5. ECG 
Frequencies on the clinical interpretation (normal, abnormal CS or NCS) will be presented by 
treatment group and assessment time. Individual tabulated data for ECG abnormalities will be also 
displayed. 
13.8.6. Coagulation parameters 
Scatter plots highlighting individual results for coagulation parameters (prothrombin time/INR, 
activated partial thromboplastin time and thrombin clotting time) before and after study treatment 
administration will be produced. 
13.9. CONCOMITANT TREATMENTS 
Concomitant treatments will be tabulated by treatment group within a descriptive perspective. 
They will be classified by therapeutic area according to the WHO-DRUG dictionary using the 
"anatomical therapeutic chemical" classification on the safety set. 
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13.10. COMPLIANCE 
 
The percentage of compliance will be described by treatment group using the quantity 
 
100
_
_
_
(%)
×
=
n
consumptio
l
Theoretica
n
consumptio
actual
Estimated
Compliance
 
 
 
with: Estimated actual consumption = number of tablets provided at the start of study (Visit 2) 
minus number of tablets returned at the end of study (Visit 9) 
Theoretical consumption = number of days of treatment intake planned between the start and the 
end of study (168 days ± 7days) 
 
13.11. INTERIM ANALYSIS AND DATA MONITORING 
No analyses of efficacy data are planned for IDMC that ensures that the overall probability of type 
I error is controlled. No Type I error and sample size adjustments are necessary. Any 
recommendations of the IDMC to alter study conduct will be based on safety, so IDMC 
monitoring of the study will not affect the statistical operating characteristics of the final analysis. 
The IDMC will review, three times during the study period (after the first 30 subjects will have 
been randomized, when the first 80 subjects will have terminated their study participation and 
when 130 subjects will have terminated their study participation), safety data results across 
treatment groups and judges whether the overall safety and feasibility (not futility) of the trial 
remain acceptable.  
14. GENERAL ETHICAL CONSIDERATIONS  
14.1. ETHICAL CONDITIONS 
This study is performed in accordance with the principles stated in the Declaration of Helsinki 
(1964) and subsequent amendments and in accordance with the Good Clinical Practice Guideline 
(CPMP/ICH/135/95). 
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14.2. ETHICS COMMITTEE AND LEGAL REQUIREMENTS 
All the documents required by National Regulations and any other informative documents that 
may be requested are submitted for review to an Ethics Committee whose procedures and 
operations meet the GCP and National Legal Requirements. 
Depending on National Regulations, the application is submitted to the Ethics Committee by the 
Sponsor (or representative) or by the Investigator. 
A copy of the formal written approval from the Ethics Committee is provided to the Sponsor 
(directly by the Ethics Committee or via the Investigator) with a list of names and qualifications 
of its members. 
The request for authorisation by the Competent Authority or its notification if required (depending 
on National Regulations) is carried out by the Sponsor. 
The screening of patients does not start before the approval of the Ethics Committee has been 
obtained and the study authorised by the Competent Authority or notified to the Competent 
Authority (depending on National Regulations). 
14.3. PATIENT'S INFORMATION LEAFLET AND INFORMED CONSENT 
 
FORM 
An information must be given to the patients before their decision to participate or abstain from 
participation. 
This information is based on the elements set out in the Declaration of Helsinki and the ICH GCP 
Guidelines. It must also describe the measures taken to safeguard patient’s privacy and protection 
of personal data, according to European Directive 95/46 EC or other local regulation. 
Restraints and risks must be explained, as well as the right to discontinue participation in the 
study at any stage, without affecting their further relationship with the Investigator and/or their 
future care. 
The written information and consent form must be submitted to the patient with an oral 
explanation. It must be agreed and signed by the patient before any study-related procedure starts. 
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This information and consent procedure is under the Investigator’s responsibility. 
The information and consent document are made in triplicate: the original copy is kept by the 
Investigator, one copy is given to the patient and the last copy is kept by the Clinical Quality 
Assurance Unit of the Sponsor in a sealed envelope at the end of study (except in case of specific 
country requirement). 
Specific areas of the Sponsor’s copy are not triplicated to avoid the reading of the patient’s 
surname (except the first 3 letters), first name, address and signature.  
If any information becomes available during the trial that may be relevant to the patient’s 
willingness to keep on participating in the trial, an updated written informed consent must be 
submitted to the patient to confirm  agreement to continue participating. 
14.4. PERSONAL DATA PROTECTION 
All information from this study (excluding data from the informed consent) is entered into a 
computer under the Sponsor’s responsibility in accordance with the French law, "Loi 
Informatique et Libertés" (January 6, 1978, and subsequent amendments) and with the European 
Directive 95/46/CE. 
14.5. INSURANCE POLICY 
In accordance with the provisions of the law and the GCP, the Sponsor Pierre Fabre Médicament, 
has an insurance policy intended to guarantee against possible damage resulting from the research. 
The studies and/or experiments performed on behalf of the Sponsor Pierre Fabre Médicament are 
specifically and expressly guaranteed. 
It is advisable to underline that non compliance with the Research Legal Conditions is a cause for 
guarantee exclusion. 
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15. ADMINISTRATIVE PROCEDURES 
15.1. PROTOCOL AMENDMENT 
Neither the Investigator nor the Sponsor may alter the protocol without the authorisation of the 
other party.  
All changes to the protocol are subject to an amendment which must be dated and signed by both 
parties and must appear as an amendment to the protocol. 
Substantial amendments are submitted for approval / authorisation to the Ethics Committees and 
Competent Authorities 
Urgent amendments are submitted for approval / authorisation to the Ethics Committees and 
Competent Authorities, but could be implemented immediately under specific conditions defined 
with the Sponsor. 
15.2. SOURCE DOCUMENTS, INVESTIGATOR'S FILE STORAGE 
The Investigator: 
• Keeps all trial-related documents in appropriate file folders. Records of patient, original 
informed consent forms, source documents, a CD Rom containing a pdf copy of e-CRF, 
drug inventory, Ethics Committees and Sponsor correspondence pertaining to the study 
must be kept on file. 
• Retains all documents relating to the screening (consent and investigation results) of all 
patients included in the trial or not. 
• Retains a list of the patient’s names, addresses (and/or number of medical file), code 
numbers to allow checking of data reported on e-CRFs with those from source documents. 
• Authorises direct access to source documents for monitoring, audits and inspections. 
• The trial-related documents must be retained as strictly confidential at the Investigator’s 
site for at least 15 years or according to local requirements, whatever is the longest after 
the completion or discontinuation of the trial (European Directive 2003/63/EC). 
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15.3. END OF THE STUDY 
15.3.1. Definition of the End of Study 
The end of study is the last visit of the last patient undergoing the trial. 
Any change to this definition during the study, for whatever reason, must be notified as a 
substantial amendment. 
15.3.2. Early Study Termination 
15.3.2.1. 
Early Study Termination Decided by the Sponsor 
The Sponsor may discontinue the study at any time for any of the following reasons: 
• Lack of recruitment 
• Deviations from good clinical practice and/or regulations 
• Poor product safety 
• New information that could jeopardise the patient’s safety 
• Stopping of the development … 
15.3.2.2. 
Early Study Termination Decided by the Competent Authorities 
The Competent Authorities may suspend or prohibit a study if they consider that either the 
conditions of authorisation are not being met or has doubt about the safety or scientific validity of 
the study. 
15.4. AUDIT 
The Sponsor is responsible for making sure that both its representatives (Study Manager, CRA...) 
and the Investigator fulfil the requirements as specified by the GCP Guideline.  
An audit can be organised internally at Pierre Fabre Médicament and at the investigational site 
where the e-CRFs are matched against source documents. 
All study documentation must be directly accessible to auditors. 
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The practical conditions for the audit are discussed between the Investigator and the Clinical 
Quality Assurance Department. 
Oral information about the audit results are given to the Investigator. 
15.5. INSPECTION 
The Health Authorities may inspect any investigation site or the Sponsor in the course of the study 
or after its completion, to verify the conduct of the study and quality of the data. The Investigator 
must provide to the inspectors direct access to study documents. 
15.6. CONFIDENTIALITY 
The present materials (protocol and related documentation, e-CRF, Investigator's Brochure) 
contain confidential information.  
Except if agreed in writing with the Study Manager, the Investigators must hold such information 
confidential, and must not disclose it to others (except where required by Applicable Law). 
15.7. CLINICAL STUDY REPORT 
Data analysis and clinical study report writing are under the Sponsor’s responsibility.  
Upon data analysis completion, a final report including a review of the objectives and methods, a 
presentation and a discussion of the results is drawn up according to ICH Guidelines (Structure 
and Content of Clinical Study Reports, ICH-E3, CPMP/ICH/137/95). 
The report is a clinical and statistical integrated report. It must be signed by the Sponsor's 
representative(s) and the Coordinating Investigator. 
15.8. STUDY RESULTS COMMUNICATION 
Upon completion of the study, the global results of the Research are communicated to the 
Investigator. According to the Local Regulation, the patient can ask the Investigator for the 
results. 
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15.9. STUDY RESULTS PUBLICATION 
The information and data collected during the conduct of this clinical study are considered 
confidential and are used by the Sponsor in connection with the development of the study drug. 
This information may be disclosed if deemed necessary by the Sponsor. 
To allow the use of the information derived from this clinical study and to insure compliance with 
Current Regulations, the Investigator must provide the Sponsor with complete test results and all 
data collected during the study.  
Only the Sponsor may make study information available to physicians and to Regulatory 
Agencies, except as required by Current Regulations. 
All the results of this study including data, reports, discoveries and inventions resulting from the 
study, are the property of the Sponsor. 
In the event the Sponsor chooses to publish study data, the manuscript must be provided to the 
author(s) at least 30 days prior to the expected date of submission to the intended publisher. 
The Investigator(s) can reserve the right to publish or present study data; if so, the manuscript or 
abstract must be provided to the Sponsor for review at least 30 days prior to the expected date of 
submission to the intended publisher or of planned presentation. 
In addition, if necessary, (the) Investigator(s) shall withhold publication for an additional 60 days, 
to allow the filing of a patent application, or to allow the Sponsor to take any measures he deems 
appropriate to establish and preserve his proprietary rights. 
It is agreed that publication of study results by each site shall be made only as part of a 
publication of the study results obtained by all sites performing the protocol, once the study is 
completed and finalised.  
The authors list is agreed by all Investigators prior to publication. The names of the authors are 
provided according to their participation in the design of the protocol as well as their recruitment 
of eligible and analysable patients. 
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16. REFERENCES 
 
[1] 
F373280 INVESTIGATOR'S BROCHURE, version October 2013 
 
[2] 
NODARI S., TRIGGIONAI M., CAMPIA U., MANERBA A., MILESI G., CESANA 
M.B., GHEORGHIADE M., DEI CAS L. 
n-3 Polyunsaturated Fatty Acids in the prevention of atrial Fibrillation Recurrences after 
electrical cardioversion. A prospective, Randomised study 
Circulation, 2011; 124:1100-1106 
 
[3] 
NODARI S., TRIGGIANI M., CAMPIA U., MANERBA A., MILESI G., CESANA 
M B., GHEORGHIADE M., DEI CAS L. 
Effects of n-3 polyunsaturated fatty acids on left ventricular function and functional 
capacity in patients with dilated cardiomyopathy 
J. Am. Coll. Cardiol. 2011;57;870-879 
 
[4] 
MOERTL D., HAMMER A., STEINER S., HUTULEAC R., VONBANK K., 
BERGER R. 
Dose-dependant effects of omega-3-polyunsaturated fatty acids on systolic left ventricular 
function, endothelial function, and markers of inflammation in chronic heart failure of non 
ischemic origin: A double-blind, placebo-controlled, 3-arm study  
American Heart Journal 2011; 161:915.e1-915.e9 - volume 161, number 5 
 
[5] 
GISSI-HF INVESTIGATORS 
Effects of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GSSI-
HF Trial): a randomised, double-blind, placebo-controlled trial 
The lancet on line - August 2008 
 
[6] 
CAMM A.J., KIRCHHOF P., LIP G.Y., SCHOTTEN U., SAVELIEVA I., ERNST S., 
VAN GELDER I.C., AL-ATTAR N., HINDRICKS G., PRENDERGAST B., 
HEIDBUCHEL H., ALFIERI O., ANGELINI A., ATAR D., COLONNA P., DE 
CATERINA R., DE SUTTER J., GOETTE A., GORENEK B., HELDAL M., 
HOHLOSER S.H., KOLH P., LE HEUZEY J.Y., PONIKOWSKI P., RUTTEN F.H. 
Guidelines for the management of atrial fibrillation: the Task Force for the Management of 
Atrial Fibrillation of the European Society of Cardiology (ESC). 
European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery,  
Eur Heart J. 2010 Oct;31(19):2369-429 
 
 
[7] 
KOWEY PR, REIFFEL JA, ELLENBOGEN KA, NACCARELLI GV, PRATT CM. 
Efficacy and safety of prescription omega-3 fatty acids for the prevention of recurrent 
symptomatic atrial fibrillation: a randomised controlled trial. 
JAMA. 2010;304:2363–2372. 
 
 
 
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[8] 
BIANCONI L., CALO L., MENNUNI M., SANTINI L., MOROSETTI P., 
AZZOLINI P., BARBATO G., BISCIONE F., ROMANO P., SANTINI M.  
N-3 polyunsaturated fatty acids for the prevention of arrhythmia recurrence after electrical 
cardioversion of chronic persistent atrial fibrillation: a randomised, double-blind, 
multicentre study  
Europace (2011) 13, 174-181 
 
[9] 
OMACOR® SUMMARY PRODUCT CARACTERISTICS (SPC) dated 17/02/2012 
 
[10] 
BEPANTHENE ® SUMMARY PRODUCT CARACTERISTICS (SPC) 
 
[11] 
TOUBOUL P, BRUGADA J, CAPUCCI A, CRIJNS HJ, EDVARDSSON N, 
 
HOHNLOSER SH.  
Dronedarone for prevention of atrial fibrillation: a dose-ranging study.  
Eur Heart J 2003;24(16):1481-7. 
 
[12] LE HEUZEY JY AND ALL.  
A Short-Term, Randomised, Double-Blind, Parallel-Group Study to Evaluate the Efficacy 
and Safety of Dronedarone versus Amiodarone in Patients with Persistent Atrial 
Fibrillation: The DIONYSOS Study. 
J Cardiovasc Electrophysiol. 
 
[13] METCALF G.R., JAMES J.M., GIBSON A.R., EDWARDS J., STUBBERFIELD J., 
STUKLIS R., YOUNG D.G., ROBERTS-THOMSON K. & CLELAND G.L.M.L. & 
OKEN H. 
Effects of fish-oil supplementation on myocardial fatty acids in humans.  
Am J Clin Nutr (2007); 85 : 1225. 
 
[14] ARTERBURN M.L. & OKEN H. 
Distribution, interconversion and dose response of n-3 fatty acids in humans.  
Am J Clin Nutr (2006);83 : 1469-1473S. 
 
[15] TIELEMAN RG, VAN GELDER IC, CRIJNS HJ, DE KAM PJ, VAN DEN BERG 
MP, HAAKSMA J, VAN DER WOUDE HJ, AND ALLESSIE MA. 
Early recurrences of atrial fibrillation after electrical cardioversion: a result of 
fibrillation-induced electrical remodelling of the atria? 
J. Am. Coll. Cardiol. 1998;31;167-173 
 
[16] 
SALM P, TAYLOR PJ, KOSTNER K 
Simultaneous quantification of total eicosapentaenoic acid, docosahexaenoic acid and 
arachidonic acid in plasma by high-performance liquid chromatography-tandem mass 
spectrometry.  
Biomed Chromatogr 2011 Jun;25(6):652-9. 
 
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[17] LEGRAND P., SCHMITT B., MOUROT J., CATHELINE D., CHESNEAU G., 
MIREAUX M., KERHOAS N., WEILL P. 
The consumption of food products from linseed-fed animals maintains erythrocyte omega-3 
fatty acids in obese human 
Lipids, 2010, 45, 11-19. 
 
[18] HARRIS WS, VON SCHACKY C. 
The Omega-3 Index: a new risk factor for death from coronary heart disease? 
Prev Med. 2004 Jul; 39(1):212-20 
 
[19] ABSTRACT: P5161 . 
NODARI S, MANERBA A., MADURERI A., BERLINGHIERI N., PULCINI E., 
FRATTINI S., METRA M, DEI CAS L. 
Effects of Polyunsaturated Fatty Acids n-3 (PUFA n-3) in the prophylaxis of atrial 
fibrillation relapses after external electric cardioversion 
World Congress of Cardiology 2006, 2-6 September, Barcelona – Spain 
 
[20] 
KIRCHHOF P., AURICCHIO A., BAX J., CRIJNS H., CAMM J., DIENER HC., 
 
GOETTE A., HINDRICKS G., HOHNLOSER S., KAPPENBERGER L., KUCK 
 
KH., LIP HYG., OLSSON B., MEINERTZ T., PRIORI S., RAVENS U., 
 
STEINBECK G., SVERHAGE E., TIJSSEN J., VINCENT A., BREITHARDT G. 
 
Outcome parameters from a consensus conference organized by the German Atrial 
 
Fibrillation Competence NETwork and the European Heart Rhythm Association. 
 
Europace 2007, 9, 1006-1023 
 
[21] 
EUROPEAN MEDICINES AGENCY 
 
Addendum to the guideline on antiarrhythmics on atrial fibrillation and atrial flutter. 
 
EMA/CHMA/EWP/213056/2010 
 
[22] 
OWEN AJ, PETER-PRZYBOROWSKA BA, HOY AJ, MCLENNAN PL. 
Dietary fish oil dose- and time-response effects on cardiac phospholipid fatty acid 
composition. 
Lipids. 2004;39:955–961 
 
[23] 
ROBERTO M. LANG, MICHELLE BIERIG, RICHARD B. DEVEREUX, FRANK 
A. FLACHSKAMPF*, ELYSE FOSTER, PATRICIA A. PELLIKKA, MICHAEL H. 
PICARD, MARY J. ROMAN, JAMES SEWARD, JACK SHANEWISE, SCOTT 
SOLOMON, KIRK T. SPENCER, MARTIN ST. JOHN SUTTON, WILLIAM 
STEWART. 
 
Recommendations for chamber quantification 
 
Eur J Echocardiography (2006) 7, 79-108 
 
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17. APPENDICES 
 
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17.1. DECLARATION OF HELSINKI 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
ETHICAL PRINCIPLES FOR MEDICAL RESEARCH INVOLVING 
HUMAN SUBJECTS 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 29th WMA 
General Assembly, Tokyo, Japan, October 1975 35th WMA General Assembly, Venice, Italy, October 1983 41st 
WMA General Assembly, Hong Kong, September 1989 48th WMA General Assembly, Somerset West, Republic of 
South Africa, October 1996 52nd WMA General Assembly, Edinburgh, Scotland, October 2000 53th WMA General 
Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 55th WMA General Assembly, Tokyo 
2004 (Note of Clarification on Paragraph 30 added) 59th WMA General Assembly, Seoul, October 2008 
 
A. INTRODUCTION  
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of 
ethical principles for medical research involving human subjects, including research on identifiable 
human material and data. The Declaration is intended to be read as a whole and each of its constituent 
paragraphs should not be applied without consideration of all other relevant paragraphs.  
2. Although the Declaration is addressed primarily to physicians, the WMA encourages other participants 
in medical research involving human subjects to adopt these principles.  
3. It is the duty of the physician to promote and safeguard the health of patients, including those who are 
involved in medical research. The physician's knowledge and conscience are dedicated to the fulfilment 
of this duty.   
4. The Declaration of Geneva of the WMA binds the physician with the words, “The health of my patient 
will be my first consideration,” and the International Code of Medical Ethics declares that, “A physician 
shall act in the patient's best interest when providing medical care.”  
5. Medical progress is based on research that ultimately must include studies involving human subjects. 
Populations that are underrepresented in medical research should be provided appropriate access to 
participation in research.  
6. In medical research involving human subjects, the well-being of the individual research subject must 
take precedence over all other interests.  
7. The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic interventions 
(methods, procedures and treatments). Even the best current interventions must be evaluated continually 
through research for their safety, effectiveness, efficiency, accessibility and quality.  
8. In medical practice and in medical research, most interventions involve risks and burdens.  
9. Medical research is subject to ethical standards that promote respect for all human subjects and protect 
their health and rights. Some research populations are particularly vulnerable and need special 
protection. These include those who cannot give or refuse consent for themselves and those who may be 
vulnerable to coercion or undue influence.  
10. Physicians should consider the ethical, legal and regulatory norms and standards for research involving 
human subjects in their own countries as well as applicable international norms and standards. No 
national or international ethical, legal or regulatory requirement should reduce or eliminate any of the 
protections for research subjects set forth in this Declaration.  
 
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B. PRINCIPLES FOR ALL MEDICAL RESEARCH  
11. It is the duty of physicians who participate in medical research to protect the life, health, dignity, 
integrity, right to self-determination, privacy, and confidentiality of personal information of research 
subjects.  
12. Medical research involving human subjects must conform to generally accepted scientific principles, be 
based on a thorough knowledge of the scientific literature, other relevant sources of information, and 
adequate laboratory and, as appropriate, animal experimentation. The welfare of animals used for 
research must be respected.   
13. Appropriate caution must be exercised in the conduct of medical research that may harm the 
environment.  
14. The design and performance of each research study involving human subjects must be clearly described 
in a research protocol. The protocol should contain a statement of the ethical considerations involved 
and should indicate how the principles in this Declaration have been addressed. The protocol should 
include information regarding funding, sponsors, institutional affiliations, other potential conflicts of 
interest, incentives for subjects and provisions for treating and/or compensating subjects who are 
harmed as a consequence of participation in the research study. The protocol should describe 
arrangements for post-study access by study subjects to interventions identified as beneficial in the 
study or access to other appropriate care or benefits.   
15. The research protocol must be submitted for consideration, comment, guidance and approval to a 
research ethics committee before the study begins. This committee must be independent of the 
researcher, the sponsor and any other undue influence. It must take into consideration the laws and 
regulations of the country or countries in which the research is to be performed as well as applicable 
international norms and standards but these must not be allowed to reduce or eliminate any of the 
protections for research subjects set forth in this Declaration. The committee must have the right to 
monitor ongoing studies. The researcher must provide monitoring information to the committee, 
especially information about any serious adverse events. No change to the protocol may be made 
without consideration and approval by the committee.  
16. Medical research involving human subjects must be conducted only by individuals with the appropriate 
scientific training and qualifications. Research on patients or healthy volunteers requires the 
supervision of a competent and appropriately qualified physician or other health care professional. The 
responsibility for the protection of research subjects must always rest with the physician or other health 
care professional and never the research subjects, even though they have given consent.  
17. Medical research involving a disadvantaged or vulnerable population or community is only justified if 
the research is responsive to the health needs and priorities of this population or community and if 
there is a reasonable likelihood that this population or community stands to benefit from the results of 
the research.   
18. Every medical research study involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and communities involved in the research in 
comparison with foreseeable benefits to them and to other individuals or communities affected by the 
condition under investigation.  
19. Every clinical trial must be registered in a publicly accessible database before recruitment of the first 
subject.  
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20. Physicians may not participate in a research study involving human subjects unless they are confident 
that the risks involved have been adequately assessed and can be satisfactorily managed. Physicians 
must immediately stop a study when the risks are found to outweigh the potential benefits or when 
there is conclusive proof of positive and beneficial results.  
21. Medical research involving human subjects may only be conducted if the importance of the objective 
outweighs the inherent risks and burdens to the research subjects.  
22. Participation by competent individuals as subjects in medical research must be voluntary. Although it 
may be appropriate to consult family members or community leaders, no competent individual may be 
enrolled in a research study unless he or she freely agrees.  
23. Every precaution must be taken to protect the privacy of research subjects and the confidentiality of 
their personal information and to minimize the impact of the study on their physical, mental and social 
integrity.   
24. In medical research involving competent human subjects, each potential subject must be adequately 
informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional 
affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort 
it may entail, and any other relevant aspects of the study. The potential subject must be informed of the 
right to refuse to participate in the study or to withdraw consent to participate at any time without 
reprisal. Special attention should be given to the specific information needs of individual potential 
subjects as well as to the methods used to deliver the information. After ensuring that the potential 
subject has understood the information, the physician or another appropriately qualified individual 
must then seek the potential subject’s freely-given informed consent, preferably in writing. If the 
consent cannot be expressed in writing, the non-written consent must be formally documented and 
witnessed.  
25. For medical research using identifiable human material or data, physicians must normally seek consent 
for the collection, analysis, storage and/or reuse. There may be situations where consent would be 
impossible or impractical to obtain for such research or would pose a threat to the validity of the 
research. In such situations the research may be done only after consideration and approval of a 
research ethics committee.   
26. When seeking informed consent for participation in a research study the physician should be 
particularly cautious if the potential subject is in a dependent relationship with the physician or may 
consent under duress. In such situations the informed consent should be sought by an appropriately 
qualified individual who is completely independent of this relationship.  
27. For a potential research subject who is incompetent, the physician must seek informed consent from the 
legally authorized representative. These individuals must not be included in a research study that has 
no likelihood of benefit for them unless it is intended to promote the health of the population 
represented by the potential subject, the research cannot instead be performed with competent persons, 
and the research entails only minimal risk and minimal burden.   
28. When a potential research subject who is deemed incompetent is able to give assent to decisions about 
participation in research, the physician must seek that assent in addition to the consent of the legally 
authorized representative. The potential subject’s dissent should be respected.  
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29. Research involving subjects who are physically or mentally incapable of giving consent, for example, 
unconscious patients, may be done only if the physical or mental condition that prevents giving 
informed consent is a necessary characteristic of the research population. In such circumstances the 
physician should seek informed consent from the legally authorized representative. If no such 
representative is available and if the research cannot be delayed, the study may proceed without 
informed consent provided that the specific reasons for involving subjects with a condition that renders 
them unable to give informed consent have been stated in the research protocol and the study has been 
approved by a research ethics committee. Consent to remain in the research should be obtained as soon 
as possible from the subject or a legally authorized representative.  
30. Authors, editors and publishers all have ethical obligations with regard to the publication of the results 
of research. Authors have a duty to make publicly available the results of their research on human 
subjects and are accountable for the completeness and accuracy of their reports. They should adhere to 
accepted guidelines for ethical reporting. Negative and inconclusive as well as positive results should 
be published or otherwise made publicly available. Sources of funding, institutional affiliations and 
conflicts of interest should be declared in the publication. Reports of research not in accordance with 
the principles of this Declaration should not be accepted for publication.  
 
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE  
31. The physician may combine medical research with medical care only to the extent that the research is 
justified by its potential preventive, diagnostic or therapeutic value and if the physician has good 
reason to believe that participation in the research study will not adversely affect the health of the 
patients who serve as research subjects.   
32. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the 
best current proven intervention, except in the following circumstances:  
• 
The use of placebo, or no treatment, is acceptable in studies where no current proven intervention 
exists; or  
• 
Where for compelling and scientifically sound methodological reasons the use of placebo is 
necessary to determine the efficacy or safety of an intervention and the patients who receive 
placebo or no treatment will not be subject to any risk of serious or irreversible harm.  Extreme 
care must be taken to avoid abuse of this option.  
33. At the conclusion of the study, patients entered into the study are entitled to be informed about the 
outcome of the study and to share any benefits that result from it, for example, access to interventions 
identified as beneficial in the study or to other appropriate care or benefits.  
34. The physician must fully inform the patient which aspects of the care are related to the research. The 
refusal of a patient to participate in a study or the patient’s decision to withdraw from the study must 
never interfere with the patient-physician relationship.  
35. In the treatment of a patient, where proven interventions do not exist or have been ineffective, the 
physician, after seeking expert advice, with informed consent from the patient or a legally authorized 
representative, may use an unproven intervention if in the physician's judgement it offers hope of 
saving life, re-establishing health or alleviating suffering. Where possible, this intervention should be 
made the object of research, designed to evaluate its safety and efficacy. In all cases, new information 
should be recorded and, where appropriate, made publicly available.  
 
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17.2. SAE REPORT FORM 
 
 
 
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N O T I F I C A T I O N  O F  S E R I O U S  A D V E R S E  E V E N T  ( S A E )  O R  P R E G N A N C Y   
T O  P I E R R E  F A B R E  C O R P O R A T E  V I G I L A N C E S  D I V I S I O N   
 
TO 
BE 
TRANSMITTED 
TO 
THE 
CORPORATE 
VIGILANCES 
DIVISION 
BY 
E-MAIL 
WITHIN 
24H 
TO 
HQ.pharmacovigilance@pierre-fabre.com OR BY FAX WITHIN 24H – Fax N°: 33 (0) 1.49.10.80.90 
Transmission date  
 
 
  
 
  
 
 
 
(ddmmyyyy) 
Country :  
........................................
 
 
 
   SAE N° 
 
 
 
                      FIRST NOTIFICATION           FOLLOW-UP   N° 
 
 SUBJECT CHARACTERISTICS  
 
 
 
 
 
 
 
 
Birth date  
 
 
 
 
 
 
 
 
  
 
 
Gender 
 
1=M,    2=F 
   Height 
 
 
 
cm 
 Weight 
 
 
 
 
 
kg 
 
 
 DESCRIPTION OF THE EVENT 
The serious adverse event resulted in : 
 Death (whatever may be the cause) 
 Hospitalisation (*) or extension thereof 
 Life threatening 
 Invalidity or disability 
 
 Congenital abnormality or abnormal pregnancy outcome 
 Cancer 
 Other  (any other serious clinical or laboratory event 
     according to the investigator or the protocol, overdosage 
      meeting seriousness criteria, suicide attempts) 
Other fact to be notified : 
 Pregnancy exposure 
Nature of the event (if clinical nature, indicate the diagnosis or the major symptom) : 
........................................................................................................................................................................................................... 
........................................................................................................................................................................................................... 
........................................................................................................................................................................................................... 
AE onset date  |__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
 
Seriousness onset date  |__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
 
Summary description (if clinical cause, significant history, progression of event, available laboratory results, etc...) : 
 
 
 
 
 
 
(*) Except hospitalisations with durations and goals planned in the protocol 
 
 THE SAE IN RELATION TO THE TRIAL 
                                                      TREATMENT NUMBER         |___|___|___|___|___|___| 
• Time of occurrence of SAE 
 
 During the selection or run-in period 
 
 During the administration phase of the study treatment 
 
 After the administration phase of the study treatment 
• Date of first study treatment administration 
• Date of last study treatment administration 
   before the occurence of SAE 
|__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
 
|__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
• Was the blind broken ?       Yes         No          Not applicable 
   If yes, or if this is an open study, drug(s) administered : 
 
 
 
 
 
  Conditions of administration (cycles(s), daily dose(s), route(s) of administration, etc..) :  
 
 
 
 
 
 
 
 
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Transmission date 
 
 
 
 
 
 
 
 
 
 
  (ddmmyyyy) 
Country : ............................................ 
 
 
 
  SAE N° 
 
 
 
                     FIRST NOTIFICATION           FOLLOW-UP   N° 
 
 CONCOMITANT MEDICATION SINCE TRIAL INITIATION and UP UNTIL THE OCCURRENCE OF THE SAE 
     (EXCEPT THE TREATMENTS GIVEN FOR THE SAE)  
 
Trade name  
(or INN) 
 
Daily dose 
 
Start date 
(dd/mm/yy) 
Ongoing at 
occurence of the 
event 
 
Stop date 
(dd/mm/yy) 
Route of 
admin. 
 
Indication 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 MEASURES TAKEN FOLLOWING THE SAE 
• Study treatment 
 
 No change 
 
 Dosage modification, specify :……………………………..….      Modification Date : 
 
 Temporarily discontinued                                                       Readministration date : 
 
 Withdrawn                                                                                                  End date : 
 
 Not applicable 
 
____/____/_____ 
 ____/____/_____ 
 ____/____/_____ 
• The event led to : 
 
 Prescription of corrective or symptomatic treatments: 
 
 
Trade name  
(or INN) 
 
Daily dose 
 
Start date 
(dd/mm/yy) 
Ongoing at 
occurence of the 
event 
 
Stop date 
(dd/mm/yy) 
Route of 
admin. 
 
Indication 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 Discontinuation of concomitant treatments: 
 
 
Trade name  
(or INN) 
 
Daily dose 
 
Start date 
(dd/mm/yy) 
Ongoing at 
occurence of the 
event 
 
Stop date 
(dd/mm/yy) 
Route of 
admin. 
 
Indication 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
 Others, specify : 
 
 
 OUTCOME 
         Not recovered/Not resolved                  Recovering/Resolving               Recovered/Resolved 
         Recovered/Resolved with sequelae     Fatal                                          Unknown 
 
                In case of death, has an autopsy been conducted ?       Yes         No 
 
 INVESTIGATOR CAUSALITY ASSESSMENT (investigator’s assessment to be done as soon as possible) 
Study drug:                                                                         Related to study protocol: 
 Not Suspected                 Suspected                             Not Suspected                          Suspected                   
Comments: ............................................................................................................................................................. 
 
Enclose in the notification the results of carried out examinations, reports of hospitalisation, etc... 
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17.3. PREDEFINED LIMITS OF LABORATORY AND VITAL SIGN 
POTENTIALLY CLINICALLY SIGNIFICANT CHANGES AND VALUES  
 
List of Predefined Potentially Clinically Significant Change For Laboratory Values(¤) 
 
 
PARAMETERS 
UNIT 
PSC 
 
 
 
Decrease 
Increase 
MUSCLE 
Creatine  Phosphokinase 
U / l 
- 
236 
KIDNEY 
Creatinine 
Urea 
Uric acid 
Phosphate 
Calcium 
µmol/l 
mmol/l 
µmol/l 
mmol/l 
mmol/l 
- 
- 
- 
0.39 
0.30 
35 
3.2 
119 
0.39 
0.30 
ELECTROLYTES 
Sodium 
Potassium 
Chloride 
Bicarbonate 
mmol/l 
mmol/l 
mmol/l 
mmol/l 
8 
1.1 
8 
7 
8 
1.1 
7 
8 
METABOLISM/ 
NUTRITIONAL 
Glucose (random) 
Albumin 
Protein 
Cholesterol 
HDL cholesterol 
LDL cholesterol 
Triglycerides 
mmol/l 
g/l 
g/l 
mmol/l 
mmol/l 
mmol/l 
mmol/l 
3 
6 
11 
- 
0.91 
2.17 
- 
3.7 
6 
10 
1.97 
0.85 
2.04 
2.91 
ERYTHROCYTES 
Erythrocyte count 
Haemoglobin 
Haematocrit 
MCV  
MCH (Fe) 
MCHC (Fe) 
T/l 
g/l 
1 
fl 
fmol 
mmol/l 
0.7 
20 
0.06 
7 
0.19 
2 
0.7 
- 
0.06 
7 
0.19 
2 
LEUKOCYTES 
Leukocyte count 
G/l 
4.2 
3.8 
DIFFERENTIAL 
COUNT 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
G/l 
G/l 
G/l 
G/l 
G/l 
3.47 
1.76 
- 
- 
- 
3.19 
1.63 
0.49 
0.41 
0.14 
URINE 
Specific gravity 
pH 
- 
- 
0.017 
2 
0.015 
2 
LIVER 
Total bilirubin 
ASAT (SGOT) 
ALAT (SGPT) 
Gamma GT 
Alkaline phosphatase 
µmol/l 
U/l 
U/l 
U/l 
U/l 
- 
- 
- 
- 
-- 
10 
N x (23/36) 
N x (28/45) 
N x (25/38) 
N x (30/95) 
 
N = upper limit of normal range 
 
(¤) Delta-limits from « Routine Laboratory Tests in Clinical Trials » W. Leigh Thompson, Rocco 
L. Brunelle, Gregory G. Enas, Patrick J. Simpson and Randy L. Walker Lilly Research 
Laboratories, Lilly Corporate Centre, Indianapolis, Indiana in « Clinical Trials and Tribulations » 
1988. 
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Definition of Clinically Noteworthy Abnormal Laboratory Values (CNALV) 
 
 
PARAMETERS 
CNALV 
HAEMOGLOBIN 
 
• Decrease of at least 2g/dl and value < 10 g/dl whatever the baseline 
value 
• If missing baseline : value <10g/dl 
NEUTROPHILS 
• < 1 500/mm3 whatever the baseline value 
WBC 
(if missing value for neutrophils) 
• < 3 000/mm3 whatever the baseline value 
PLATELETS 
• < 100 000/mm3 whatever the baseline value 
SERUM CREATININE 
• Increase of at least 30 % as compared to baseline value and 
value > 150 µmol/l whatever the baseline value 
• If missing baseline : value > 150 µmol/l 
LIVER FUNCTION TESTS 
 
 
ALAT 
 
 If normal baseline :  
 
 
•ALAT > 2 N 
 If abnormal baseline : 
→if baseline value ≤ 2.5 N : 
  
• increase of at least 100 % as compared to baseline value 
→ if baseline value > 2.5 N :  
 
 
• value > 5 N 
and/or 
ASAT 
 
  If normal baseline :  
 
 
• ASAT > 2 N 
  If abnormal baseline : 
→ if baseline value ≤ 2.5 N : 
  
• increase of at least 100 % as compared to baseline value 
→ if baseline value > 2.5 N :  
 
 
• value > 5 N 
and/or 
Alkaline phosphatase (AP) 
 
  If normal baseline :  
 
 
• AP > 1.25 N 
  If abnormal baseline :  
 
 
• AP > 2 N 
and/or 
Total bilirubin (TB) 
  If normal baseline :  
 
 
• TB > 1.5 N 
  If abnormal baseline :  
 
 
• TB > 2 N 
N=upper limit of normal range 
International consensus Meeting. International Journal of Clinical Pharmacology, Therapy and Toxicology, 1990;28:317-322 
Standardisation of definitions and criteria of causality assessment of adverse drug reactions: drugs-induced liver disorders: report 
of an Standardisation of definitions and criteria of causality assessment of adverse drug reactions: drugs-induced cytopenia. 
International Journal of Clinical Pharmacology, Therapy and Toxicology, 1991;29:75-81 
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Cardiovascular Safety 
 
Table 1: Predefined Limits for Potentially Clinically Significant Changes (PSC) and PSC 
Leading to Clinically Significant Values (PSCV) 
 
Parameter 
PSC 
PSCV 
SBP 
Increase ≥ 20 mmHg 
Decrease ≥ 20 mmHg 
SBP ≥ 160 mmHg and increase ≥ 20 mmHg 
SBP ≤ 90 mmHg and decrease ≥ 20 mmHg 
DBP 
Increase ≥ 10 mmHg 
Decrease ≥ 10 mmHg 
DBP ≥ 100 mmHg and increase ≥ 10 mmHg 
DBP ≤ 50 mmHg and decrease ≥ 10 mmHg 
HR 
Increase ≥ 10 bpm 
Decrease ≥ 10 bpm 
HR ≥ 110 bpm and increase ≥ 10 bpm 
HR ≤ 50 bpm and decrease ≥ 10 bpm 
 
Table 2: Predefined Classes for changes from Baseline to the Maximum (and/ or Minimum) 
Post-baseline Value 
Classes of Change from Baseline to the Maximum 
Post-baseline Value 
Classes of Change from Baseline to the 
Minimum Post-baseline Value 
SBP  mmHg 
DBP  mmHg 
HR bpm 
SBP  mmHg 
DBP  mmHg 
HR bpm 
All 
All 
All 
All 
All 
All 
≥  0 
≥  0 
≥  0 
≤  0 
≤  0 
≤  0 
>  0 
>  0 
>  0 
<  0 
<  0 
<  0 
≥ 10 
≥  5 
≥ 10 
≤ -10 
≤ - 5 
≤ -10 
≥ 20 
≥ 10 
≥ 20 
≤ -20 
≤ -10 
≤ -20 
≥ 30 
≥ 15 
≥ 30 
≤ -30 
≤ -15 
≤ -30 
≥ 40 
≥ 20 
 
≤ -40 
≤ -20 
 
 
≥ 25 
 
 
≤ -25 
 
 
≥ 30 
 
 
≤ -30 
 
 
Table 3: Classes for Vital Signs Maximum or Minimum Values 
Classes  for  the Maximum Post-baseline Value 
for each parameter 
Classes  for  the Minimum Post-baseline Value 
for each parameter 
SBP  mmHg 
DBP  mmHg 
HR bpm 
SBP  mmHg 
DBP  mmHg 
HR bpm 
< 120 
< 80 
≤ 50 
≤ 90 
≤ 50 
≤ 50 
[120 ;140[ 
[80;90[ 
]50 ;75[ 
[90 ;120[ 
[50;80[ 
]50 ;75[ 
[140;160[ 
 [90;100[ 
[75;100[ 
[120;140[ 
 [80;90[ 
[75;100[ 
≥ 160 
≥ 100 
≥ 100 
≥ 140 
≥ 90 
≥ 100 
 
Table 4: Classes for Maximum or Minimum of BP in its entirety 
Classification of Maximum Values for Blood 
Pressure (mmHg) 
Classification of Minimum Values Blood 
Pressure (mmHg) 
SBP < 140 and DBP < 90 
SBP > 90 and DBP > 50 
SBP [140;160[ and DBP < 100 
or DBP [90;100[ and SBP < 160 
SBP ≤  90 or DBP ≤  50 
SBP ≥ 160 or DBP ≥ 100 
 
 
Table 5: Definition of orthostatic hypotension 
Orthostatic Hypotension * 
SBP Decrease ≥ 20 mmHg or DBP Decrease ≥ 10 mmHg between supine and standing positions 
* Consensus Committee of the American Autonomic Society and the American Academy of Neurolog :Consensus statement on the definition of 
orthostatic hypotension, pure autonomic failure and multiple system atrophy. Neurology 1996;46:1470-3. 
 
 
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16.1.1.8. 
Protocol amendment n° PA05 - General and 
substantial dated on 22 October 2014 linked to 
Protocol and appendices  
(version 8: 22 October 2014) 
 
 
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CLINICAL STUDY PROTOCOL AMENDMENT n° PA05 
(General – Substantial) 
 
 
 
Final version
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Pierre Fabre Médicament 
Represented by: Institut de Recherche Pierre Fabre 
45, Place Abel Gance 
F-92100 Boulogne, France 
 
 
CLINICAL STUDY PROTOCOL AMENDMENT n° PA05  
 
(General – Substantial) 
 
 
Efficacy and safety study of F373280 for maintenance of sinus rhythm after electrical 
cardioversion in patients with persistent Atrial Fibrillation and Chronic Heart Failure. 
 
International, multicentric, randomised, double-blind, placebo controlled study 
 
Pierre Fabre Study Code: 
F373280 CA 2 01  
EudraCT Number or equivalent: 2012-003487-48 
Sponsor’s Representative: 
Gaëlle ALCARAZ 
INSTITUT DE RECHERCHE PIERRE FABRE   
Centre de R&D Pierre Fabre - BP 13562  
3 avenue Hubert Curien  
31035 TOULOUSE Cedex 1 
 
Study Coordinating Investigator: 
Pr Savina NODARI 
Department of Clinical and Surgical Specialities, Radiological Science 
and Public Health 
Section of Cardiovascular Diseases 
University Medical School and Spedali Civili Hospital of Brescia 
c/o Spedali Civili di Brescia 
Piazzale Spedali Civili, 1 
25123 - BRESCIA, ITALY 
 
Date of amendment PA05: 
 22OCT2014 
 
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COUNTRY COORDINATING INVESTIGATOR SIGNATURE FORM 
STUDY: Efficacy and safety study of F373280 for maintenance of sinus rhythm after 
electrical cardioversion in patients with persistent Atrial Fibrillation and Chronic Heart 
Failure. 
 
International, multicentric, randomised, double-blind, placebo controlled study 
 
Clinical Study Protocol Amendment n° PA05 
(General –  Substantial) 
Dated:  22OCT2014 
 
 
Country Coordinating Investigator: 
Date:  
Signature: 
 
 
 
 
 
 
 
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INVESTIGATOR SIGNATURE FORM  
STUDY: Efficacy and safety study of F373280 for maintenance of sinus rhythm after 
electrical cardioversion in patients with persistent Atrial Fibrillation and Chronic Heart 
Failure. 
 
International, multicentric, randomised, double-blind, placebo controlled study 
 
Clinical Study Protocol Amendment n° PA05  
(General – Substantial) 
Dated:  22OCT2014      
 
 
By my signature below, I, Dr _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _, hereby confirm that I have read, 
taken note of (and will apply) the modifications brought by the protocol amendment n° PA05 and I 
will conduct the trial according to these new modalities. 
 
 
Date: 
Signature: 
 
 
 
Final version
812/1185


HISTORY OF AMENDMENTS  
N° 
TYPE 
APPLICATION 
AREA 
DATE 
MODIFICATIONS 
NA 
NA 
General 
NA 
Corresponding to Protocol Version 2:  
Following French CA request (ANSM) and leading 
to protocol version 2: 
- Add of a non inclusion criteria: “Breast-feeding 
female patient” 
- Add of haematology examination at visit 3 and 6 
 
PA01 
Substantial 
Local (Italy) 
01MAR2013 
Corresponding to Protocol Version 3: 
- Integration of the modification included in the 
protocol version 2 
- Harmonisation of the protocol and the Informed 
Consent Form: 
• 
adjustment of the selection criteria n°10 
related to the contraception method  
• 
addition of a letter that is given by the 
patient to his/her general practitioner (GP) 
• 
precision that the sponsor can not collect a 
copy of the Informed Consent Form  
• 
precision that the patient card is in Italian 
language only (without any English 
mention)   
PA02 
Non 
Substantial 
General 
28MAR2013 
Corresponding to Protocol Version 4 : 
- change of Sponsor’s Representative (Clinical 
Study Manager),  
- modification of the technical handling of the blood 
samples for determination of red blood cells 
concentration of DHA: the centrifugation is no more 
needed, 
- precision on the function and address of the 
International Study Coordinator Pr Nodari,  
- add of address and contacts details of two CRO 
newly involved in the study: Theradis (in charge of 
transportation of blood samples to the Analytical 
centre and material supply) and “Clinact” (in charge 
of refund of patients expenses linked to the study), 
 - adjustment of the wording, in agreement with the 
commitment to the French Ethics Committee. In the 
paragraphe 8.3.2.1, the wording "hematology 
examination” is replaced by "standard hematologic 
dosage", 
  - precision of the full title in the study synopsis (in 
agreement with the commitment to the Spanish 
Ethics Committee),  
- correction of a mistake in section 8.1.1.3 (related 
to TTEM transmission) and sections 3, 9 and study 
synopsis (related to the definition of INR not 
stabilized). 
- addition of the changes included in the local italian 
substantial protocol amendment (i.e: contraception 
method, letter to General Practionner, patient card 
Final version
813/1185


N° 
TYPE 
APPLICATION 
AREA 
DATE 
MODIFICATIONS 
in Italian and no collection of the consent form by 
the sponsor in Italy). 
 
PA03 
Substantial 
General 
23OCT2013 
Corresponding to Protocol Version 5:  
- Fax modification of the sponsor’s representatives 
- Planned end of study postponed to January 2015. 
- The authorized history of the first documented 
persistent atrial fibrillation is less than 3 years. 
- At selection a hyperkalemia or a hypokalemia is 
better defined by the standards of the local 
laboratories.  
- Regarding previous treatments by amiodarone the 
non inclusion criteria of the protocol are adapted as 
follow: 
• 
Previous treatment with oral amiodarone 
within 4 months prior to inclusion 
• 
Intake of oral amiodarone for more than 1 
month within 4 to 12 months before 
inclusion 
• 
Previous 
treatment 
with 
intravenous 
amiodarone within 4 weeks prior to 
inclusion. 
- For male with a child-bearing potential partner (in 
Italy only): taking into account the duration of 
spermatogenesis the absolute abstention from 
sexual intercourse or the use of double barrier 
contraception method are extended to 3 months 
after the end of the study. 
- Ranolazine is an antiarrhythmic treatment added 
to the prohibited treatments. 
- Update of Serious Adverse Events (SAEs) form: 
Main change is the SAE sending: SAEs have to be 
reported to the Corporate Vigilance Department, 
and not anymore to the clinical study manager. Also 
SAEs can be sent by e-mail and by fax. 
- Addition of Alpha Bioresearch as CRO involved 
for Feasibility, Monitoring and Regulatory issues in 
Spain. 
- Correction of some minor typographic errors  
 
PA04 
Non 
Substantial 
General 
03JUN2014 
Corresponding to protocol V7: 
- Precision on the temperature storage of DHA 
samples 
- Precision on the BSA formula 
- Addition of QTcB and QTcF 
- Precision on TTEM recording timelines 
- Clarification of the section Interim analysis 
and data monitoring (13.11) 
- Clarifications and specifications on some 
minor points 
 
 
Final version
814/1185


1. AMENDMENT RATIONALE 
 
The purpose of this amendment is mainly to clarify some points of the protocol regarding the 
management of vitamin K antagonist (VKA) treatment and to decrease constraints of the 
study for patients. 
This amendment relates also to a precision regarding the primary efficacy criterion, to an 
adjustment of some selection criteria in order to improve the feasibility of the study and 
relates to minor changes as typographical errors or style. 
The clinical study protocol is updated with the following changes: 
- Due to a recruitment rate lower than expected the planned end of study is postponed to 
April 2016. 
- In order to have a better harmonization between the centres in the management of 
treatment with VKA some clarifications are incorporated in Chapter 8.4.6 Coagulation 
parameters. 
- Atrial fibrillation and Atrial flutter are not the same rhythm disorder, but they are very 
similar and both are the expression of abnormal electrical impulses starting in the atria. So 
regarding the definition of the primary criterion, the atrial flutter emergence should be 
considered as having the same meaning as a recurrence in persistent AF. This primary 
criterion will be more precisely defined by the time to the first Atrial Fibrillation 
recurrence or Atrial Flutter emergence. 
− To reduce constraints of patients follow-up, the number of scheduled visits passes from 9 
to 7 and the TTEM will be weekly transmitted from week 6 to the end of the study instead 
of to be transmitted daily from week 6 to week 8 and then every two days from week 9 to 
week 24.These changes do not affect the overall risk of the study. The frequency of visits 
remains what is usually done in daily practice. A weekly TTEM has no impact on patient 
safety because on one hand patients are treated with an anticoagulant throughout the study 
and on the other hand a TTEM can be performed at any time in case of AF or atrial flutter 
symptoms. 
− Patients must have a previous history of a first documented persistent Atrial Fibrillation 
without limitation in time instead of no longer than 3 years. This modification will expand 
the target population without changing the characteristics of the selected patients by 
enabling the management of patients who could experience a long period without AF 
relapse nor atrial flutter emergence. 
− Patients must have a systolic heart failure defined by a reduced ventricular ejection 
fraction and or defined also through other echocardiographic parameters mentioned in the 
ESC guidelines for the diagnosis and treatment of acute and chronic heart failure (2012). 
- Regarding previous prohibited treatments by amiodarone or droderanone, the non 
inclusion criteria of the protocol are adapted as follow: 
• Concomitant treatment with oral amiodarone or dronedarone from selection 
• Concomitant treatment with intravenous amiodarone from selection 
 
Final version
815/1185


Despite the long half life of amiodarone, these time limits relating to its non-use before 
inclusion should not interfere in a major way with the assessment of the product 6 months 
after inclusion.  
 
 
 
 
 
 
 
Final version
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2. CHANGES DESCRIPTION 
 
PREVIOUS VERSION 
MODIFIED VERSION 
CLINICAL RESEARCH ORGANISATIONS 
For Feasibility, Monitoring and Regulatory issues: 
Pharmaceutical Service Network (PSN) 
Rufino Gonzalez 
28 037 Madrid - SPAIN 
Phone: +34 91 375 6930 - Fax: +34 91 375 6931 
E-mail: www.psnglobal.org 
 
 
For refund of patients expenses linked to the study (in 
France): 
CLINACT 
6-10 rue TROYON 
92310 SEVRES – FRANCE 
Phone: +33 1 46 90 27 27 - Fax: +33 1 46 23 01 56 
Email: sebastien.beaumont@clinact.com 
CLINICAL RESEARCH ORGANISATIONS 
For Feasibility, Monitoring and Regulatory issues (in 
Hungary, Czech Republic and Italy): 
Pharmaceutical Service Network (PSN) 
Rufino Gonzalez 
28 037 Madrid - SPAIN 
Phone: +34 91 375 6930 - Fax: +34 91 375 6931 
E-mail: rzurita@psnglobal.org 
 
For refund of patients expenses linked to the study (in 
France): 
CLINACT 
6-10 rue TROYON 
92310 SEVRES – FRANCE 
Phone: +33 1 46 90 27 27 - Fax: +33 1 46 23 01 56 
Email: sebastien.beaumont@clinact.com 
SYNOPSIS 
Planned Study Period: January 2013 –  January 2015 
SYNOPSIS 
Planned Study Period: January 2013 –  April 2016 
Methodology : 
- Start of treatment 4 weeks before ECV 
• 
Condition to ECV:  
− 
INR 2-3 (anti-vitamin K should be given at least 
3 weeks before ECV) 
− 
No spontaneous cardioversion before ECV 
 
• 
Cardiac monitoring: 
- 
TTEM: daily transmission from week 6 to week 
8; then every two days from week 9 to week 24, 
and in case of AF symptoms. 
 
Methodology : 
- Start of treatment 4 weeks before ECV 
• 
Condition to ECV:  
− 
Ideally INR 2-3 (vitamin K antagonist should be 
given at least 3 weeks before ECV) 
− 
No spontaneous cardioversion before ECV 
 
• 
Cardiac monitoring: 
− TTEM: one transmission per week from the day of 
visit 4 (end of week 5) to visit 9 (week 24) and at 
any time in case of AF or atrial flutter symptoms. 
 
Study Schedule: 
9 visits will be scheduled: 
- V1/ W-4 to W-1: selection visit (7 to 28 days before the 
inclusion visit)  
- V2/ D1: Inclusion visit (start of study treatment) 
- V3/ W4 (D28 -2/+7 days): cardioversion visit 
(outpatient or hospitalization according to clinical 
Study Schedule: 
7 visits will be scheduled: 
- V1/ W-4 to W-1: selection visit (7 to 28 days before the 
inclusion visit)  
- V2/ D1: Inclusion visit (start of study treatment) 
- V3/ W4 (D28 -2/+7 days): cardioversion visit (outpatient 
or hospitalization according to clinical practice of the 
Final version
817/1185


PREVIOUS VERSION 
MODIFIED VERSION 
practice of the centre) (installation of the Holter device) 
- V4/ W5 (D35 -2/+7 days): follow-up visit (removing of 
the Holter device and installation of the TTEM) 
- V5/ W8 (D56± 7 days): follow-up visit 
- V6/ W12 (D84 ± 7 days): follow-up visit 
-  V7/ W16 (D112 ± 7 days): follow-up visit 
- V8/ W20 (D140 ± 7 days): follow-up visit 
-  V9/ W24 (D168 ± 7 days): final study visit 
centre) (installation of the Holter device) 
-   V4/ W5 (D35 -2/+7 days): follow-up visit (removing of 
the Holter device and installation of the TTEM) 
- V5/ W8 (D56± 7 days): follow-up visit 
- V6/ W12 (D84 ± 7 days): follow-up visit 
- V7/ W16 (D112 ± 7 days): follow-up visit 
- V8/ W20 (D140 ± 7 days): follow-up visit 
- V9/ W24 (D168 ± 7 days): final study visit 
Diagnosis and Criteria for Inclusion: 
Inclusion Criteria: 
Demographic Characteristics and Other Baseline 
Characteristics: 
[…] 
3. History of first documented persistent AF less than 3 
years. 
4. History of ischemic or non ischemic heart failure 
 
 […] 
6. Reduced left ventricular ejection fraction between 
30% and 45% inclusive (using the two-dimensional 
echocardiography biplane Simpson’s rule) at selection 
and at inclusion 
[…] 
Diagnosis and Criteria for Inclusion: 
Inclusion Criteria: 
Demographic Characteristics and Other Baseline 
Characteristics: 
[…] 
3. Previous history of first documented episode of
persistent AF  
 4.  Previous history of ischemic or non ischemic heart 
failure  
[…] 
6.    Left ventricular systolic dysfunction defined at 
selection and at inclusion by a reduced left ventricular 
ejection fraction (LVEF) ≥ 30% and ≤ 45% or for 
patients with a LVEF > 45%: 
• an increased left ventricular end-diastolic size  
(diameter ≥ 60 mm and/or > 32 mm/m² and/or 
volume > 97 ml/m²) 
• and/or an increased left ventricular end-
systolic size 
(diameter > 45 mm and/or > 25 mm/m² and/or 
volume > 43 ml/m²) 
• and/or a reduced left ventricular outflow tract 
velocity time integral < 15 cm 
[…] 
Final version
818/1185


PREVIOUS VERSION 
MODIFIED VERSION 
Non-Inclusion Criteria: 
Criteria related to pathologies: 
1.  History of first documented episode of persistent AF 
more than 3 years 
[…] 
Criteria related to treatments: 
12. Concomitant treatment with ranolazine or any 
antiarrhythmic drug (within 7 days prior to selection), 
except stable dose of digoxin, betablockers, calcium-
blockers 
13. Oral amiodarone: 
            13a  Previous treatment with oral amiodarone within 
4 months prior to inclusion 
           13b  Intake of oral amiodarone for more than 1 
month within 4 to 12 months before inclusion 
 
14. Previous treatment with intravenous amiodarone 
within 4 weeks prior to inclusion 
[…] 
19. Patient treated with other anticoagulant treatment than 
antivitamin K: thrombin inhibitor such as Dabigatran 
or treated with antiaggregant P2Y12 inhibitors such as 
Clopidogrel or Prasugrel 
 
Non-Inclusion Criteria: 
Criteria related to pathologies: 
1. No previous history of first documented episode of 
persistent AF 
 […] 
Criteria related to treatments: 
12. Concomitant treatment with ranolazine or any 
antiarrhythmic drug (within 7 days prior to selection), 
except  amiodarone, dronedarone and stable dose of 
digoxin, betablockers, calcium-blockers 
13. Concomitant  treatment with oral amiodarone or 
dronedarone from selection  
 
 
 
 
14. Concomitant 
treatment 
with 
intravenous 
amiodarone from selection  
 
[…] 
19. Patient treated with oral anticoagulant treatment other 
than vitamin K antagonist: new oral anticoagulants 
(dabigatran, rivaroxaban, apixaban), or treated with 
irreversible antiplatelet agents P2Y12 inhibitors 
such as ticlopidine, clopidogrel or prasugrel 
 
Exclusion criteria before V3: 
Patients not stabilized for INR (i.e. values not between 2 
and 3) on at least 3 consecutive weekly tests performed 
before ECV will be excluded from the study, unless the 
presence of atrial thrombosis may be excluded with ECHO 
–TE (trans-esophageal echocardiograph) performed  in the 
same day (before ECV) 
ECV will be performed in patients without dyskalemia 
Exclusion criteria before V3: 
Patients without dyskalemia who will not have INR 
values ≥ 2 on the 3 last tests performed before ECV 
should not have an ECV and will be excluded from the 
study. 
However, if only 2 INR values are ≥ 2 among those 3 last 
tests, an ECV can be performed if the presence of atrial 
thrombosis can be excluded with an ECHO–TE 
(transesophageal echocardiography) performed on the 
Final version
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PREVIOUS VERSION 
MODIFIED VERSION 
If necessary for obtaining stabilized INR between 2 and 3, 
the ECV (and following visits) could be postponed by 7 
days. 
[…] 
same day (before ECV) and the patient can continue the 
study.  
If necessary, for meeting these INR conditions, the ECV 
(and following visits) could be postponed by 7 days. 
[…] 
Evaluation Criteria: 
Efficacy evaluation variables: 
Primary evaluation variable: 
- Time to first Atrial Fibrillation recurrence defined by the 
first episode of AF lasting for at least 10 minutes 
(Follow up of 20 weeks after visit 3 – ECV visit). 
Handling of AF recurrences: 7-day continuous ECG (5-
leads/2 or 3 channels) ambulatory recording (holter ECG) 
between visit 3 (ECV visit) and visit 4 (week 5). Then, the 
follow up will be documented using the TTEM: daily 
transmission from week 6 to week 8. Then, every two days 
from week 9 to week 24. 
For randomised patients with spontaneous cardioversion 
before ECV, the recurrence of AF will be assessed after 
visit 3 (week 5).  
Moreover, during this TTEM period, if patient experiences 
any AF symptoms, it should be recorded and documented 
using the TTEM.  
All ECG traces will be evaluated by a Central Reading 
Laboratory. 
[…] 
Evaluation Criteria: 
Efficacy evaluation variables: 
Primary evaluation variable: 
- Time to first Atrial Fibrillation recurrence or atrial 
flutter emergence defined by the time to first episode of 
AF or atrial flutter lasting for at least 10 minutes 
(Follow up of 20 weeks after visit 3 – ECV visit). 
Handling of AF recurrences or atrial flutter emergences: 
7-day 
continuous 
ECG 
(5-leads/2 
or 3 
channels) 
ambulatory recording (holter ECG) between visit 3 (ECV 
visit) and visit 4 (week 5). Then, the follow up will be 
documented using the TTEM: one transmission per week 
from the day of visit 4 (end of week 5) to visit 9 (week 
24). 
For randomised patients with spontaneous cardioversion 
before ECV, the recurrence of AF or the emergence of 
atrial flutter will be assessed after visit 3 (from week 5).  
Moreover, during this TTEM period, if patient experiences 
any AF or atrial flutter symptoms, it should be recorded 
and documented using the TTEM. 
All ECG (Holter and TTEM) will be evaluated by a Central 
Reading Laboratory. 
 […] 
Statistical Methods: 
Sample Size: 
Assuming an AF recurrence rate under placebo of 85%, a 
power of 80%, an alpha risk of 5% and a rate of not 
assessable patients of 15%, 76 randomised patients per 
Statistical Methods: 
Sample Size: 
Assuming an AF recurrence or atrial flutter emergence 
rate under placebo of 85%, a power of 80%, an alpha risk 
of 5% and a rate of not assessable patients of 15%, 76 
Final version
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PREVIOUS VERSION 
MODIFIED VERSION 
group will be necessary, using a log-rank test of survival 
curves, a difference between groups of 20%. 
randomised patients per group will be necessary, using a 
log-rank test of survival curves, a difference between 
groups of 20%.  
STUDY FLOW CHART 
Please see flow-chart of previous version in appendix 1 
STUDY FLOW CHART 
Please see flow-chart of modified version in appendix 2 
3.  ETHICAL CONSIDERATIONS RELATING 
TO THE STUDY 
[…] 
During the study, in case of AF recurrence that would 
require cardioversion or the introduction of an anti-
arrhythmic because of intolerable and/or uncomfortable 
clinical symptoms for instance, patients will be withdrawn 
and the tested product stopped. 
[…] 
- ECV in patients with stabilized INR (i.e. values between 
2 and 3;sp to ) on at least 3 consecutive weekly tests 
performed. Patients not stabilized for INR (i.e. values not 
between 2 and 3) on at least 3 consecutive weekly tests 
performed before ECV will be excluded from the study, 
unless the presence of atrial thrombosis may be excluded 
with ECHO –TE (trans-esophageal echocardiograph) 
performed in the same day (before ECV). Patients who do 
not revert to sinus rhythm or present an early relapse 
within the observation period after ECV will be withdrawn 
and the tested product stopped. 
During the whole study, patients will remain under 
medical control: visits in cardiology units will be 
scheduled at least every month. This follow up will include 
clinical signs, ECG, biological and coagulation parameters. 
Moreover, patient’s cardiac rhythm will be monitored 
between visits using daily, then every 2 days Trans 
Telephonic ECG Monitoring (TTEM) reviewed by a 
Central Reading Laboratory. 
[…] 
3.  ETHICAL CONSIDERATIONS RELATING 
TO THE STUDY 
[…] 
During the study, in case of AF recurrence or atrial flutter 
emergence that would require cardioversion or the 
introduction of an anti-arrhythmic because of intolerable 
and/or uncomfortable clinical symptoms for instance, 
patients will be withdrawn and the tested product stopped. 
[…] 
- ECV will be performed in patients with AF and 
without dyskalemia. An INR value control must be 
performed within 24h before ECV. INR values ≥ 2 on 
the 3 last tests performed before ECV are required. 
However, if only 2 INR values are ≥ 2 among those 3 last 
tests, an ECV can be performed if the presence of atrial 
thrombosis can be excluded with an ECHO–TE 
(transesophageal echocardiography) performed on the 
same day (before ECV) and the patient can continue the 
study. Patients who do not revert to sinus rhythm or present 
an early AF relapse or an early atrial flutter emergence 
within the observation period after ECV will be withdrawn 
and the tested product stopped. 
During the whole study, patients will remain under medical 
control: visits in cardiology units will be performed 
throughout the study period. This follow up will include 
clinical signs, ECG, biological and coagulation parameters. 
Moreover, patient’s cardiac rhythm will be monitored once 
a week between visits using Trans Telephonic ECG 
Monitoring (TTEM) reviewed by a Central Reading 
Final version
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PREVIOUS VERSION 
MODIFIED VERSION 
Laboratory. 
 […] 
4.  STUDY DESIGN 
4.1 OVERALL DESCRIPTION 
 
[…] 
Nine visits are planned for the study: 
- 
Visit 1 (V1): W-4 to W-1: Selection visit (7 to 28 days 
before the Inclusion Visit) 
- 
Visit 2 (V2): D1: Inclusion visit (start of study 
treatment)  
- 
Visit 3 (V3): W4 (D28 -2/+7D): cardioversion visit 
(outpatient or hospitalization according to clinical 
practice of the centre) (installation of the Holter ECG 
device) 
- 
Visit 4 (V4): W5 (D35 -2/+7D): follow-up visit 
(removing of Holter ECG device and installation of 
the TTEM) 
- 
Visit 5 (V5): W8 (D56 ± 7D): follow-up visit 
- 
Visit 6 (V6): W12 (D84 ± 7D): follow-up visit 
- 
Visit 7 (V7): W16 (D112 ± 7D) : follow-up visit 
- 
Visit 8 (V8): W20 (D140 ± 7D): follow-up visit 
- 
Visit 9 (V9): W24 (D168 ± 7D): final study visit 
[…] 
4.  STUDY DESIGN 
4.1 OVERALL DESCRIPTION 
 
[…] 
Seven visits are planned for the study: 
- 
Visit 1 (V1): W-4 to W-1: Selection visit (7 to 28 days 
before the Inclusion Visit) 
- 
Visit 2 (V2): D1: Inclusion visit (start of study 
treatment)  
- 
Visit 3 (V3): W4 (D28 -2/+7D): cardioversion visit 
(outpatient or hospitalization according to clinical 
practice of the centre) (installation of the Holter ECG 
device) 
- 
Visit 4 (V4): W5 (D35 -2/+7D): follow-up visit 
(removing of Holter ECG device and installation of the 
TTEM) 
- 
Visit 5 (V5): W8 (D56 ± 7D): follow-up visit 
- 
Visit 6 (V6): W12 (D84 ± 7D): follow-up visit 
- 
Visit 7 (V7): W16 (D112 ± 7D) : follow-up visit 
- 
Visit 8 (V8): W20 (D140 ± 7D): follow-up visit 
- 
Visit 9 (V9): W24 (D168 ± 7D): final study visit 
[…] 
4.2. DISCUSSION OF THE STUDY DESIGN 
4.2.1. Choice of the Study Population 
[…] 
The study aim is to investigate the product effect in 
patients with: 
- Persistent AF history (less than three years) with a 
duration of the current episode from 7 days to 6 
months. 
- a moderately abnormal systolic heart failure (Left 
Ventricular Ejection Fraction (LVEF) between 30 to 
45% as defined in the report from the American 
Society of Echocardiography’s Guideline).  
4.2. DISCUSSION OF THE STUDY DESIGN 
4.2.1. Choice of the Study Population 
[…] 
The study aim is to investigate the product effect in patients 
with: 
- 
Previous history of persistent AF with duration of the 
current episode from 7 days to 6 months. 
- 
A systolic heart failure defined by a reduced left 
ventricular ejection fraction (≥ 30% and ≤ 45%) or 
for patients with a LVEF > 45%: 
• 
an increased left ventricular end-diastolic size 
(diameter ≥ 60 mm and/or > 32 mm/m² and/or 
Final version
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PREVIOUS VERSION 
MODIFIED VERSION 
  
 
 
 
 
 
 
[…] 
- a Left Atrial Area (LAA) not severely abnormal (less 
than 40 cm2 as defined in the report from the 
American Society of Echocardiography’s Guideline). 
volume > 97 ml/m²),  
• 
and/or an increased left ventricular end-
systolic size (diameter > 45 mm and/or > 25 
mm/m² and/or volume > 43 ml/m²),  
• 
and/or a reduced left ventricular outflow tract 
velocity time integral < 15 cm [23, 24].  
 […] 
- A Left Atrial Area (LAA) not severely abnormal (no 
greater than 40 cm2 as defined in the report from the 
American Society of Echocardiography’s Guideline) 
[23]. 
4.2.2. Choice of the Study Design 
 
[…] 
According to the target indication, only patients with 
persistent AF and requiring an ECV will be included in 
order to assess the time to first documented recurrence of 
AF since cardioversion. 
To confirm the persistent nature of AF, a 24-hour holter 
monitoring will be performed during the selection visit.  
Eligible participants will enter a selection phase in which 
anticoagulant treatment (AVK) will be adjusted to achieve 
an International Normalized Ratio (INR) of 2.0 to 3.0 
before ECV. According to guidelines for the management 
of AF [6], AVK should be given at least 3 weeks before 
cardioversion because of risk of thrombo-embolism due to 
post-cardioversion.   
[…] 
Finally, during the study, patients will be scheduled for a 
clinical visit every month (with an additional visit 7 days 
after visit 3 (ECV visit)) in order to ensure a close medical 
monitoring and to assess efficacy and safety parameters. 
[…] 
4.2.2. Choice of the Study Design 
 
[…] 
According to the target indication, only patients with 
persistent AF and requiring an ECV will be included in 
order to assess the time to first documented recurrence of 
AF (or emergence of atrial flutter) since cardioversion. 
To confirm the persistent nature of AF, a 24-hour holter 
monitoring will be performed during the selection visit.  
Eligible participants will enter a selection phase in which 
anticoagulant treatment (VKA) will be adjusted to achieve 
ideally an International Normalized Ratio (INR) of 2 to 3 
before ECV. According to guidelines for the management 
of AF [6], VKA should be given at least 3 weeks before 
cardioversion because of risk of thrombo-embolism due to 
post-cardioversion. 
[…] 
Finally, during the study, patients will be scheduled for a 
clinical visit every 4 weeks or 8 weeks (with an additional 
visit 7 days after visit 3 (ECV visit)) in order to ensure a 
close medical monitoring and to assess efficacy and safety 
parameters. 
[…] 
 
 
Final version
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PREVIOUS VERSION 
MODIFIED VERSION 
5.  STUDY POPULATION 
5.1 INCLUSION CRITERIA 
Demographic Characteristics and Other Baseline 
Characteristics: 
[…] 
3. History of first documented persistent AF less than 
3 years 
4. History of ischemic or non ischemic heart failure 
[…] 
 
6.  Reduced left ventricular ejection fraction between 30% 
and 45% inclusive (using the two-dimensional 
echocardiography biplane Simpson’s rule) at selection 
and at inclusion 
 […] 
5.  STUDY POPULATION 
5.1 INCLUSION CRITERIA 
Demographic Characteristics and Other Baseline 
Characteristics: 
[…] 
3. Previous history of first documented episode of 
persistent AF  
4. Previous history of ischemic or non ischemic heart 
failure  
[…] 
6.  Left ventricular systolic dysfunction defined at selection 
and at inclusion by a reduced left ventricular ejection fraction 
(LVEF) ≥ 30% and ≤ 45% or for patients with a LVEF > 
45%: 
• an increased left ventricular end-diastolic size (diameter 
≥ 60 mm and/or > 32 mm/m² and/or volume > 97 ml/m²) 
• and/or an increased left ventricular end-systolic size 
(diameter > 45 mm and/or > 25 mm/m² and/or volume > 
43 ml/m²) 
• and/or a reduced left ventricular outflow tract velocity 
time integral < 15 cm 
 […] 
 
 
 
 
Final version
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PREVIOUS VERSION 
MODIFIED VERSION 
5.2  NON INCLUSION CRITERIA 
Criteria related to pathologies: 
1. History of first documented episode of persistent AF 
more than 3 years, 
[…] 
Criteria related to treatments: 
[…] 
 
12. Concomitant treatment with ranolazine or any 
antiarrhythmic drug (within 7 days prior to selection), 
except stable dose of digoxin, betablockers, calcium-
blockers 
13. Oral amiodarone: 
            13a  Previous treatment with oral amiodarone within 
4 months prior to inclusion 
           13b  Intake of oral amiodarone for more than 1 
month within 4 to 12 months before inclusion 
 
14. Previous treatment with intravenous amiodarone 
within 4 weeks prior to inclusion  
[…] 
 
19. Patient treated with other anticoagulant treatment than 
antivitamin K: thrombin inhibitor such as Dabigatran 
or treated with antiaggregant P2Y12 inhibitors such as 
Clopidogrel or Prasugrel 
 
5.2  NON INCLUSION CRITERIA 
Criteria related to pathologies: 
1. No previous history of first documented episode 
of persistent Atrial Fibrillation 
  […] 
Criteria related to treatments: 
[…] 
 
12. Concomitant treatment with ranolazine or any 
antiarrhythmic drug (within 7 days prior to selection), 
except  amiodarone, dronedarone and stable dose of 
digoxin, betablockers, calcium-blockers 
13. Concomitant  treatment with oral amiodarone or 
dronedarone from selection 
 
 
 
 
14. Concomitant 
treatment 
with 
intravenous 
amiodarone from selection  
[…] 
 
19.  Patient treated with oral anticoagulant treatment other 
than vitamin K antagonist: new oral anticoagulants  
(dabigatran, rivaroxaban, apixaban), or treated with 
irreversible antiplatelet agents P2Y12 inhibitors such as 
ticlopidine, clopidogrel or prasugrel 
 
5.6 WITHDRAWAL CRITERIA 
[…] 
• 
Erroneous inclusion according to the study protocol. 
Any inclusion not respecting inclusion/non inclusion 
criteria will immediately be withdrawn and an 
appropriate treatment will be given by the investigator 
5.6 WITHDRAWAL CRITERIA 
[…] 
• Erroneous inclusion according to the study protocol. 
The decision to maintain or not the patient in the 
study will be taken jointly by the investigator and the 
sponsor. Erroneous inclusions will not be paid to the 
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under his/her responsibility. Erroneous inclusions will 
not be paid to the investigator.  
• 
Patients who could not be treated with AVK for at 
least 3 weeks before ECV. 
• 
Patients who will not have a stabilized INR between 2 
and 3 on at least 3 consecutive weekly tests. 
• 
Patients with only 2 consecutives INR tests between 2 
and 3 in the last 3 weeks for whom a trans-
oesophagoal echocardiography can not be performed 
before ECV or for whom a trans-oesophagoal 
echocardiography shows a thrombus in the atria. 
• 
Patients who will not revert to sinus rhythm (i.e. 
unsuccessful ECV) or with early relapse within the 
observation period after ECV will be considered to 
have finished follow-up. 
• 
Occurrence of AF recurrence that would require, at 
the investigator’s judgement, a cardioversion or an 
introduction of an anti-arrhythmic because of 
intolerable and/or uncomfortable clinical symptoms 
for instance.  
[…] 
investigator. 
• Patients who could not be treated with VKA for at least 
3 weeks before ECV or who will experience a VKA 
intolerance during the study. 
• Patients without dyskalemia who will not have INR 
values ≥ 2 on the 3 last tests performed before ECV 
should not have an ECV and will be excluded from 
the study. However, if  only 2 INR values are ≥ 2 
among those 3 last tests, an ECV can be performed if 
the presence of atrial thrombosis can be excluded 
with 
an 
ECHO–TE 
(transesophageal 
echocardiography) performed on the same day 
(before ECV) and the patient can continue the study. 
• Patients who will not revert to sinus rhythm (i.e. 
unsuccessful ECV) or with early AF relapse or early 
atrial flutter emergence within the observation period 
after ECV will be considered to have finished follow-up. 
•  Occurrence of AF recurrence or atrial flutter 
emergence that would require, at the investigator’s 
judgement, a cardioversion or an introduction of an anti-
arrhythmic because of intolerable and/or uncomfortable 
clinical symptoms for instance. 
[…] 
6. STUDY TREATMENT 
6.2. 
PACKAGING AND LABELLING 
6.2.1. 
Packaging 
[…] 
The Investigator will provide the patient with the treatment 
according to the following schedule: 
At Inclusion Visit (V2): a 12-week treatment unit will 
contain 3 cases, each case containing: 
- 10 blister packs of four 1 g F373280 soft capsules or 
placebo soft capsules each. 
At Visit 6 (V6): a 12-week treatment unit will contain 3 
cases, each case containing: 
6. STUDY TREATMENT 
6.2.   PACKAGING AND LABELLING 
6.2.1. 
Packaging 
[…] 
Two 12-week treatment units will contain 3 cases, each 
case of 4-week treatment containing: 10 blister packs of 
four 1 g F373280 soft capsules or 1 g placebo soft capsules 
each. 
 […] 
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- 10 blister packs of four 1 g F373280 soft capsules or 
placebo soft capsules each. 
[…] 
6.4 ALLOCATION OF TREATMENTS AND 
DISPENSATION TO PATIENT 
 
[…] 
Practically, once patient’s eligibility is confirmed at 
selection visit (V1):  
• The Investigator: 
− Contacts the IVRS/IWRS 
− Answers the questions relating to the patient  
− In return, the treatment number to be allocated for the 
first 12-week period to the patient is given by the 
IVRS/IWRS.  
[…] 
 
The Investigator will dispense to the patient the case which 
label indicates the treatment number and the administration 
period. 
At visit 6, the Investigator will contact again the 
IVRS/IWRS to obtain the treatment number for the last 12-
week period of treatment according to the same process as 
described above. 
6.4 ALLOCATION OF TREATMENTS AND 
DISPENSATION TO PATIENT 
 
[…] 
At selection visit (V1), practically, once patient’s eligibility 
is confirmed:  
• The Investigator: 
− Contacts the IVRS/IWRS 
− Answers the questions related to the patient  
 […] 
 
At inclusion visit (V2), the treatment number to be 
allocated for the first 12-week period to the patient is 
given by the IVRS/IWRS.  
At visit 6, the Investigator will contact again the 
IVRS/IWRS to obtain the treatment number for the last 12-
week period of treatment according to the same process as 
described above. 
The Investigator will dispense to the patient the 4-week 
treatment cases (one or two according to the visit) which 
label 
indicates 
the 
treatment 
number 
and 
the 
administration period. 
 
7. CONCOMITANT TREATMENTS 
7.1. ANTI-VITAMIN K TREATMENT 
AVK should be given for at least 3 weeks before ECV and 
continued for the whole study duration. The AVK used 
will be left to the decision of the each Investigator 
according to his/her local practice. 
7. CONCOMITANT TREATMENTS 
7.1. VITAMIN K ANTAGONIST TREATMENT 
VKA should be given for at least 3 weeks before ECV and 
continued for the whole study duration. However, VKA 
should be stopped in case of occurrence of VKA 
intolerance during the study and the patient should be 
withdrawn from the study. The VKA used will be left to 
the decision of each Investigator according to his/her local 
practice. 
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7.2. PROHIBITED TREATMENTS 
[…] 
Any anticoagulant treatment other than AVK: thrombin 
inhibitor such as Dabigatran or antiaggregant P2Y12 
inhibitors such as Clopidogrel or Prasugrel 
[…] 
7.2. PROHIBITED TREATMENTS 
[…] 
Any oral anticoagulant treatment other than VKA: new 
oral 
anticoagulants 
(dabigatran, 
rivaroxaban, 
apixaban), or irreversible antiplatelet agents P2Y12 
inhibitors such as ticlopidine, clopidogrel or prasugrel  
[…] 
 
8.  EVALUATION CRITERIA 
8.1  PRIMARY EFFICACY CRITERIA 
8.1.1. 
Time to the first Atrial Fibrillation Recurrence 
8.1.1.1. Definition 
Time to first AF recurrence is defined by the first episode 
of AF (symptomatic or not) lasting for at least 10 minutes. 
 
 
8.1.1.2. Schedule 
The heart rhythm follow up will be performed from the 
end of ECV visit (visit 3) to the final study visit (visit 9).  
For randomised patients with spontaneous cardioversion 
before ECV, the recurrence of AF will be assessed after 
visit 3 (week 5). 
 
8.1.1.3. Evaluation Methods 
[…] 
• 
Trans Telephonic ECG Monitoring: 
The ECG follow up will be documented using the TTEM: 
daily transmission from the day after visit 4 (week 6) to 
visit 5 (week 8). Then every two days from the day after 
visit 5 (week 9) to visit 9 (week 24 – End of study). 
Moreover, if patient experiences AF symptoms during this 
TTEM period, it should be documented using the TTEM. 
In case of AF recurrence and provided that the patient does 
not require a cardioversion or an introduction of an anti-
8.  EVALUATION CRITERIA 
8.1  PRIMARY EFFICACY CRITERIA 
8.1.1. 
Time to the first Atrial Fibrillation Recurrence 
or Atrial Flutter Emergence 
8.1.1.1. Definition 
Time to first AF recurrence or atrial flutter emergence is 
defined by the time to first episode of AF or atrial flutter 
(symptomatic or not) lasting for at least 10 minutes. 
 
8.1.1.2. Schedule 
The heart rhythm follow up will be performed from the end 
of ECV visit (visit 3) to the final study visit (visit 9).  
For randomised patients with spontaneous cardioversion 
before ECV, the recurrence of AF or the emergence of 
atrial flutter will be assessed after visit 3 (from week 5). 
 
8.1.1.3. Evaluation Methods 
[…] 
• Trans Telephonic ECG Monitoring: 
The ECG follow up will be documented using the TTEM: 
one transmission per week from the day of visit 4 (end 
of week 5) to visit 9 (week 24, end of study). The patient 
will be requested to contact the Central Reading 
Laboratory for transmission of each stored TTEM. 
Moreover, if patient experiences AF or atrial flutter 
symptoms during this TTEM period, it should be 
documented using the TTEM. 
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arrhythmic at Investigator’s judgement, the patient could 
be maintained in the study with the treatment in order to 
assess a spontaneous cardioversion. For that purpose the 
patient will continue to transmit a TTEM once a week. 
The TTEM will be centralized by the Central Reading 
Laboratory. The patient will be requested to contact the 
Central Reading Laboratory for transmission of each 
stored TTEM. The TTEM will be validated by a trained 
technician, then analysed by a cardiologist. The 
cardiologist interpretation will be emailed to the site (or 
per fax on request of the site). The investigator will be 
asked to review and sign this document. 
The TTEM process will be fully described in a separate 
document. 
In case of AF recurrence or atrial flutter emergence and 
provided that the patient does not require a cardioversion or 
an introduction of an anti-arrhythmic at Investigator’s 
judgement, the patient could be maintained in the study 
with the treatment in order to assess a spontaneous 
cardioversion. For that purpose the patient will continue to 
transmit a TTEM once a week. 
• Process of centralisation of ECG (Holter and TTEM) 
ECG (Holter and TTEM) will be centralized by the 
Central Reading Laboratory. The ECG will be validated by 
a trained technician, then analysed by a cardiologist. The 
cardiologist interpretation will be emailed to the site (or per 
fax on request of the site). The investigator will be asked to 
review and sign these documents. 
The Holter and TTEM process will be fully described in 
separate documents. 
 
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8.1.2 Secondary Efficacy Criteria 
8.1.2.3. Clinical parameters evaluation 
8.1.2.3.1. EHRA score assessment 
8.1.2.3.1.3. Evaluation Methods 
EHRA evaluation will be collected by Central Reading 
Laboratory during all the study period. 
8. 2 SECONDARY EFFICACY CRITERIA 
8.2.3. 
Clinical parameters evaluation 
8.2.3.1. EHRA score assessment 
8.2.3.1.3. Evaluation Methods 
EHRA evaluation will be collected by Central Reading 
Laboratory during TTEM period. 
 
 
8.2.3.2. Time to first AF recurrence less than 10 
minutes 
 
Time to first AF recurrence less than 10 minutes will be 
assessed during TTEM period. 
 
8.1.2.3.2. Number of recurrence of symptomatic AF  
It consists of the number of AF recurrences associated with 
a symptom (palpitation, fatigue, dizziness, dyspnea, chest 
pain and anxiety) and confirmed by an ECG. 
8.2.3.3 Recurrence of symptomatic AF  
Recurrence of symptomatic AF will be assessed during 
TTEM period. 
The number of recurrences of symptomatic AF consists 
of the number of AF recurrences associated with a 
symptom (palpitation, fatigue, dizziness, dyspnea, chest 
pain and anxiety) and confirmed by an ECG. 
The time to first symptomatic AF recurrence is defined 
by the time to first episode of symptomatic AF. 
 
8.2. BIOMARKER ASSESSMENT: RED BLOOD 
CELL CONCENTRATIONS OF DHA 
8.2.2 Blood samples 
8.2.2.2. Technical handling 
Two blood samples (4 ml) will be collected in EDTA 
tubes. They will be gently shaken, stored between 
+2°C/+8°C in a fridge (no freezing will be allowed) and 
sent to Analytical Centre in refrigerated conditions 
(between +2°C and +8°C). 
[…] 
8.3. BIOMARKER ASSESSMENT: RED BLOOD 
CELL CONCENTRATIONS OF DHA 
8.3.2 Blood samples 
8.3.2.2. Technical handling 
Two blood samples (2 x 4 ml) will be collected in EDTA 
tubes. They will be homogenized slowly by inverting the 
tube without shaking, stored between +2°C/+8°C in a 
fridge (no freezing will be allowed) and sent to Analytical 
Centre in refrigerated conditions (between +2°C and +8°C). 
[…] 
 
 
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8.3 SAFETY ASSESSMENT  
8.3.2 Laboratory Investigations 
8.3.2.2 Technical Procedures and Parameters 
Haematology: hematocrit, haemoglobin, RBC count, 
white blood cells (WBC) count, WBC 
differential counts (% and absolute), 
reticulocytes, platelets.  
 
Chemistry: 
 […] 
 
 
Additional tests may be done at the Investigator’s 
discretion, in the patient’s interest. In case of any abnormal 
or clinically significant results, the Investigator will order 
laboratory control tests. 
 
8.4 SAFETY ASSESSMENT  
8.4.2 Laboratory Investigations 
8.4.2.2 Technical Procedures and Parameters 
[…] 
Haematology: 
haematocrit, haemoglobin, RBC count, 
white blood cells (WBC) count, WBC 
differential counts (% and/or absolute), 
reticulocytes, platelets.  
 
Biochemistry       […] 
 
 
Additional tests may be done at the Investigator’s 
discretion, in the patient’s interest. In case of any abnormal 
and/or clinically significant results, the Investigator should 
order laboratory control tests. 
 
8.3.3. Global Physical Examination 
A global physical examination including the measurement 
of body weight will be carried out on each body system at 
visit 1, visit 2, visit 3, visit 5, visit 6, visit 7, visit 8 and 
visit 9. 
[…] 
8.4.3. Global Physical Examination 
A global physical examination including the measurement 
of body weight will be carried out on each body system at 
visit 1, visit 2, visit 3, visit 4, visit 5, visit 6, visit 7, visit 8  
and visit 9 
[…]. 
8.3.5. 
Electrocardiogram (ECG)  
8.3.5.1. 
Schedule 
An ECG will be recorded after at least 10 minutes of rest 
at visit 1, visit 2, visit 3, visit 5, visit 6, visit 7, visit 8 and 
visit 9 using an usual standardised 12-lead cardiograph. 
[…] 
8.4.5. 
Electrocardiogram (ECG)  
8.4.5.1. 
Schedule 
An ECG will be recorded after at least 10 minutes of rest at 
visit 1, visit 2, visit 3, visit 5, visit 6, visit 7, visit 8 and visit 
9 using an usual standardised 12-lead cardiograph. 
[…] 
8.3.6 Coagulation parameters 
[…] 
During the pre-cardioversion period, if the anticoagulation 
by AVK should be initiated, then the INR monitoring will 
be as follow:  
- 
INR 2-3 times a week for the first week of 
treatment 
8.4.6 Coagulation parameters 
[…] 
The recommendations for the controls of INR are the 
following [25, 26]: 
1) 
During 
the 
pre-cardioversion 
period, 
if 
the 
anticoagulation by VKA has to be initiated, the 
treatment must be initiated at least 3 weeks prior to 
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- 
INR weekly up to ECV 
- 
INR every 4 weeks after ECV 
For patients already treated with AVK, INR monitoring 
will be as follow: 
- 
INR weekly up to ECV 
- 
INR every 4 weeks after ECV 
aPTT and TCT will be performed at visit 1, visit 2, visit 3, 
visit 5, visit 6, visit 7, visit 8 and visit 9. 
Anti-coagulation by AVK should be given at least 3 weeks 
before ECV and continued for the whole study duration. 
The quantity of blood samples collected at each time for 
coagulation parameters will be 2 mL. 
Additional tests may be done at the Investigator’s 
discretion, in the patient’s interest. In case of any abnormal 
or clinically significant results, the Investigator will order 
laboratory control tests. 
 
 […] 
cardioversion then the INR will be monitored as follow:  
− 
The adjustment of the dosage of VKA should be 
performed stepwise by controlling INR 2 to 3 
times a week until stabilization within the target 
range (2 - 3) on 2 successive tests. 
− 
When the INR is within the target range (2 - 3) 
on 2 successive tests, the dose of VKA should be 
maintained. Then the controls of INR will be 
progressively spaced within a few weeks. 
− 
When INR is stabilized, at least one test should 
be performed each week. 
− 
In all cases, an INR control must be performed 
within 24 h before ECV. 
2) 
During 
the 
pre-cardioversion 
period, 
if 
the 
anticoagulation by VKA was already initiated, the INR 
will be monitored as follow: 
− 
One INR per week up to ECV 
− 
An INR control must be performed within 24 h 
before ECV 
3)  After cardioversion : one INR each month  
4) Throughout the duration of the study if INR > 3 the 
advocated actions are: 
− 
No 
transesophageal 
echocardiography 
before 
cardioversion 
− 
For asymptomatic patients:  
- 
3 < INR < 4: no omission of VKA (dose 
adjustment if required), no vitamin K 
- 
4 ≤ INR < 6: omit one dose of VKA, no vitamin K 
- 
6 ≤ INR < 10: interrupt VKA, vitamin K 2 mg 
orally 
- 
INR ≥ 10: interrupt VKA, vitamin K 5 mg orally 
For INR ≥ 6, an adverse event has to be reported 
(asymptomatic overdose). 
Anti-coagulation by VKA should be given at least 3 weeks 
before ECV and continued for the whole study duration. 
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aPTT and TCT will be performed at visit 1, visit 2, visit 3, 
visit 5, visit 6, visit 7, visit 8 and visit 9. 
The quantity of blood samples collected at each time for 
coagulation parameters will be 2 ml. 
Additional tests may be done at the Investigator’s 
discretion, in the patient’s interest. In case of any 
abnormal and/or clinically significant results, the 
Investigator should order laboratory control tests. 
 […] 
8.4 CONCOMITANT TREATMENTS 
 
Concomitant treatments will be evaluated at each study 
visit. 
Requirements relating to patient's concomitant treatments 
started before screening visit and continued throughout the 
trial, or started during the trial, can be found in section 7.  
8.5 CONCOMITANT TREATMENTS 
 
Concomitant treatments will be evaluated at each study 
visit. 
Requirements related to patient's concomitant treatments 
started before selection visit and continued throughout the 
trial, or started during the trial, can be found in section 7.  
9. 
STUDY PROCEDURES 
Visit 1 - Selection Visit (Week - 4 to Week -1): 
 […] 
• The patient will enter the selection period in which 
anticoagulant (AVK) will be adjusted to achieve an 
International Normalized Ratio (INR) of 2 to 3 before 
ECV. 
[…] 
The patient will receive from the investigational centre the 
study card to be kept for the duration of the study. 
 
9. 
STUDY PROCEDURES 
Visit 1 - Selection Visit (Week - 4 to Week -1): 
[…] 
•  The patient will enter the selection and pre-
cardioversion periods in which anticoagulant (VKA) will 
be adjusted to achieve ideally an International Normalized 
Ratio (INR)  in the range of 2 to 3 before ECV.  
[…] 
The patient will receive from the investigational centre the 
participant card to be kept for all the duration of the study. 
 
Visit 2 - Inclusion Visit (Day 1) 
If the patient's behaviour during the selection period and/or 
the result of complementary examinations, particularly the 
confirmation of the presence of persistent AF by the 
Visit 2 - Inclusion Visit (Day 1):  
If the patient's behaviour during the selection period and/or 
the result of complementary examinations, particularly the 
confirmation of the presence of persistent AF by the Central 
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Central Reading Laboratory during this period, the INR 
and laboratory tests, are compatible with the inclusion 
criteria, the patient will be assessed for the following: 
[…] 
If the results of the above assessments are compatible with 
the inclusion criteria, the patient will be included and 
allocated a treatment number using the IVRS/IWRS. 
Between this Inclusion visit and the next visit (V3), the 
INR will be closely monitored (refer to paragraph 8.3.6) in 
order to ensure that the INR is stable (between 2 to 3 
before electrical cardioversion). 
 
[…] 
At the end of the visit, the Investigator will organise the 
appointment for the next visit and will give the treatment 
for the next 4-week period. 
 
Reading Laboratory during this period, the INR and the 
laboratory tests, are compatible with the inclusion criteria, 
the patient will be assessed for the following: 
[…] 
If the results of the above assessments are compatible with 
the inclusion criteria, the patient will be included and the 
investigator will contact the IVRS/IWRS to obtain the 
treatment unit number to be dispensed at visit 2 for the 
first 12-week period. 
Between this Inclusion visit and the next visit (V3), the INR 
will be closely monitored (refer to paragraph 8.4.6) in order 
to fulfil the ECV conditions (refer to paragraph 3). 
[…] 
At the end of the visit, the Investigator will organise the 
appointment for the next visit and will give the treatment 
for the next 4-week period (one case of treatment). 
 
Vist 3 (Week 4: D28 -2/+7 days) cardioversion 
[…] 
Electrocardioversion (ECV): ECV has to be scheduled 4 
weeks after randomization and after target International 
Normalized Ratio levels will be stabilized (between 2 and 
3) on at least 3 consecutive weekly tests in patients with 
AF. Patients not stabilized for INR (i.e. values not between 
2 and 3) on at least 3 consecutive weekly tests before ECV 
will be excluded from the study, unless the presence of 
atrial thrombosis may be excluded with ECHO –TE 
performed in the same day (and before ECV). ECV will be 
performed in the morning, with the patient in the fasting 
state and without dyskalemia. 
[…] 
Patients who will not revert to sinus rhythm or with early 
relapse within the observation period after ECV will be 
withdrawn from the study and will be considered to have 
finished their follow-up. 
[…] 
Vist 3 (Week 4: D28 -2/+7 days) cardioversion 
[…] 
Electrocardioversion (ECV): ECV has to be performed 4 
weeks after randomization in patients with AF. ECV will 
be performed in the morning, with the patient in the 
fasting state and without dyskalemia. An INR value 
control must be performed within 24h before ECV. INR 
values ≥ 2 on the 3 last tests performed before ECV are 
required. However, if only 2 INR values are ≥ 2 among 
those 3 last tests, an ECV can be performed if the 
presence of atrial thrombosis can be excluded with an 
ECHO–TE 
(transesophageal 
echocardiography) 
performed on the same day (before ECV) and the 
patient can continue the study. 
[…] 
Patients who will not revert to sinus rhythm or with early 
AF relapse or early atrial flutter emergence within the 
observation period after ECV will be withdrawn from the 
study and will be considered to have finished their follow-
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At the end of the visit, the Investigator will organise the 
appointment for the next visit and give the treatment to be 
taken during the next 4-week period. 
[…] 
up. 
[…] 
The Investigator will collect all unused cases, blisters 
and soft capsules, and will count the unused capsules for 
each 4-week treatment period. 
At the end of the visit, the Investigator will organise the 
appointment for the next visit and give the treatment to be 
taken during the next 8-week period (two cases of 
treatment).   
[…] 
Visit 4 (Week 5: D35 -2/+7 days) 
 […] 
 The patient will be requested to perform daily 
transmission from the day after visit 4 (week 6) to visit 5 
(week 8), then every two days from the day after visit 5 
(week 9) to visit 9 (week 24 – End of study). Moreover, in 
case of AF symptoms, additional transmissions may be 
performed. 
[…] 
Visit 4 (Week 5: D35 -2/+7 days) 
 […] 
 The patient will be requested to perform one transmission 
per week from this visit (initial call to perform with the 
patient) to the visit 9 (week 24 – end of study). Moreover, 
in case of AF or atrial flutter symptoms, additional 
transmissions may be performed.  
 […] 
 
Visit 5 (Week 8: D56 ± 7 days) – Visit 6 (Week 12: D84 
± 7 days) - Visit 7 (Week 16: D112 ± 7 days) - Visit 8 
(Week 20: D140 ± 7 days) 
[…] 
• 
Laboratory examination: 
Prothrombin Time/INR 
(PT/INR), Activated Partial Thromboplastin Time 
(aPTT), Thrombin Clotting Time (TCT). However, in 
case of discontinuation of anticoagulation after ECV, 
the monitoring of INR, aPTT and TCT should be 
stopped. 
[…] 
• 
The cardiac monitoring will be continued using a 
TTEM device. The device will be given to the patient 
who will be requested to perform daily transmission 
from the day after visit 4 (week 6) to visit 5 (week 8), 
then every two days from the day after visit 5 (week 
Visit 5 (Week 8: D56 ± 7 days) – Visit 6 (Week 12: D84 ± 
7 days) - Visit 7 (Week 16: D112 ± 7 days) - Visit 8 
(Week 20: D140 ± 7 days): 
[…] 
• 
Laboratory examination: 
Prothrombin Time/INR 
(PT/INR), Activated Partial Thromboplastin Time 
(aPTT), Thrombin Clotting Time (TCT). However, in 
case of discontinuation of anticoagulation after ECV 
due to occurrence of VKA intolerance, the 
monitoring of INR, aPTT and TCT should be stopped. 
[…] 
• 
The cardiac monitoring will be continued using the 
TTEM device through one transmission per week 
from the day of visit 4 (end of week 5) to visit 9 
(week 24, end of study). Moreover, in case of AF or 
atrial flutter symptoms, additional transmissions may 
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9) to visit 9 (week 24 – End of study). Moreover, in 
case of AF symptoms, additional transmissions may 
be performed. 
[…] 
The Investigator will collect all unused cases, blisters and 
soft capsules, and will count the unused capsules for each 
4-week treatment period. 
At the end of the visit, the Investigator will organise the 
appointment for the next visit and give the treatment to be 
taken during the next 4-week treatment period. 
In addition, : 
- at visit 6: 
• the investigator will contact the IVRS/IWRS to obtain 
the treatment unit number to be dispensed at visit 6 for the 
last 12-week period. 
• an echocardiography will be performed, an haematology 
examination will be done and the RBC concentration of 
DHA will be measured. 
[…] 
be performed. 
 
 
[…] 
The Investigator will collect all unused cases, blisters and 
soft capsules, and will count the unused capsules for each 
4-week treatment period. 
In addition, at visit 6: 
• the investigator will contact the IVRS/IWRS to obtain the 
treatment unit number to be dispensed at visit 6 for the last 
12-week period. 
• an echocardiography will be performed, an haematology 
examination will be done and the RBC concentration of 
DHA will be measured. 
At the end of each visit, the Investigator will organise 
the appointment for the next visit and give the 
treatment to be taken during the next treatment period: 
one case at visit 6 and two cases at visit 7.  
[…] 
End-of-Study Visit - Visit 9 (Week 24: D168 ± 7 days): 
 […] 
The Investigator will collect all unused cases, blisters and 
soft capsules, and will count the unused soft capsules 
 
[…] 
 
Visit 9 - End-of-Study Visit (Week 24: D168 ± 7 days): 
 […] 
The Investigator will collect all unused cases, blisters and 
soft capsules, and will count the unused soft capsules.  
The total volume of blood collected should be about 90 
mL for the study duration (30 mL for the total volume 
of haematology and biochemistry, 2 mL for each blood 
samples for coagulations parameters and 4 mL for each 
blood samples of DHA). 
[…] 
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PREVIOUS VERSION 
MODIFIED VERSION 
13. STATISTICAL ANALYSIS 
13.2. SAMPLE SIZE 
Assuming an AF recurrence or flutter emergence rate of 
85% under placebo and 65% under active group, i.e. a 
clinically relevant difference ∆ of 20%, a sample size of 64 
assessable patients per group is required, using a log-rank 
test of survival curves with a 80 % power and a 5 % two-
sided significance level. 
13. STATISTICAL ANALYSIS 
13.2. SAMPLE SIZE 
Assuming an AF recurrence or atrial flutter emergence 
rate of 85% under placebo and 65% under active group, i.e. 
a clinically relevant difference ∆ of 20%, a sample size of 
64 assessable patients per group is required, using a log-
rank test of survival curves with a 80 % power and a 5 % 
two-sided significance level. 
 
13.7. EFFICACY ANALYSIS 
13.7.1. Primary Criterion 
13.7.1.1. Primary Analysis 
The primary criteria, time to first recurrence, will be 
analysed using the Kaplan Meier method and compared 
with the Log rank test. Hazard ratios and 95% confidence 
intervals will be estimated with the Cox regression model. 
[…] 
 
13.7.2. Secondary Criteria 
13.7.2.1. Numbers of Atrial Fibrillation Episodes  
[…] 
13.7.2.2. Duration of Atrial Fibrillation Episodes  
[…] 
13.7. EFFICACY ANALYSIS 
13.7.1. Primary Criterion 
13.7.1.1. Primary Analysis 
The primary criteria, time to first recurrence of AF or 
atrial flutter emergence, will be analysed using the 
Kaplan Meier method and compared with the Log rank test. 
Hazard ratios and 95% confidence intervals will be 
estimated with the Cox regression model. 
[…] 
13.7.2. Secondary Criteria 
13.7.2.1. Numbers of Atrial Fibrillation Episodes in the 
first week following V3 
[…] 
13.7.2.2. Duration of Atrial Fibrillation Episodes in the 
first week following V3 
[…] 
 
16. 
REFERENCES  
3 added references: 
[24]. 
JOHN 
J.V. 
MCMURRAY, 
STAMATIS 
ADAMOPOULOS, STEFAN D. ANKER, ANGELO 
AURICCHIO, 
MICHAEL 
BÖHM, 
KENNETH 
DICKSTEIN, VOLKMAR FALK, GERASIMOS 
FILIPPATOS, 
CÂNDIDA 
FONSECA, 
MIGUEL 
ANGEL GOMEZ-SANCHEZ, TINY JAARSMA, 
LARS KØBER, GREGORY Y.H. LIP, ALDO 
PIETRO 
MAGGIONI, 
ALEXANDER 
PARKHOMENKO, 
BURKERT 
M. 
PIESKE, 
BOGDAN A. POPESCU, PER K. RØNNEVIK, 
FRANS H. RUTTEN, JUERG SCHWITTER, PETAR 
SEFEROVIC, JANINA STEPINSKA, PEDRO T. 
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PREVIOUS VERSION 
MODIFIED VERSION 
TRINDADE, 
ADRIAAN 
A. 
VOORS, 
FAIEZ 
ZANNAD, ANDREAS ZEIHER 
ESC Guidelines for the diagnosis and treatment of acute 
and chronic heart failure 2012 
European Heart Journal (2012) 33, 1787–1847 
 
[25]. 
AGENCE NATIONALE DE SECURITE DU 
MEDICAMENT ET DES PRODUITS DE SANTE 
(ANSM). 
Bon usage des médicaments antivitamine K (AVK) 
Actualisation – Juillet 2012 
 
[26]. 
GILLES PERNOD, ANNE GODIER, CLAIRE 
GOZALO, BENJAMIN TREMEY, PIERRE SIE 
French clinical practice guidelines on the management of 
patients on vitamin K antagonists in at-risk situations 
(overdose, risk of bleeding, and active bleeding) 
Thrombosis Research 126 (2010) e167–e174 
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ANNEXE 1 
STUDY FLOW-CHART FROM PROTOCOL VERSION 7 
 
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F373280 CA 201 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
Weeks 
W-4 to W-1 
D1 
W4 
(28 -2D/+7 D) 
W5 
(35 -2D/+7 D) 
W8 
(56+/-7D) 
W12 
(84+/-7D) 
W16 
(112+/-7D) 
W20 
(140+/-7D)  
W24 
(168+/-7D) 
  
  
  
  
  
  
  
  
  
  
Outpatient or Hospitalization (1) 
  
  
X 
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
  
  
  
  
  
  
  
  
Demographic characteristics 
X 
  
  
  
  
  
  
  
  
Medico-surgical history 
X 
  
  
  
  
  
  
  
  
Concomitant disease 
X 
  
  
  
  
  
  
  
  
Concomitant treatment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Habits 
X 
  
  
  
  
  
  
  
  
Global physical examination (body weight) 
X 
X 
X 
 
X 
X 
X 
X 
X 
Echocardiography 
X 
X 
  
X 
  
X 
  
  
X 
Eligibility criteria check 
X 
X 
  
  
  
  
  
  
  
Blood pressure, heart rate  
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead  ECG Recording 
X 
X 
X 
  
X 
X 
X 
X 
X 
INR  
 
 
                     (2) 
  
X 
X 
X 
X 
X 
aPTT, TCT  
X 
X 
X 
  
X 
X 
X 
X 
X 
Biochemistry 
X 
  
  
  
  
  
  
  
X 
Hematology 
X 
  
X 
  
  
X 
  
  
X 
Urinary pregnancy test 
  
X 
  
  
  
  
  
  
X 
Red Blood Cell concentrations of DHA  
  
X 
X 
  
  
X 
  
  
X 
Treatment allocation 
  
X 
  
  
  
X 
  
  
  
IVRS/IWRS 
X 
X 
  
  
 
X 
  
  
  
ECV (3) 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Drug administration  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Adverse events recording 
  
X 
X 
X 
X 
X 
X 
X 
X 
Holter ECG 
                (4) 
  
 
                (5) 
 
 
 
 
 
TTEM (6) 
  
  
 
 
 
  
  
  
  
(1) Outpatient or hospitalization according to clinical practice of the centre (less or more than 24 hours) 
(2) In case of AVK introduction: INR 2 to 3 times a week, then weekly until the ECV, then every 4 weeks after ECV 
(3) In patients with AF 
(4) 24-hour Holter ECG 
(5) 7-day Holter ECG 
(6) TTEM: everyday from week 6 to week 8;. then every 2 days from week 9 to week 24; at any time in case of AF symptoms. 
In case of AF recurrence for at least 10 minutes and if the patient does not stop the study treatment, then TTEM once a week 
 
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ANNEXE 2 
STUDY FLOW-CHART FROM PROTOCOL VERSION 8 
 
 
 
 
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F373280 CA 201 
V1 
V2 
V3 
V4 
V6 
V7 
V9 
Weeks 
W-4 to W-1 
D1 
W4 
(28 -2D/+7 D) 
W5 
(35 -2D/+7 D) 
W12 
(84+/-7D) 
W16 
(112+/-7D) 
W24 
(168+/-7D) 
 
  
  
  
  
  
  
  
Outpatient or Hospitalization (1) 
  
  
X 
  
  
  
  
 
 
 
 
 
 
 
Informed consent 
X 
  
  
  
  
  
  
Demographic characteristics 
X 
  
  
  
  
  
  
Medico-surgical history 
X 
  
  
  
  
  
  
Concomitant disease 
X 
  
  
  
  
  
  
Concomitant treatment 
X 
X 
X 
X 
X 
X 
X 
Habits 
X 
  
  
  
  
  
  
Global physical examination (body weight) 
X 
X 
X 
 
X 
X 
X 
Echocardiography 
X 
X 
  
X 
X 
  
X 
Eligibility criteria check 
X 
X 
  
  
  
  
  
Blood pressure, heart rate  
X 
X 
X 
X 
X 
X 
X 
12-Lead  ECG Recording 
X 
X 
X 
  
X 
X 
X 
INR  
 
 
                       
 
 
                     (2) 
aPTT, TCT  
X 
X 
X 
  
X 
X 
X 
Biochemistry 
X 
  
  
  
  
  
X 
Haematology 
X 
  
X 
  
X 
  
X 
Urinary pregnancy test 
  
X 
  
  
  
  
X 
Red Blood Cell concentrations of DHA  
  
X 
X 
  
X 
  
X 
Treatment number allocation 
  
X 
  
  
X 
  
  
IVRS/IWRS 
X 
X 
  
  
X 
  
  
ECV (3) 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
Drug administration  
  
 
  
  
  
  
  
 
  
  
  
  
  
  
  
Adverse events recording 
  
X 
X 
X 
X 
X 
X 
Holter ECG 
                (4) 
  
 
                (5) 
 
 
 
TTEM (6) 
  
  
 
 
  
  
  
(1) Outpatient or hospitalization according to clinical practice of the centre (less or more than 24 hours) 
(2) In case of VKA introduction: INR 2 to 3 times a week until stabilization, then weekly until the ECV, then every 4 weeks after ECV 
(3) In patients with AF 
(4) 24-hour Holter ECG 
(5) 7-day Holter ECG 
(6) TTEM: one transmission per week from the day of visit 4 (end of week 5) to visit 9 (week 24) and at any time in case of AF or atrial flutter symptoms. 
TTEM once a week even in case of AF recurrence or atrial flutter emergence for at least 10 minutes. 
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F 373280 CA 2 01 
 
 
 
 
 
 
 
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Pierre Fabre Médicament 
Represented by: Institut de Recherche Pierre Fabre 
45, Place Abel Gance 
F-92100 Boulogne 
CLINICAL STUDY PROTOCOL 
 
Efficacy and safety study of F373280 for maintenance of sinus rhythm after 
electrical cardioversion in patients with persistent Atrial Fibrillation and 
Chronic Heart Failure. 
International, multicentric, randomised, double-blind, placebo controlled study 
F373280 / Soft Capsules / 1g  
Pierre Fabre Study Code: 
EudraCT Number: 
 
Sponsor's Representative: 
 
 
 
 
 
 
 
 
Study Coordinating Investigator 
F 373280 CA 2 01  
2012 – 003487 - 48 
 
Gaëlle ALCARAZ 
INSTITUT DE RECHERCHE PIERRE FABRE - 
Centre de R&D Pierre Fabre - BP 13562  
3 avenue Hubert Curien  
31035 TOULOUSE Cédex 1, FRANCE 
Phone: +33 5 34 50 62 16  
Fax:+33 5 34 50 69 69  
E-mail:gaelle.alcaraz@pierre-fabre.com  
 
Pr Savina NODARI 
Associate Professor of Cardiology 
Department of Clinical and Surgical Specialities, 
Radiological Science and Public Health 
Section of Cardiovascular Diseases 
University Medical School and Spedali Civili Hospital of 
Brescia 
c/o Spedali Civili di Brescia 
Piazzale Spedali Civili, 1 
25123 - BRESCIA, ITALY 
Phone: +39 030 3996 587 – +39 030 393849 
Fax: +39 030 3700 359 
E-mail: savinanodari@gmail.com; nodari@med.unibs.it 
 
Version 8 – 22OCT2014 
The information contained in this document is confidential and is the property of the Sponsor, Pierre Fabre 
Medicament. This information is given for the needs of the study and must not be disclosed without prior written 
consent of the Sponsor Pierre Fabre Medicament. Persons to whom this information is given for the needs of the 
study must be informed that it is confidential and must not be disclosed. 
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SPONSOR PERSONNEL 
PIERRE FABRE MEDICAMENT 
represented by 
Institut de Recherche Pierre Fabre 
 
Clinical Study Manager (Monitor) 
Gaëlle ALCARAZ 
Phone: +33 5 34 50 62 16  
Fax: + 33 5 34 50 69 69 
E-mail: gaelle.alcaraz@pierre-
fabre.com 
Institut de Recherche Pierre Fabre 
Centre de R&D Pierre Fabre 
BP 13 562 
3, Avenue Hubert Curien 
31035 TOULOUSE Cedex 1, FRANCE 
 
 
Medical Director 
Richard ROCHE, MD 
Phone: +33 5 34 50 61 94 
Fax: +33 5 34 50 69 69 
E-mail: richard.roche@pierre-
fabre.com 
Institut de Recherche Pierre Fabre 
Centre de R&D Pierre Fabre 
BP 13 562 
3, Avenue Hubert Curien 
31035 TOULOUSE Cedex 1, FRANCE 
 
 
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CONTRACT RESEARCH ORGANISATIONS 
 
For Feasibility, Monitoring and Regulatory issues (in Hungary, Czech Republic and Italy): 
Pharmaceutical Service Network (PSN) 
Rufino Gonzalez 
28 037 Madrid - SPAIN 
Phone: +34 91 375 6930 - Fax: +34 91 375 6931 
E-mail:  rzurita@psnglobal.org 
 
For Feasibility, Monitoring and Regulatory issues (in Spain): 
Alpha Bioresearch 
Paseo de la Castellana, 163 - 2º Izquierda 
28 046 Madrid - SPAIN 
Phone: +34 91 745 2520 - Fax: +34 91 745 0653 
E-mail: teresa.bricio@alphabioresearch.com 
 
For Centralised Randomisation and Electronic Case Report Form 
S-Clinica 
6, Chaussée de Boondael 
B-1050 Brussels - BELGIUM 
Phone: +32 2 645 0567 - Fax: +32 2 645 0569 
E-mail: irena.seredina@s-clinica.com 
 
For Centralised Reading of Holder ECG and TTEM and equipment supply: 
Biomedical System 
1945 Chaussée de Wavre 
B-1160 Brussels - BELGIUM 
Phone: +32 2 661 20 70 - Fax: +32 2 661 20 71 
E-mail: sjacobs@biomedsys.com 
 
For intra erythrocyte DHA dosage: 
Agrocampus Ouest 
Laboratoire de Biochimie 
65 rue de Saint Brieuc – CS 84215 
35042 RENNES Cedex - FRANCE 
Phone: +33 2 23 48 55 49 - Fax: +33 2 23 48 55 50 
E-mail: daniel.catheline@agrocampus-ouest.fr 
 
For transportation of blood sample to the Analytical centre (Agrocampus) and material 
supply: 
Theradis Pharma 
41, chemin des Presses 
06800 CAGNES-SUR-MER – FRANCE 
Phone: +33 (0)4 97 02 07 07 - Fax: +33 (0)4 97 10 08 78 
E-mail: chantal.raffy@theradis.pharma.com 
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Protocol F 373280 CA 2 01 
COUNTRY COORDINATING INVESTIGATOR  
SIGNATURE FORM 
Protocol Version 8 – 22OCT2014 
 
 
Country: …………………….. 
 
Country Coordinating Investigator:  
"Name"  
Date:   
 
 
 
 
 
 
Signature:  
 
 
 
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Protocol F 373280 CA 2 01 
INVESTIGATOR SIGNATURE FORM 
Protocol Version 8 – 22OCT2014 
 
 
 
By my signature below, I, Dr / Pr "                                         ", hereby confirm that I agree: 
♦ to conduct the trial described in the protocol F 373280 CA 2 01, dated 22OCT2014 in 
compliance with GCP, with applicable regulatory requirements and with the protocol 
agreed upon by the Sponsor Pierre Fabre Médicament and given approval / favourable* 
opinion by the Ethics Committee; 
♦ to document the delegation of significant study-related tasks and to notify the Sponsor of 
changes in site personnel involved in the study; 
♦ to comply with the procedure for data recording and reporting; 
♦ to allow monitoring, auditing and inspection; 
♦ to retain the trial-related essential documents until the Sponsor informs that these documents 
are no longer needed. 
Furthermore, I hereby confirm that I will have and will use the available adequate resources, 
personnel and facilities for conduct this trial. 
 
I have been informed that certain regulatory authorities require the Sponsor Pierre Fabre 
Médicament to obtain and supply details about the investigator’s ownership interest in the 
Sponsor or the study drug, and more generally about his/her financial relationships with the 
Sponsor. The Sponsor will use and disclose the information solely for the purpose of complying 
with regulatory requirements. 
Hence I agree: 
♦ to supply the Sponsor with any information regarding ownership interest and financial 
relationships with the Sponsor (including those of my spouse and dependent children); 
♦ to promptly update this information if any relevant changes occur during the course of the 
study and for 1 year following completion of the study; 
♦ that the Sponsor may disclose this information about such ownership interests and financial 
relationships to regulatory authorities. 
* To be adapted  
 
Date:  
Signature:  
 
 
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TABLE OF CONTENTS OF CLINICAL STUDY PROTOCOL 
 
1. 
INTRODUCTION AND STUDY RATIONALE ................................................................ 22 
1.1. 
TARGET PATHOLOGY AND THERAPY ........................................................................ 22 
1.2. 
INFORMATION ON THE TEST PRODUCT .................................................................... 24 
1.2.1. 
Chemical and pharmaceutical characteristics .................................................................... 25 
1.2.1.1. 
Nomenclature and structure ............................................................................................ 25 
1.2.1.2. 
Physical and chemical general properties ...................................................................... 25 
1.2.2. 
Non-clinical Data .............................................................................................................. 25 
1.2.2.1. 
Pharmacological profile ................................................................................................. 26 
1.2.2.2. 
Safety pharmacology ...................................................................................................... 27 
1.2.2.3. 
Toxicology profile .......................................................................................................... 27 
1.2.2.4. 
Pharmacokinetic data ..................................................................................................... 27 
1.2.3. 
Clinical data ....................................................................................................................... 27 
1.3. 
STUDY RATIONALE ......................................................................................................... 29 
1.4. 
OVERALL RISK AND BENEFIT ASSESSMENT ............................................................ 30 
2. 
STUDY OBJECTIVES ......................................................................................................... 32 
2.1. 
PRIMARY OBJECTIVE ..................................................................................................... 32 
2.2. 
SECONDARY OBJECTIVES ............................................................................................. 32 
3. 
ETHICAL CONSIDERATIONS RELATING TO THE STUDY .................................... 33 
4. 
STUDY DESIGN ................................................................................................................... 34 
4.1. 
OVERALL DESCRIPTION ................................................................................................ 34 
4.2. 
DISCUSSION OF THE STUDY DESIGN .......................................................................... 35 
4.2.1. 
Choice of the Study Population ......................................................................................... 35 
4.2.2. 
Choice of the Study Design ............................................................................................... 36 
4.2.3. 
Choice of the Dose ............................................................................................................ 37 
4.2.4. 
Choice of the Sample Size ................................................................................................. 38 
5. 
STUDY POPULATION ........................................................................................................ 38 
5.1. 
INCLUSION CRITERIA ..................................................................................................... 38 
5.2. 
NON INCLUSION CRITERIA ........................................................................................... 40 
5.3. 
NUMBER OF PATIENTS ................................................................................................... 41 
5.4. 
RECRUITMENT MODALITIES ........................................................................................ 41 
5.5. 
PATIENT IDENTIFICATION ............................................................................................ 42 
5.6. 
WITHDRAWAL CRITERIA ............................................................................................... 42 
5.7. 
REPLACEMENT OF PATIENTS ....................................................................................... 43 
5.8. 
POST-STUDY EXCLUSION PERIOD .............................................................................. 43 
5.9. 
STUDY CARD AND LETTER FOR GENERAL PRACTITIONER(S) ............................ 43 
6. 
STUDY TREATMENT ......................................................................................................... 44 
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6.1. 
SOURCE, PRESENTATION AND COMPOSITION OF  INVESTIGATIONAL 
PRODUCT ........................................................................................................................... 44 
6.2. 
PACKAGING AND LABELLING ..................................................................................... 44 
6.2.1. 
Packaging .......................................................................................................................... 44 
6.2.2. 
Labelling ............................................................................................................................ 44 
6.3. 
DISTRIBUTION TO CENTRE AND STORAGE .............................................................. 45 
6.4. 
ALLOCATION OF TREATMENTS AND DISPENSATION TO PATIENT ................... 46 
6.5. 
DRUG ADMINISTRATION ............................................................................................... 47 
6.5.1. 
Duration of Treatment ....................................................................................................... 47 
6.5.2. 
Dose Schedule ................................................................................................................... 47 
6.5.3. 
Route and Conditions of Administration ........................................................................... 47 
6.6. 
ACCOUNTABILITY ON SITE AND RETURN/DESTRUCTION OF  
INVESTIGATIONAL PRODUCT ...................................................................................... 48 
6.7. 
RECALL OF INVESTIGATIONAL PRODUCTS ............................................................. 48 
7. 
CONCOMITANT TREATMENTS ..................................................................................... 48 
7.1. 
VITAMIN K ANTAGONIST TREATMENT ..................................................................... 49 
7.2. 
PROHIBITED TREATMENTS ........................................................................................... 49 
7.3. 
AUTHORISED TREATMENTS ......................................................................................... 50 
8. 
EVALUATION CRITERIA ................................................................................................. 50 
8.1. 
PRIMARY EFFICACY CRITERION ................................................................................. 50 
8.1.1. 
Time to the first Atrial Fibrillation Recurrence or Atrial Flutter Emergence ................... 50 
8.1.1.1. 
Definition ........................................................................................................................ 50 
8.1.1.2. 
Schedule ......................................................................................................................... 50 
8.1.1.3. 
Evaluation Methods ........................................................................................................ 50 
8.2. 
SECONDARY EFFICACY CRITERIA .............................................................................. 51 
8.2.1. 
Numbers of AF episodes in the first week following visit 3 (ECV visit) ......................... 51 
8.2.1.1. 
Definition ........................................................................................................................ 51 
8.2.1.2. 
Schedule ......................................................................................................................... 52 
8.2.1.3. 
Evaluation Methods ........................................................................................................ 52 
8.2.2. 
Duration of AF episodes in the first week following visit 3 (ECV visit) .......................... 52 
8.2.2.1. 
Definition ........................................................................................................................ 52 
8.2.2.2. 
Schedule ......................................................................................................................... 52 
8.2.2.3. 
Evaluation Methods ........................................................................................................ 52 
8.2.3. 
Clinical parameters evaluation .......................................................................................... 52 
8.2.3.1. 
EHRA score assessment ................................................................................................. 52 
8.2.3.2. 
Time to first AF recurrence less than 10 minutes .......................................................... 53 
8.2.3.3. 
Recurrence of symptomatic AF ...................................................................................... 53 
8.2.3.4. 
Number and duration of hospitalizations ....................................................................... 53 
8.2.4. 
Cardioversion assessment .................................................................................................. 54 
8.2.5. 
Evolution of echocardiographic parameters ...................................................................... 54 
8.2.5.1. 
Definition ........................................................................................................................ 54 
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8.2.5.2. 
Schedule ......................................................................................................................... 54 
8.2.5.3. 
Evaluation method .......................................................................................................... 54 
8.3. 
BIOMARKER ASSESSMENT: RED BLOOD CELL  CONCENTRATIONS OF 
DHA ..................................................................................................................................... 55 
8.3.1. 
Definition ........................................................................................................................... 55 
8.3.2. 
Blood samples ................................................................................................................... 55 
8.3.2.1. 
Collection schedule ........................................................................................................ 55 
8.3.2.2. 
Technical handling ......................................................................................................... 55 
8.3.3. 
DHA concentration measurement ..................................................................................... 55 
8.4. 
SAFETY ASSESSMENT .................................................................................................... 56 
8.4.1. 
Adverse Events .................................................................................................................. 56 
8.4.2. 
Laboratory Investigations .................................................................................................. 56 
8.4.2.1. 
Schedule ......................................................................................................................... 56 
8.4.2.2. 
Technical Procedures and Parameters ............................................................................ 56 
8.4.3. 
Global Physical Examination ............................................................................................ 57 
8.4.4. 
Vital Signs ......................................................................................................................... 58 
8.4.4.1. 
Schedule ......................................................................................................................... 58 
8.4.4.2. 
Technical Procedure and Parameters.............................................................................. 58 
8.4.5. 
Electrocardiogram (ECG) .................................................................................................. 58 
8.4.5.1. 
Schedule ......................................................................................................................... 58 
8.4.5.2. 
Technical Procedure and Parameters.............................................................................. 58 
8.4.6. 
Coagulation parameters ..................................................................................................... 59 
8.5. 
CONCOMITANT TREATMENTS ..................................................................................... 60 
8.6. 
COMPLIANCE .................................................................................................................... 60 
9. 
STUDY PROCEDURES ....................................................................................................... 60 
10. ADVERSE EVENTS: DEFINITION AND REPORTING ............................................... 66 
10.1. ADVERSE EVENTS ........................................................................................................... 66 
10.1.1. Definition of Adverse Events ............................................................................................ 66 
10.1.2. Grading of Adverse Events ............................................................................................... 67 
10.1.3. Reporting of Adverse Events ............................................................................................ 67 
10.2. SERIOUS ADVERSE EVENTS (SAE) .............................................................................. 67 
10.2.1. Definition ........................................................................................................................... 67 
10.2.2. Reporting of SAE .............................................................................................................. 68 
10.2.3. Follow-up of SAE ............................................................................................................. 68 
10.2.4. SAE Occurring After the Study ......................................................................................... 69 
10.3. REPORTING OF OVERDOSAGE TO THE SPONSOR ................................................... 69 
10.4. REPORTING OF PREGNANCY TO THE SPONSOR ...................................................... 69 
10.5. SPONSOR'S RESPONSIBILITIES FOR SAFETY REPORTING  PURPOSES ............... 70 
11. DATA COLLECTION AND STUDY MONITORING ..................................................... 70 
11.1. DATA COLLECTION ......................................................................................................... 70 
11.1.1. Case Report Form .............................................................................................................. 70 
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11.1.2. Source Documents ............................................................................................................. 71 
11.2. STUDY MONITORING ...................................................................................................... 71 
11.2.1. Monitoring visits ............................................................................................................... 71 
11.2.1.1. Site Preselection Visit .................................................................................................... 72 
11.2.1.2. Initiation Visit ................................................................................................................. 72 
11.2.1.3. Follow-up Visits ............................................................................................................. 72 
11.2.1.4. Closing Visit ................................................................................................................... 73 
11.2.2. Direct Access to Source Documents ................................................................................. 73 
11.3. INDEPENDENT DATA MONITORING COMMITTEE ................................................... 73 
12. DATA MANAGEMENT ...................................................................................................... 74 
12.1. DATA ENTRY ..................................................................................................................... 74 
12.2. DATA CLEANING ............................................................................................................. 74 
12.3. DATA CODING .................................................................................................................. 74 
12.4. DATA STORAGE ............................................................................................................... 75 
12.5. DATABASE LOCK ............................................................................................................. 75 
13. STATISTICAL ANALYSIS ................................................................................................. 75 
13.1. GENERAL CONSIDERATIONS ........................................................................................ 75 
13.2. SAMPLE SIZE ..................................................................................................................... 75 
13.3. PROTOCOL DEVIATIONS ................................................................................................ 76 
13.4. DATA SETS ANALYSED .................................................................................................. 76 
13.5. HANDLING OF DROPOUTS AND MISSING DATA ..................................................... 77 
13.5.1. Dropouts ............................................................................................................................ 77 
13.5.2. Repositioning of Visits ...................................................................................................... 77 
13.5.3. Missing Data ...................................................................................................................... 77 
13.6. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ............................... 77 
13.7. EFFICACY ANALYSIS ...................................................................................................... 78 
13.7.1. Primary Criterion ............................................................................................................... 78 
13.7.1.1. Primary Analysis ............................................................................................................ 78 
13.7.1.2. Supportive Analysis ....................................................................................................... 78 
13.7.2. Secondary Criteria ............................................................................................................. 78 
13.7.2.1. Numbers of Atrial Fibrillation Episodes in the first week following V3 ....................... 78 
13.7.2.2. Duration of Atrial Fibrillation Episodes in the first week following V3 ....................... 78 
13.7.2.3. Time to first AF recurrence less than 10 minutes or symtomatic .................................. 79 
13.7.2.4. Clinical parameters evaluation ....................................................................................... 79 
13.7.2.5. Biomarker analysis: red blood cell concentrations of DHA ........................................... 79 
13.8. SAFETY ANALYSIS .......................................................................................................... 79 
13.8.1. Adverse Events .................................................................................................................. 79 
13.8.2. Clinical Laboratory Evaluation ......................................................................................... 81 
13.8.3. Global Physical Examination ............................................................................................ 82 
13.8.4. Vital Signs, Physical Findings and Other Observations Related to Safety ....................... 83 
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13.8.4.1. Vital Sign Measurements Over Time ............................................................................. 83 
13.8.4.2. Body weight ................................................................................................................... 83 
13.8.4.3. Individual Patient Changes ............................................................................................. 83 
13.8.5. ECG ................................................................................................................................... 83 
13.8.6. Coagulation parameters ..................................................................................................... 84 
13.9. CONCOMITANT TREATMENTS ..................................................................................... 84 
13.10. COMPLIANCE .................................................................................................................... 84 
13.11. INTERIM ANALYSIS AND DATA MONITORING ........................................................ 84 
14. GENERAL ETHICAL CONSIDERATIONS .................................................................... 85 
14.1. ETHICAL CONDITIONS ................................................................................................... 85 
14.2. ETHICS COMMITTEE AND LEGAL REQUIREMENTS ................................................ 85 
14.3. PATIENT'S INFORMATION LEAFLET AND INFORMED CONSENT  FORM ........... 86 
14.4. PERSONAL DATA PROTECTION ................................................................................... 86 
14.5. INSURANCE POLICY ........................................................................................................ 87 
15. ADMINISTRATIVE PROCEDURES ................................................................................ 87 
15.1. PROTOCOL AMENDMENT .............................................................................................. 87 
15.2. SOURCE DOCUMENTS, INVESTIGATOR'S FILE STORAGE ..................................... 87 
15.3. END OF THE STUDY ......................................................................................................... 88 
15.3.1. Definition of the End of Study .......................................................................................... 88 
15.3.2. Early Study Termination ................................................................................................... 88 
15.3.2.1. Early Study Termination Decided by the Sponsor ......................................................... 88 
15.3.2.2. Early Study Termination Decided by the Competent Authorities.................................. 88 
15.4. AUDIT .................................................................................................................................. 89 
15.5. INSPECTION ....................................................................................................................... 89 
15.6. CONFIDENTIALITY .......................................................................................................... 89 
15.7. CLINICAL STUDY REPORT ............................................................................................. 89 
15.8. STUDY RESULTS COMMUNICATION .......................................................................... 90 
15.9. STUDY RESULTS PUBLICATION ................................................................................... 90 
16. REFERENCES ...................................................................................................................... 92 
17. APPENDICES ....................................................................................................................... 96 
17.1. DECLARATION OF HELSINKI ........................................................................................ 97 
17.2. SAE REPORT FORM ........................................................................................................ 101 
17.3. PREDEFINED LIMITS OF LABORATORY AND VITAL SIGN POTENTIALLY 
CLINICALLY SIGNIFICANT CHANGES AND VALUES ............................................ 104 
 
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SYNOPSIS 
 
Name of Sponsor: 
Pierre Fabre Médicament represented by the Institut de Recherche Pierre Fabre (IRPF) 
Name of Finished Product: 
Not applicable 
Name of Active Substance:  
F373280 (Panthenyl-Ester of DHA) 
Title of the Study: 
Efficacy and safety study of F373280 for maintenance of sinus rhythm after electrical 
cardioversion in patients with persistent Atrial Fibrillation and Chronic Heart Failure. 
International, multicentric, randomised, double-blind, placebo controlled study 
Abbreviated Title: 
Not applicable 
Study Coordinating Investigator: 
Pr Savina NODARI 
Study Centres: 
International, multicentric 
Publication / Rationale: 
F373280 is a new therapy based on DHA delivery (pro-drug) developed for the maintenance 
of sinus rhythm after electrical cardioversion in persistent atrial fibrillation (AF) patients with 
chronic heart failure. 
The results of a pharmacological study performed in animals evidenced that DHA reduces the 
duration of AF induced by burst pacing.[1] 
Moreover, the effectiveness of PolyUnsaturated Fatty Acid (PUFA) has been proven in the 
following conditions: 
− 
prevention of AF recurrence in patients with persistent AF, in co-administration 
with amiodarone (add on therapy) [2]  
− 
Improvement of ventricular functional parameters, morbi-mortality and duration of 
hospitalisation in patients with heart failure [3, 4, 5] 
Taking into account these studies, it seems that DHA might be of therapeutic interest in the 
treatment of patients with both persistent atrial fibrillation and chronic heart failure. 
This phase IIa study is designed to assess the efficacy and the safety of the investigational 
product (F373280) for maintenance of sinus rhythm after electrical cardioversion (ECV) in 
patients with persistent atrial fibrillation and chronic heart failure. 
Planned Study Period: 
January 2013 –  April 2016 
Clinical Phase: IIa 
Objectives: 
Primary: 
- Efficacy of F373280 on the maintenance of sinus rhythm after direct electrical 
cardioversion in patients with persistent atrial fibrillation and chronic heart failure 
Secondary: 
- Efficacy of F373280 on the efficiency of direct electrical cardioversion 
- Effect of F373280 on echocardiographic parameters 
- Safety and tolerability of F373280 
Methodology: 
- International, multicentre, randomised, double-blind, placebo-controlled 
- Selection period 
- Start of treatment 4 weeks before ECV 
• 
Condition to ECV:  
− 
Ideally INR 2-3 (vitamin K antagonist should be given at least 3 weeks before 
ECV) 
− 
No spontaneous cardioversion before ECV 
- Follow-up 20 weeks after visit 3 (ECV visit) 
• 
Condition: successful ECV or spontaneous CV 
- Cardiac monitoring: 
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• 
7-days continuous ECG ambulatory recording (Holter ECG) between visit 3 (ECV 
visit) and visit 4 (week 5) in patients with sinusal rhythm 
• 
TTEM: one transmission per week from the day of visit 4 (end of week 5) to visit 9 
(week 24) and at any time in case of AF or atrial flutter symptoms. 
- Treatment duration: 24 weeks 
Study Schedule: 
 7 visits will be scheduled: 
- V1/ W-4 to W-1: selection visit (7 to 28 days before the inclusion visit)  
- V2/ D1: Inclusion visit (start of study treatment) 
- V3/ W4 (D28 -2/+7 days): cardioversion visit (outpatient or hospitalization according to 
clinical practice of the centre) (installation of the Holter device) 
- V4/ W5 (D35 -2/+7 days): follow-up visit (removing of the Holter device and 
installation of the TTEM) 
- V6/ W12* (D84 ± 7 days): follow-up visit    
 *see amendment PA05 dated 22OCT2014 
- V7/ W16 (D112 ± 7 days): follow-up visit     
- V9/ W24* (D168 ± 7 days): final study visit    
 *see amendment PA05 dated 22OCT2014 
Number of  Patients: 
76 x 2 patients  
Diagnosis and Criteria for Inclusion: 
Inclusion Criteria: 
 
Demographic Characteristics and Other Baseline Characteristics: 
1. 
Men or women aged more than 18 years (inclusive) 
2. 
Patients with current episode of persistent AF between 7 days and 6 months duration for 
whom electrical cardioversion is warranted 
3. 
Previous history of first documented episode of persistent AF. 
4. 
Previous history of ischemic or non ischemic heart failure  
5. 
NYHA class I or II chronic heart failure at selection and at inclusion 
6. 
Left ventricular systolic dysfunction defined at selection and at inclusion by a reduced 
left ventricular ejection fraction (LVEF) ≥ 30% and ≤ 45% or for patients with a LVEF 
> 45%: 
• an increased left ventricular end-diastolic size  
(diameter ≥ 60 mm and/or > 32 mm/m² and/or volume > 97 ml/m²) 
• and/or an increased left ventricular end-systolic size 
(diameter > 45 mm and/or > 25 mm/m² and/or volume > 43 ml/m²) 
• and/or a reduced left ventricular outflow tract velocity time integral < 15 cm 
7. 
On appropriate, stable medical treatments for heart failure, including a diuretic and/or 
angiotensin-converting enzyme, and/or angiotensin-receptor blocker and/or 
mineralocorticoid receptor (MR) antagonists, and/or betablockers 
8. 
Left atrial area ≤ 40 cm² at selection and at inclusion 
9. 
Patients treated or having to be treated by vitamin K antagonist 
10. For female patient of child-bearing potential:  
• 
In all the countries except Italy:  
- Use of an effective method of contraception (hormonal contraception or intra-
uterine device) assessed by the investigator, for at least 2 months before the 
selection in the study, and agreement to go on using it during the whole duration of 
the study and up to 1 month after the last dose of the study treatment 
- Documented as surgically sterilized 
• 
In Italy only:  
- Absolute abstention from sexual intercourse during the whole duration of the study 
and for a month after the end of the study or 
- Use of double barrier contraception method (use of effective medical contraception 
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method) from at least 2 months before the start of the study to the entire duration of 
the study and for a month after the end of the study or 
- Documented as surgically sterilized 
11. For female patient of child-bearing potential: negative urine pregnancy test at inclusion 
12. For male with a child-bearing potential partner (In Italy only): 
- Absolute abstention from sexual intercourse during the whole duration of the study 
and for 3 months after the end of the study or 
- Use of double barrier contraception method (use of condom for male and effective 
contraception method for the partner) from the entire duration of the study to 3 
months after the end of the study. 
Ethical / legal considerations: 
13. Having signed his/her written informed consent, 
14. Affiliated to a social security system, or is beneficiary (if applicable in the national 
regulation) 
 
Non-Inclusion Criteria: 
Criteria related to pathologies: 
1. 
No previous history of first documented episode of persistent AF  
2. 
More than two successful cardioversions (electrical or pharmacological) in the last 6 
months 
3. 
Secondary Atrial Fibrillation due to alcohol or severe valvular heart disease (grade III to 
IV) 
4. 
NYHA class III or IV heart failure at selection or at inclusion 
5. 
Thyroid disease uncontrolled by treatment: TSH ± T4L ± T3L to be checked in case of 
treatment for thyroid disease 
6. 
Myocardial infarction or unstable angina or presence of unstable ischemic 
coronaropathy assessed by coronarography or cardiac stress test (Echo stress, exercise 
stress test, nuclear or MR perfusion evaluation methods) within 6 months before 
selection 
7. 
Severe chronic kidney disease (creatinine ≥ 25 mg/L or estimated glomerular filtration 
rate < 30 ml/min) at selection 
8. 
Bradycardia (HR ≤ 50 bpm) 
9. 
Hyperkalemia or hypokalemia (according to the standards of local laboratories) at 
selection  
10. Cardiac surgery within 3 months before selection or planned during the study duration 
Criteria related to treatments: 
11. Previously ineffective pharmacological or electrical cardioversion 
12. Concomitant treatment with ranolazine or any antiarrhythmic drug (within 7 days prior 
to selection), except amiodarone, dronedarone and stable dose of digoxin, betablockers, 
calcium-blockers 
13. Concomitant treatment with oral amiodarone or dronedarone from selection  
14. Concomitant treatment with intravenous amiodarone from selection  
15. Patient requiring a cardiac resynchronization therapy (CRT) or having undergone CRT 
implantation within the last 6 months  
16. Treatment with any Polyunsaturated Fatty Acid (PUFA) within the last 3 months 
17. Dietary supplement with ω 3 or ω 6 according to investigator’s judgement 
18. Having undergone any form of ablation therapy for AF 
19. Patient treated with oral anticoagulant treatment other than vitamin K antagonist: new 
oral anticoagulants (dabigatran, rivaroxaban, apixaban), or treated with irreversible 
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antiplatelet agents P2Y12 inhibitors such as ticlopidine, clopidogrel or prasugrel 
 
Other criteria: 
20. Patient liable not to comply with protocol instructions and/or with treatment, in the 
investigator’s opinion 
21. Patient having taken part in a clinical trial in the preceding 2 months or taking part in a 
trial at the time of selection 
22. Patient linguistically or mentally unable to understand the nature, objectives and 
possible consequences of the trial, or refusing to patient himself/herself to its constraints 
23. Patient family member or work associate (secretary, nurse, technician,..) of the 
Investigator 
24. Patient having forfeited his / her freedom by administrative or legal award or being 
under guardianship 
25. Breastfeeding female patient 
 
Exclusion criteria before V3: 
Patients without dyskalemia who will not have INR values ≥ 2 on the 3 last tests performed 
before ECV should not have an ECV and will be excluded from the study. 
However, if only 2 INR values are ≥ 2 among those 3 last tests, an ECV can be performed if 
the presence of atrial thrombosis can be excluded with an ECHO–TE (transesophageal 
echocardiography) performed on the same day (before ECV) and the patient can continue the 
study. 
If necessary, for meeting these INR conditions, the ECV (and following visits) could be 
postponed by 7 days. 
Test Product:  
F373280  
Soft Capsules  
Dose: 
Arm with 1g of F373280 
Mode of Administration: 
Oral, one capsule each evening with dinner. 
Duration of Treatment: 
24 weeks of treatment exposure with F373280 (25 weeks if ECV postponed by 1 week) 
Reference Therapy 
Placebo soft capsules 
Placebo will be administered in the same conditions as the tested product. 
Mode of Administration: 
Oral, one capsule each evening with dinner 
Evaluation Criteria: 
Efficacy evaluation variables: 
Primary evaluation variable: 
- Time to first Atrial Fibrillation recurrence or atrial flutter emergence defined by the time to 
first episode of AF or atrial flutter lasting for at least 10 minutes (Follow up of 20 weeks 
after visit 3 – ECV visit). 
Handling of AF recurrences or atrial flutter emergences: 7-day continuous ECG (5-leads/2 
or 3 channels) ambulatory recording (holter ECG) between visit 3 (ECV visit) and visit 4 
(week 5). Then, the follow up will be documented using the TTEM: one transmission per 
week from the day of visit 4 (end of week 5) to visit 9 (week 24). 
For randomised patients with spontaneous cardioversion before ECV, the recurrence of AF 
or the emergence of atrial flutter will be assessed after visit 3 (from week 5).  
Moreover, during this TTEM period, if patient experiences any AF or atrial flutter 
symptoms, it should be recorded and documented using the TTEM.  
All ECG (Holter and TTEM) will be evaluated by a Central Reading Laboratory. 
Secondary evaluation variables: 
During the 7-day continuous ECG monitoring, 
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• 
Numbers of AF episodes 
• 
Duration of AF episodes 
Clinical parameters: 
During the whole study: 
• 
Number of recurrence of symptomatic AF episodes 
• 
EHRA score 
• 
Hospitalization for cardiovascular events 
• 
Hospitalization for thromboembolic stroke 
• 
All causes of hospitalization 
Cardioversion: 
• 
Assessment of spontaneous cardioversion 
• 
Assessment of successful cardioversion 
• 
Shocks distribution (1, 2 or 3 shocks) 
• 
Number of patients needing an other cardioversion after the initial ECV 
 
Other: 
• 
Evolution of echocardiographic parameters (at V4,  V6 and V9) (Left atrial 
diameter (mm), Left atrial area (cm²), Left atrial volume (ml), Left atrial 
volume/BSA (ml/m2), Left ventricular ejection fraction (%), Left ventricular end 
diastolic volume/BSA (ml/m2), Left ventricular end systolic volume/BSA(ml/m2), 
Left ventricular end diastolic diameter (mm), Left ventricular end diastolic volume 
(ml) Left ventricular end systolic diameter (mm), Left ventricular end systolic 
volume (ml)) 
• 
Evolution of omega 3 index and intra erythrocyte DHA (For this assessment 
samples will be centralized). 
 
Safety criteria: 
• 
Adverse events (observed and / or spontaneously reported) 
• 
Vital signs (Blood pressure (supine and standing), heart rate) 
• 
Physical examination (body weight, body surface area)  
• 
Standard 12-lead ECG: heart rate (bpm), PR (ms), QRS (ms), QT (ms), QTcB 
(ms), QTcF (ms), repolarisation patterns (ECG not centralized) 
• 
Haematology: haematocrit, haemoglobin, red blood cell (RBC) count, white blood 
cell (WBC) count, WBC differential count, reticulocytes, platelets 
• 
Biochemistry: sodium, potassium, bicarbonate, chloride, alkaline phosphatase, 
gamma GT, albumin, total bilirubin, conjugated bilirubin, creatinine, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), fasting glucose, total 
cholesterol, cholesterol (HDL, LDL), triglycerides, creatin phosphokinase (CPK) 
fibrinogen (local laboratory) 
• 
Coagulation parameters: Activated partial thromboplastin time (aPTT), thrombin 
clotting time (TCT), INR (local laboratory), Prothrombine Time (PT). 
 
Concomitant treatments 
 
Compliance 
 
Statistical Methods: 
Sample Size: 
Assuming an AF recurrence or atrial flutter emergence rate under placebo of 85%, a power of 
80%, an alpha risk of 5% and a rate of not assessable patients of 15%, 76 randomised patients 
per group will be necessary, using a log-rank test of survival curves, a difference between 
groups of 20%.  
Primary Efficacy Analysis 
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The primary analysis, performed on the Full Analysis Set (FAS: all randomised patients with 
at least one dose of treatment and with a successful cardioversion observed at visit 3), will be 
a survival analysis using the Kaplan Meier method and Cox regression model. 
Secondary Analyses  
All secondary efficacy criteria will be described and compared using appropriate tests on the 
FAS. 
Safety Analyses 
Descriptive statistics will be performed on the Safety Set (all randomised patients with at 
least one dose of treatment).  
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STUDY FLOW-CHART 
F373280 CA 201 
V1 
V2 
V3 
V4 
 
V6 
V7 
 
V9 
Weeks 
W-4 to W-1 
D1 
W4 
(28 -2D/+7 D) 
W5 
(35 -2D/+7 D) 
 
W12 
(84+/-7D) 
W16 
(112+/-7D) 
 
W24 
(168+/-7D) 
  
  
  
  
  
  
  
  
  
  
Outpatient or Hospitalization (1) 
  
  
X 
  
 
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
  
  
  
  
  
  
  
  
Demographic characteristics 
X 
  
  
  
  
  
  
  
  
Medico-surgical history 
X 
  
  
  
  
  
  
  
  
Concomitant disease 
X 
  
  
  
  
  
  
  
  
Concomitant treatment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Habits 
X 
  
  
  
  
  
  
  
  
Global physical examination (body weight) 
X 
X 
X 
 
X 
X 
X 
X 
X 
Echocardiography 
X 
X 
  
X 
  
X 
  
  
X 
Eligibility criteria check 
X 
X 
  
  
  
  
  
  
  
Blood pressure, heart rate  
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead  ECG Recording 
X 
X 
X 
  
X 
X 
X 
X 
X 
INR  
 
 
                   
  
X 
 
 
X 
                     (2) 
aPTT, TCT  
X 
X 
X 
  
X 
X 
X 
X 
X 
Biochemistry 
X 
  
  
  
  
  
  
  
X 
Haematology  
X 
  
X 
  
  
X 
  
  
X 
Urinary pregnancy test 
  
X 
  
  
  
  
  
  
X 
Red Blood Cell concentrations of DHA  
  
X 
X 
  
  
X 
  
  
X 
Treatment number allocation 
  
X 
  
  
  
X 
  
  
  
IVRS/IWRS 
X 
X 
  
  
 
X 
  
  
  
ECV (3) 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Drug administration  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Adverse events recording 
  
X 
X 
X 
X 
X 
X 
X 
X 
Holter ECG 
                (4) 
  
 
                (5) 
 
 
 
 
 
TTEM (6) 
  
  
 
 
 
  
  
  
  
(1) Outpatient or hospitalization according to clinical practice of the centre (less or more than 24 hours) 
(2) In case of VKA introduction: INR 2 to 3 times a week until stabilization, then weekly until the ECV, then every 4 weeks after ECV 
(3) In patients with AF 
(4) 24-hour Holter ECG 
(5) 7-day Holter ECG 
(6) TTEM: one transmission per week from the day of visit 4 (end of week 5) to visit 9 (week 24) and at any time in case of AF or atrial flutter symptoms. 
TTEM once a week even in case of AF recurrence or atrial flutter emergence for at least 10 minutes. 
 
 
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LIST OF ABBREVIATIONS 
 
aPTT 
: 
Activated partial thromboplastin time 
AE 
: 
Adverse event 
AF 
: 
Atrial fibrillation 
ALA 
: 
Alpha-linoleic acid 
ALT 
: 
Alanine aminotransferase 
AST 
: 
Aspartate aminotransferase 
AUC 
: 
Area under the plasma concentration versus time curve 
AUCinf 
: 
Total area under the curve extrapolated to infinity 
βHCG 
: 
beta human chorionic gonadotrophin 
BLQ 
: 
Below the limit of quantification 
BMI 
: 
Body mass index 
BP 
: 
Blood pressure 
BSA 
: 
Body Surface Area 
CEP 
: 
Protocol evaluation committee 
CHMP 
: 
Committee for medicinal products for human use 
Cmax 
: 
Maximum concentration 
Cmin 
: 
Minimum concentration 
CNALV 
: 
Clinically noteworthy abnormal laboratory value 
CPK 
: 
Creatin phosphokinase 
CPP 
: 
Comité de protection des personnes  
CRA 
: 
Clinical research associate 
CRT 
: 
Cardiac resynchronization therapy 
CSC 
: 
“Clinically Significant Change”, i.e., Predefined potentially clinically significant 
change leading to a potentially clinically significant value (vital signs) 
CV 
: 
Coefficient of variation 
DBP 
: 
Diastolic blood pressure 
DHA 
: 
Docosahexaenoic acid 
EC 
: 
Ethics committee 
ECG 
: 
Electrocardiogram 
ECHO –TE : 
Transesophageal echocardiograph 
ECV 
: 
Electrical cardioversion 
EHRA 
: 
European heart rhythm association 
EPA 
: 
Eicosapentaenoic acid 
e-CRF 
: 
Electronic case report form 
FAS 
: 
Full analysis set 
Fe 
: 
Fraction of the administered drug excreted in urine 
GCP 
: 
Good clinical practice 
GFR 
:  Glomerular Filtration Rate 
HBs 
: 
Hepatitis B antigen 
HCV 
: 
Hepatitis C virus 
HDL 
: 
High density lipoprotein 
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HF 
: 
Heart failure 
HIV 
: 
Human immunodeficiency virus 
HR 
: 
Heart rate 
ICH 
: 
International conference on harmonisation of technical requirements for 
registration of pharmaceuticals for human use 
IDMC 
: 
Independent data monitoring committee 
INR 
: 
International normalized ratio 
IRPF 
: 
Institut de Recherche Pierre Fabre 
IVRS 
: 
Interactive voice response system 
LAA 
: 
Left atrial area 
LC/MS-MS : 
Liquid chromatography with tandem mass spectrometry 
LDL 
: 
Low density lipoprotein 
LOQ 
: 
Limit of quantification 
LVEF 
: 
Left ventricular ejection fraction 
MedDRA 
: 
Medical dictionary for regulatory activities 
MR 
: 
Mineralocorticoid receptor 
MR perfusion : 
Magnetic Resonance perfusion 
MTD 
: 
Maximum tolerated dose 
N 
: 
Number of determinations or replicates 
NOAEL 
: 
No observed adverse effect level 
NYHA 
: 
New York heart association 
od 
: 
Once a day 
PC 
: 
“Predefined Change”, i.e., Predefined potentially clinically significant change (lab 
or vital signs) 
PCA 
: 
PC leading to an out-of-range value (lab values) 
PFB 
: 
Pierre Fabre Biométrie 
PSC 
: 
Potentially Clinically Significant Change 
PSCV 
: 
Potentially Clinically Significant Value 
PUFA 
: 
PolyUnsaturated fatty acid 
p.o. 
: 
Per os 
PP 
: 
Per protocol data set 
QTcB 
: 
QT interval using Bazett’s correction formula 
QTcF 
: 
QT interval using Fridericia’s correction formula 
RBC 
: 
Red blood cells 
SAE 
: 
Serious adverse event 
SBP 
: 
Systolic blood pressure 
SD 
: 
Standard deviation 
T1/2 
: 
Terminal half-life 
T0 
: 
Time of drug administration 
Tmax 
: 
Time to reach the maximal concentration 
TCT 
: 
Thrombin clotting time 
TEAEs 
: 
Treatment emergent adverse events 
TTEM 
: 
TransTelephonic ECG monitoring 
VKA 
: 
Vitamin K Antagonist 
WBC 
: 
White blood cells 
WHO-DRUG : 
World health organization drug reference list 
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1. INTRODUCTION AND STUDY RATIONALE 
1.1. 
TARGET PATHOLOGY AND THERAPY 
 
Atrial Fibrillation (AF) is a supraventricular arrhythmia characterized by uncoordinated atrial 
electric activity with consequent deterioration of atrial mechanical function. It is the most 
common sustained cardiac rhythm disorder, increasing in prevalence with age. Haemodynamic 
impairment and thromboembolic events related to AF result in significant morbidity and mortality 
[7]. 
In 2009, Decision Resources estimated that there were 7.8 million diagnosed prevalent cases of 
AF in US, Europe and Japan. This age-related pathology should increase to 9.4 million cases in 
2019.  
Except for the conventional class I and class III anti-arrhythmic agents, the Polyunsaturated Fatty 
Acids (PUFAs) constitute one emerging antiarrhythmic therapy. These compounds potently 
address the AF substrate by directly targeting both the electrical and the structural remodelling of 
the deficient atria. The n-3 PUFAs, essential for human, are alpha-linoleic acid (ALA), 
eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). First, PUFAs specifically 
modulate ionic channels by fastening their inactivating mode which renders these compounds 
selective for pathological situations (such as AF) without any major effect in normal conditions. 
PUFAs are “open Kv1.5 channel blockers” leading to a lengthening of atrial action potential 
duration and are “persistent Nav1.5 channel blockers” leading to hyperpolarization of diastolic 
resting potential. Second, PUFAs influence structural remodelling through their anti-inflammatory 
effects as they directly compete with arachidonic acid in the production of inflammatory 
eicosanoids. In summary, PUFAs share unique, well-tolerated antiarrhythmic potential by 
interacting with the electrical and structural remodelling during sustained AF. In animal studies, it 
was recently demonstrated that DHA is particularly effective in pathologic conditions such as 
ischemia and/or AF. 
The potential anti-arrythmic effects of a PUFA were previously developed in AF: nicotinyl ester 
of DHA (pro-drug based on DHA delivery) was assessed in a two-week ventricular tachypaced 
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canine model. Dogs were subjected to 4 weeks of medication prior to undergoing an 
electrophysiology study, and received either placebo or nicotinyl ester of DHA. Dogs were 
tachypaced at 240 beats per min for the final two weeks of the treatment plan. The results showed 
that the tested PUFA reduced the duration of AF induced by burst pacing, and the incidence of 
sustained AF, compared to dogs treated with the placebo [1]. 
In clinical practice, Nodari and coll [2] assessed n-3 PUFAs in the prevention of AF recurrences 
after electrical cardioversion (ECV). All included patients were treated with amiodarone and a 
renin-angiotensin-aldosterone system inhibitor. The 199 patients were assigned either to placebo 
or n-3 PUFAs 2 g/d and then underwent direct ECV 4 weeks later. The primary end point was the 
maintenance of sinus rhythm at 1 year after cardioversion. At the 1-year follow up, the 
maintenance of sinus rhythm was significantly higher in the n-3 PUFAs treated patients compared 
with the placebo group (hazard ratio, 0.62 [95% confidence interval, 0.52 to 0.72] and 0.36 [95% 
confidence interval, 0.26 to 0.46], respectively; p = 0.0001). The study concludes that in patients 
with persistent AF on amiodarone and a renin-angiotensin-aldosterone system inhibitor, the 
addition of n-3 PUFAs 2 g/d improves the probability of the maintenance of sinus rhythm after 
direct current cardioversion. Previously, during the World Congress of Cardiology in 2006, an 
abstract reported the effectiveness of PUFAs on top of traditional treatment (amiodarone, beta 
blockers, renin-angiotensin-aldosterone system inhibitor) in the prevention of AF relapses in 
patients having undergone ECV. In the PUFA group, AF relapses were significantly lower than in 
the placebo group at 1 month (3.3% vs 10%; p = 0.043), at 3 months (10% vs 25%; p = 0.004) and 
at 6 months (13.3% vs 40%; p < 0.0001) [19]. 
In contrast, in the general AF population (paroxystic atrial fibrillation and persistent atrial 
fibrillation), PUFAs failed to prove their efficacy [7] because of the absence of cardiac 
remodelling or because of a short pre-treatment duration before ECV (1 week) [8]. The effects of 
PUFAs were only observed in patients with persistent AF on add on therapy and after a sufficient 
pre-treatment before ECV. Persistent AF is commonly associated to heart failure. Previous studies 
performed in heart failure population demonstrated the benefit of PUFAs on the improvement of 
functional ventricular parameters and morbi-mortality, and on the reduction of hospitalisation [3, 
4, 5]. 
Nodari and coll [3] performed a trial in patients with chronic heart failure (NYHA I to III and 
LVEF< 45%). After a treatment of 133 patients with PUFAs (n=67) or placebo (n=66) at a dosage 
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of 5 g/day for 1 month, then 2 g/day for 11 months, the n-3 PUFAs group and the placebo group 
differed significantly (p <0.001) in regard to:  
− LVEF (increased by 10.4% and decreased by 5.0%, respectively) 
− peak VO2 (increased by 6.2% and decreased by 4.5%, respectively) 
− exercise duration (increased by 7.5% and decreased by 4.8%, respectively) 
− mean New York Heart Association functional class (decreased from 1.88+/- 0.33 to 1.61 
+/- 0.49 and increased from 1.83+/- 0.38 to 2.14 +/- 0.65, respectively).  
The hospitalization rates for patients with HF were 6% in the n-3 PUFAs and 30% in the placebo 
group (p <0.0002). 
Moertl and coll [4] performed a dose-ranging study in patients with a more severe chronic heart 
failure (NYHA III and IV and LVEF < 35%). It was a double-blind, randomised, controlled pilot 
trial in 43 patients treated with PUFAs or placebo for 3 months (1 g/d n3-PUFA (n = 14), 4 g/d 
n3-PUFA (n = 13), or placebo (n = 16)). After treatment, left ventricular ejection fraction 
increased in a dose-dependent manner (p = 0.01 for linear trend) in the 4 g/d (baseline vs 3 
months [mean ± SD]: 24% ± 7% vs 29% ± 8%, p = 0.005) and 1 g/d treatment groups (24% ± 8% 
vs 27% ± 8%, p = 0.02). 
No changes in any investigated parameters were noted with placebo. 
Taking into account these studies performed with PUFAs, it seems that the best target for DHA is 
persistent AF in patients with heart failure. The aim of this proof of concept study is to assess in 
stand alone therapy (without association of other anti-arrhythmic treatments), the effect of 
F373280 in patients with persistent AF and heart failure in the maintenance of sinus rhythm after 
ECV. 
1.2. 
INFORMATION ON THE TEST PRODUCT 
F373280 or panthenyl ester of DHA is the mono-ester of panthotenic alcohol and DHA, selected 
to be developed for the management of AF.  
F373280 is a prodrug of DHA. 
A brief summary of F373280 known characteristics is presented in this section. For further details, 
please refer to the F373280 Investigator’s Brochure. [1] 
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1.2.1. Chemical and pharmaceutical characteristics 
1.2.1.1. 
Nomenclature and structure 
Chemical name (IUPAC):  
(4Z,7Z,10Z,13Z,16Z,19Z)-3-((R)-2,4-dihydroxy-3,3-diméthylbutanamido) 
propyl 
docosa-
4,7,10,13,16,19-hexaenoate 
Structural formula: 
O
O
O
O
NNHH
O
O
OHH
O
OHH
 
Laboratory code: F373280 
Molecular formula: C31H49NO5 
Molecular mass: 515.7 
1.2.1.2. Physical and chemical general properties 
Appearance: Clear oily viscous liquid 
Solubilities:  
− Water: Practically insoluble 
− Alcohol: Very soluble  
− Trimethylpentane: Slightly soluble  
1.2.2. Non-clinical Data 
Non-clinical data are exhaustively detailed in the Investigator’s brochure [1]. A brief summary is 
provided below. 
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1.2.2.1. 
Pharmacological profile 
F373280 (mono-ester of panthotenic alcohol and DHA) is a novel pro-drug of DHA which exerts 
antiarrhythmic properties by interacting with the electrical and structural remodelling of the atria.  
Experimental investigations were conducted in HEK293 cell line transfected with human Kv1.5 
channel using the whole cell patch clamp technique to evaluate whether F373280 could block the 
sustained component of IKv1.5. F373280 concentration-dependently reduced Kv1.5 channel activity 
with an IC50 value of 13.7 µM. 
The effects of F373280 on atrial effective refractory period were investigated in anesthetized pig 
using a conventional pacing protocol through epicardial electrodes placed on the left atrium. 
F373280 administered as a bolus and an infusion (10 mg/kg) significantly increased atrial 
effective refractory period (23.8 ± 2.2 ms versus -7.3 ± 11.5 ms in the presence of vehicle, p < 
0.05). In addition, F373280 was devoid of significant effect on the hemodynamic and the 
electrocardiogram (ECG) intervals.  
Proof of the pharmacological concept was performed with a different DHA derivative named: 
Nicotinyl ester of DHA (pro-drug based on DHA delivery). Ventricular tachypacing-induced 
congestive heart failure provides a clinically-relevant animal model of AF associated with 
structural remodelling, as is often seen clinically. It has been shown that sustained oral PUFA 
administration suppresses congestive heart failure-induced AF-promotion and fibrosis in the 
ventricular tachypacing canine model. Nicotinyl ester of DHA was tested in this model, at 1 g/day 
and 5 g/day, during 4 weeks, to prevent congestive heart failure-related atrial structural 
remodelling and AF promotion in dogs. Nicotinyl ester of DHA dose dependently reduced heart 
failure-induced increases in AF duration (989 ± 111 sec, n=5 in the presence of placebo versus 
637 ± 196 sec, n=5 in the presence of 1 g/kg/d Nicotinyl ester of DHA and 79 ± 51 sec, n=5, in 
the presence of 5 g/kg/d Nicotinyl ester of DHA). The protective effect of Nicotinyl ester of DHA 
was associated with a marked increase of plasma level of DHA and important incorporation of 
DHA in the left atrial tissue. Because F373280 similarly to Nicotinyl ester of DHA increases 
plasma level of DHA, it could be estimated that the compound may exert a similar protective 
effect [1]. 
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1.2.2.2. 
Safety pharmacology 
A battery of safety pharmacology studies was performed to evaluate the effects of F373280 on the 
central nervous, cardiovascular and respiratory systems. Data of these studies are exhaustively 
detailed in the Investigator’s brochure [1]. 
No particular alerts were evidenced with F373280. 
1.2.2.3. 
Toxicology profile 
Concerning the toxicological data, 4-week and 26-week repeat-dose studies in rat and dog were 
performed. Compared to the high administered doses of F373280 (500 to 2000 mg/kg/day), low 
circulating concentrations of F373280 were measured.  
During these toxicity studies, no toxicity was observed in rat after 4 and 26 weeks of dosing and 
in dog after 4 weeks of dosing. A NOAEL of 2000 mg/kg/day was established in these repeat 
toxicity studies.  
During the 26-week toxicity study in dogs, the NOAEL was set at 1000 mg/kg/day based on 
changes observed on red blood cell parameters. 
Based on toxicological profiles, F373280 is considered to support the proposed clinical trial. 
1.2.2.4. 
Pharmacokinetic data  
According to animal studies described in the Investigator’s brochure [1], the non-clinical 
pharmacokinetic profile of F373280 is not associated with particular alerts concerning the 
proposed clinical phase IIa study. 
1.2.3. Clinical data 
Part A: Single dose 
Six consecutive single ascending doses were tested (0.5 g, 1 g, 2 g, 4 g, 8 g and 16 g) on 6 
independent cohorts of 8 subjects (6 verum + 2 placebo). 49 subjects were treated and 48 
completed the study. 
No Serious Adverse Events (SAE) occurred in the course of the study. 
Regarding the reported Treatment Emergent Adverse Events (TEAEs) that were judged by the 
Investigator as having a causal relationship with the study drug administration in the absence of 
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an alternative explanation, 3 TEAEs were observed in the placebo group (palpitation, dizziness in 
standing position, symptomatic orthostatic hypotension without loss of consciousness) and 4 in 
the group of F373280 at the dosage of 16 g (meteorism, liquid stool, symptomatic orthostatic 
hypotension and dizziness in standing position). None of these adverse events (AE) were reported 
in the groups of F373280 at the dosages of 0.5 g, 1 g, 2 g, 4 g and 8 g. 
After a single administration of the different tested doses no difference between the tested product 
and placebo has been reported, regarding vital signs (heart rate, systolic blood pressure and 
diastolic blood pressure), biological parameters (related to coagulation: platelets and fibrinogen) 
and coagulation parameters (bleeding time, prothrombin time/INR, activated partial 
thromboplastin time, thrombin clotting time). Variations of these parameters were within the 
physiological ranges. 
After single oral administration of F373280 from 0.5 g to 16 g in 36 young healthy male subjects 
(6 per dose level), the following was observed: 
 
- 
F373280: Whatever the tested dose there is no circulating F373280 in plasma: only few, 
sparse and non consecutive samples with quantifiable level of F373280 close to LOQ were 
observed. This confirms that F373280 is a prodrug. 
- 
Panthenol: Cmax and AUC increased with the administered dose between 0.5 and 16 g. 
Panthenol concentrations were rapidly cleared from plasma with a mean terminal half-life 
around 2 hours. 
- 
DHA: after 0.5 and 1 g, low increased in DHA plasma concentrations compared to the 
baseline levels led to a high inter-individual variability of the corresponding 
Pharmacokinetics parameters. Plasma exposure in DHA increased with the administered 
dose between 2 and 16 g with no departure from proportionality (baseline corrected 
parameters). 
 
Part B: Multiple doses 
Three consecutive repeated ascending doses (1, 2 and 4 g) were tested on 3 independent cohorts of 
12 subjects (9 verum + 3 placebo, double blind). 36 subjects completed the study. Each treatment 
was administered over a period of 28 days. Pharmacokinetic parameters were assessed over a 
period of 14 days.  
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Among the TEAE judged by the investigator as suspected to F373280, 5/9 TEAEs were classified 
according the System Organ Class in vascular system disorder with orthostatic hypotension (2 in 
the 1 g group, 1 in the 2 g group and 2 in the 4 g group) and 4/9 were classified in nervous system 
disorder with 3 dizziness (2 in the 2 g group and 1 in the 4 g group) and 1 migraine (in the 1 g 
group). These TEAEs have already been reported with PUFAs and are commonly observed in 
phase I studies. 
After a repeated administration of the different tested doses, no difference between the tested 
products and placebo was reported regarding vital signs (heart rate, systolic blood pressure and 
diastolic blood pressure), biological parameters. The assessment of coagulation parameters and 
platelet function after administration of repeated dose of F373280 did not report any bleeding 
issue. The reported changes in coagulation parameters and platelet function were within 
physiological ranges. 
After a 14-day repeated oral administration of F373280 from 1 g to 4 g, the following was 
observed: 
 Panthenol: Cmax and AUC increased with the administered dose between 1 and 4 g. No 
accumulation of panthenol in plasma was observed. 
 
 DHA: Plasma exposure increased with dose. A 2-fold accumulation in total plasma exposure 
of DHA was observed after 14 days of administration, whatever the administered dose. 
1.3. 
STUDY RATIONALE 
F373280 is a new therapy based on DHA delivery (pro-drug) developed for the maintenance of 
sinus rhythm after ECV in persistent AF patients with chronic heart failure. 
The results of a pharmacological study performed in animals evidenced that DHA reduces the 
duration of AF induced by burst pacing [1]. 
Moreover, the effectiveness of PUFAs has been proven in the following conditions: 
− Prevention of AF recurrence in patients with persistent AF in co-administration with 
amiodarone (add on therapy) [2], 
− Improvement of ventricular functional parameters, morbi-mortality and duration of 
hospitalisation in patients with heart failure [3, 4, 5]. 
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Taking into account these studies, it seems that DHA might be of therapeutic interest in the 
treatment of patients with both persistent AF and chronic heart failure. 
This phase IIa study is designed to assess the efficacy and the safety of the investigational product 
(F373280) for maintenance of sinus rhythm after ECV in patients with persistent AF and chronic 
heart failure. 
1.4. 
OVERALL RISK AND BENEFIT ASSESSMENT 
F373280 is a new pro-drug of DHA.  
DHA is a well-known long chain PUFAs with a long-term clinical experience in cardiovascular 
diseases. DHA is contained in several medicinal products such as Omacor, (1 g of Omacor 
contains about 320 mg of DHA acid) marketed by Laboratoires Pierre Fabre for 
hypertriglyceridemia and as an adjuvant treatment for secondary prevention after myocardial 
infarction. According to the summary product characteristics of Omacor [9]: 
 
- The frequencies of adverse reactions are ranked according to the following: common 
(>1/100, <1/10); uncommon (>1/1000, <1/100); rare (>1/10000, <1/1000); very rare (<1/10000), 
not known (cannot be estimated from the available data). 
- The reported adverse events are: 
• Infection and infestations: 
Uncommon: gastroenteritis 
• Immune system disorders: 
Uncommon: hypersensitivity 
• Metabolism and nutrition disorders: 
Rare: hyperglycaemia 
• Nervous system disorders: 
Uncommon: dizziness, dysgeusia 
Rare: headache 
• Vascular disorders: 
Very rare: hypotension 
• Respiratory thoracic and mediastinal disorders:  
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Very rare: nasal dryness 
• Gastrointestinal disorders: 
Common: dyspepsia, nausea 
Uncommon: abdominal pain, gastrointestinal disorders, gastritis, abdominal pain upper 
Rare: gastrointestinal pain 
Very rare: lower gastrointestinal haemorrhage 
• Hepatobiliary disorders:  
Rare: hepatic disorders  
• Skin and subcutaneous tissue disorders:  
Rare: acne, rash pruritic 
Very rare: urticaria 
• General disorders and administration site conditions: 
Rare: malaise sensation 
• Investigations: 
Very rare: white blood count increased, blood lactate dehydrogenase increased 
Moderate elevation of transaminases has been reported in patients with hypertriglyceridaemia. 
Panthenol is a well-known substance with a long-term experience in medical, nutraceutic and 
cosmetic uses. According to the summary product characteristics of a product such as 
Bépanthene (tablet indicated in alopecia) which contains panthenol (100 mg), adverse event 
observed are rare cases of urticaria and erythema [10]. Panthenol is metabolised in panthotenic 
acid, i.e. B5 vitamin. 
Concerning toxicological studies performed results can support the administration of F373280 in 
the proposed clinical phase II study without particular alert [1]. 
Any safety warning was reported during a phase I study performed with F373280 administered to 
84 healthy volunteers in single dose in a range between 500 mg and 16 g or in repeated dose 
during 28 days in a range between 1 g and 4 g. Adverse events reported and related to study 
treatment were minor to moderate. The adverse events were palpitations, orthostatic hypotension, 
dizziness, meteorism and liquid stool. Most were reported in both groups (placebo and F373280) 
without a dose relationship. The assessment of coagulation parameters and platelet function after 
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administration of repeated dose of F373280 did not report any bleeding concern: the reported 
changes in coagulation parameters and platelet function were within physiological ranges. 
Moreover, DHA has been associated with anticoagulant products in AF studies [2, 8]. The range 
of PUFAs doses tested was between 2 g to 3 g (640 mg to 960 mg of DHA) and the range of study 
durations between 6 to 12 months. This association did not report a significant side effect of 
bleeding. 
DHA has already been used in HF patients in several studies without safety concern [3, 4, 5]. The 
range of PUFAs doses tested was between 1 g to 5 g (1 g of the tested PUFAs contains about 320 
mg of DHA acid) and the range of study durations was between 3 months to 3.9 years. 
Thus, inclusion of patients with no specific antiarrhythmic treatment is acceptable. They will 
receive an anticoagulant treatment to prevent the thrombo-embolic complications of AF 
(particularly stroke) and the adequate treatments to control the heart rate and heart failure.   
In conclusion, the overall available data allow in safe conditions the treatment of patients with 
persistent AF and chronic heart failure with F373280 in safe conditions. 
2. STUDY OBJECTIVES 
2.1. 
PRIMARY OBJECTIVE 
The primary objective of the study is to assess the efficacy of F373280 on the maintenance of 
sinus rhythm after direct ECV in patients with persistent AF and chronic heart failure. 
2.2. 
SECONDARY OBJECTIVES 
The secondary objectives of the study are to assess: 
• the efficacy of F373280 on the efficiency of direct ECV 
• the effect of F373280 on echocardiographic parameters 
• the safety and tolerability of F373280 
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3. ETHICAL CONSIDERATIONS RELATING TO THE STUDY 
The trial is conducted according to Good Clinical Practices (CPMP/ICH/135/95), the National 
regulations and the Declaration of Helsinki and its subsequent amendments (see Appendix 17.1). 
This protocol and the informed consent form will be submitted for approval to independent local 
or national Institutional Review Boards/Ethics Committees before the study set up, according to 
national regulation. 
All the protocol amendments or critical events liable to increase the risks incurred by the patients 
or to compromise the validity of the study or patients' rights will be submitted to the coordinator 
and to the Ethics Committees. 
After being informed orally and in writing of all potential risks and constraints of the trial, as well 
as their freedom to withdraw their participation at any time, patients will then sign a consent form.  
A time of reflection will be given to the patients, before giving a written consent and starting the 
study procedures. 
The use of a placebo is in accordance with EMA Addendum to the guideline on antiarrhythmics 
on AF and atrial flutter (EMA/CHMP/EWP/213056/2010) [21] and is acceptable because the 
included patients will remain under the standard treatment of AF and chronic heart failure. Except 
antiarrythmics, they will receive anticoagulant (vitamin K antagonist, VKA), rate control 
treatment, chronic heart failure treatment. During the study, in case of AF recurrence or atrial 
flutter emergence that would require cardioversion or the introduction of an anti-arrhythmic 
because of intolerable and/or uncomfortable clinical symptoms for instance, patients will be 
withdrawn and the tested product stopped. These patients will be considered as treatment failure. 
In this study, patients will be carefully screened, particularly for their cardiac condition, with 
ECG, 24-hour holter monitor and echocardiographic data, and their biologic and coagulation 
condition. 
The study will be addressed only to patients requiring an ECV due to their persistent AF, in the 
following conditions: 
- ECV in patients not presenting a contra-indication 
- Anticoagulation with vitamin K antagonist (VKA) for at least 3 weeks before ECV 
- ECV will be performed in patients with AF and without dyskalemia. An INR value 
control must be performed within 24h before ECV. INR values ≥ 2 on the 3 last 
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tests performed before ECV are required. However, if only 2 INR values are ≥ 2 
among those 3 last tests, an ECV can be performed if the presence of atrial 
thrombosis 
can 
be 
excluded 
with 
an 
ECHO–TE 
(transesophageal 
echocardiography) performed on the same day (before ECV) and the patient can 
continue the study. Patients who do not revert to sinus rhythm or present an early 
AF relapse or an early atrial flutter emergence within the observation period after 
ECV will be withdrawn and the tested product stopped. 
During the whole study, patients will remain under medical control: visits in cardiology units will 
be performed throughout the study period. This follow up will include clinical signs, ECG, 
biological and coagulation parameters. Moreover, patient’s cardiac rhythm will be monitored once 
a week between visits using Trans Telephonic ECG Monitoring (TTEM) reviewed by a Central 
Reading Laboratory.  
Patients may withdraw from the study at any time without having to give a reason and can expect 
to receive regular conventional therapy. 
4. STUDY DESIGN 
4.1. 
OVERALL DESCRIPTION 
This phase IIa trial will be conducted as an international, multicentric, 24 weeks, double-blind, 
placebo-controlled, randomised, parallel group design, trial in 152 patients suffering from 
persistent AF and chronic heart failure. 
After a 1 to 4-week of run-in period without study treatment, patients will be randomised into one 
of the following treatment groups: F373280 1g or placebo for 24 weeks.  
Seven visits are planned for the study: 
- 
Visit 1 (V1): W-4 to W-1: Selection visit (7 to 28 days before the Inclusion Visit) 
- 
Visit 2 (V2): D1: Inclusion visit (start of study treatment)  
- 
Visit 3 (V3): W4 (D28-2/+7D): cardioversion visit (outpatient or hospitalization according 
to clinical practice of the centre) (installation of the Holter ECG device) 
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- 
Visit 4 (V4): W5 (D35 -2/+7D): follow-up visit (removing of Holter ECG device and 
installation of the TTEM) 
- 
Visit 6* (V6): W12 (D84 ± 7D): follow-up visit 
 
 
*see amendment PA05 dated 22OCT2014 
- 
Visit 7 (V7): W16 (D112 ± 7D) : follow-up visit 
- 
Visit 9* (V9): W24 (D168 ± 7D): final study visit 
 
 
*see amendment PA05 dated 22OCT2014 
4.2. 
DISCUSSION OF THE STUDY DESIGN 
4.2.1. Choice of the Study Population 
The target indication of F373280 will be the maintenance of sinus rhythm after cardioversion of 
patients with persistent AF and chronic heart failure. In the present proof of concept study, the 
evaluation will focus on patients within this indication. This target population is justified by: 
- 
The proved efficacy of PUFAs in patients with persistent AF with or without heart failure 
in co-administration with amiodarone (add on therapy) [2] 
- 
The proved efficacy of PUFAs on the improvement of ventricular functional parameters, 
morbi-mortality and duration of hospitalisation in patients with heart failure [3, 4, 5] 
The study aim is to investigate the product effect in patients with: 
- 
Previous history of persistent AF with duration of the current episode from 7 days to 6 
months. 
- 
A systolic heart failure defined by a reduced left ventricular ejection fraction (≥ 30% and ≤ 
45%) or for patients with a LVEF > 45%: 
• an increased left ventricular end-diastolic size (diameter ≥ 60 mm and/or > 32 
mm/m² and/or volume > 97 ml/m²),  
• and/or an increased left ventricular end-systolic size (diameter > 45 mm and/or > 
25 mm/m² and/or volume > 43 ml/m²),  
• and/or a reduced left ventricular outflow tract velocity time integral < 15 cm [23, 
24].  
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According to a sub-group analysis performed in patients with persistent AF associated to 
heart failure (Nodari S. personal data), PUFAs would be effective to prevent recurrence of 
AF after cardioversion in patients with moderately abnormal LVEF. 
- 
A Left Atrial Area (LAA) not severely abnormal (no greater than 40 cm2 as defined in the 
report from the American Society of Echocardiography’s Guideline) [23]. According to a 
sub-group analysis performed in patients with persistent AF associated to heart failure 
(Nodari S. personal data), PUFAs would not be effective to prevent recurrence of AF after 
cardioversion of patients with severely abnormal LAA. 
For the successful rate of ECV, patients should have a stable medical treatment of heart failure 
and should not have any myocardial infarction or unstable angina or unstable ischemic 
coronaropathy assessed by coronarography or cardiac stress test (Echo stress, exercise stress test, 
nuclear or MR perfusion evaluation methods) within 6 months before selection.  
4.2.2. Choice of the Study Design 
As the target indication would be the prevention of AF recurrence after ECV, the study design 
meets 
the 
requirements 
of 
EMA 
guideline 
on 
antiarrhythmics 
in 
AF 
(EMA/CHMP/EWP/213056/2010) [21]. 
As F373280 aims to be a safe treatment for the prevention of AF recurrence, it will not be tested 
as an add-on therapy during the study. To avoid any interaction with the tested product, 
antiarrhythmics class I and III will be forbidden during the study. 
The study design is defined in order to avoid methodological bias. A double blind study is 
appropriate to assess the efficacy and safety of the use of F373280 to prevent recurrence of AF 
episodes. Moreover, this study design is similar to the design of almost all trials that have assessed 
intervention for rhythm control [2, 8, 11, 12].  
According to the target indication, only patients with persistent AF and requiring an ECV will be 
included in order to assess the time to first documented recurrence of AF (or emergence of atrial 
flutter) since cardioversion. 
To confirm the persistent nature of AF, a 24-hour holter monitoring will be performed during the 
selection visit.  
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Eligible participants will enter a selection phase in which anticoagulant treatment (VKA) will be 
adjusted to achieve ideally an International Normalized Ratio (INR) of 2 to 3 before ECV. 
According to guidelines for the management of AF [6], VKA should be given at least 3 weeks 
before cardioversion because of risk of thrombo-embolism due to post-cardioversion.  
Experimental data suggest that the maximal incorporation of n-3 PUFAs in the myocardial cell 
membrane takes up to 28 days to occur [22]. In addition, as shown in Nodari’s study [2], the 
duration of pre-treatment with PUFAs before cardioversion appears to be a contributing factor in 
success. Therefore, before starting follow up for the assessment of AF recurrence, treatment with 
F373280 should be started 28 days before ECV.  
Detection of AF recurrence will be performed using systematic (scheduled) ECG recording, thus 
allowing detection of asymptomatic (about 50% of episodes) as well as symptomatic AF episodes. 
According to previous studies, most of AF recurrences occurred during the first days after 
cardioversion [11, 15]. So that, the heart rhythm will be closely monitored during the first week 
after successful cardioversion using an ambulatory continuous 7-day holter ECG recording in 
order to increase sensibility to detect asymptomatic AF episodes. Thereafter, to improve patient 
compliance, this follow up will be continued using an easier device to carry and to use, i.e. a 
TTEM.  
Finally, during the study, patients will be scheduled for a clinical visit every 4 weeks or 8 weeks 
(with an additional visit 7 days after visit 3 (ECV visit)) in order to ensure a close medical 
monitoring and to assess efficacy and safety parameters. 
4.2.3. Choice of the Dose  
According to a previous study in patients with AF [2], the tested PUFA product (Omacor) at the 
dose of 2 g (i.e. 640 mg of DHA acid) was effective in the prevention of AF after cardioversion. 
Moreover, PUFAs at dosage of 1 g and 2 g were also effective on the improvement of ventricular 
functional parameters, morbi-mortality and duration of hospitalisation in patients with heart 
failure [3, 4, 5].  
From the F373280 phase I study, after a 14-day repeated administration of F373280 (1 g/day), 
observed plasma concentrations of DHA measured before treatment (Cmin) were similar to that of 
an effective dose of Omacor at 2 g/day (60 to 95 mg/ml and 60 to 90 mg/ml, respectively) (phase 
I study of F373280 and [16]). With regard to the rhythm of administration, mean peak/trough 
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fluctuation (baseline corrected) was around 0.3. This value supports a once-daily administration 
allowing a 24-hour plasma exposure in DHA. Therefore, a 1 g daily dose of F373280 is 
considered to be appropriate for this proof of concept study. 
4.2.4. Choice of the Sample Size 
See chapter 13. 
5. STUDY POPULATION 
Each patient fulfilling all the inclusion criteria and none of the non inclusion criteria will be 
eligible. 
5.1. 
INCLUSION CRITERIA 
Demographic Characteristics and Other Baseline Characteristics: 
1. Men or women aged more than 18 years (inclusive) 
2. Patient with current episode of persistent AF between 7 days and 6 months duration for whom 
electrical cardioversion is warranted 
3. Previous history of first documented episode of persistent AF  
4. Previous history of ischemic or non ischemic heart failure 
5. NYHA class I or II chronic heart failure at selection and at inclusion 
6. Left ventricular systolic dysfunction defined at selection and at inclusion by a reduced left 
ventricular ejection fraction (LVEF) ≥ 30% and ≤ 45% or for patients with a LVEF > 45%: 
• an increased left ventricular end-diastolic size  
(diameter ≥ 60 mm and/or > 32 mm/m² and/or volume > 97 ml/m²) 
• and/or an increased left ventricular end-systolic size 
(diameter > 45 mm and/or > 25 mm/m² and/or volume > 43 ml/m²) 
• and/or a reduced left ventricular outflow tract velocity time integral < 15 cm 
7. On appropriate, stable medical treatments for heart failure, including a diuretic and/or 
angiotensin-converting enzyme, and/or angiotensin-receptor blocker and/or mineralocorticoid 
receptor (MR) antagonists, and/or betablockers 
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8. Left atrial area ≤ 40 cm² at selection and at inclusion 
9. Patient treated or having to be treated by vitamin K antagonist 
10. For female patient of child-bearing potential:  
• In all the countries except Italy: 
 
- 
Use of an effective method of contraception (hormonal contraception or intra-uterine 
device) assessed by the investigator for at least 2 months before the selection in the 
study and agreement to go on using it during the whole duration of the study and up to 
1 month after the last dose of the study treatment or 
- 
Documented as surgically sterilized 
• In Italy only: 
- 
Absolute abstention from sexual intercourse during the whole duration of the study and 
for a month after the end of the study or 
- 
Use of double barrier contraception method (use of effective medical contraception 
method) from at least 2 months before the start of the study to the entire duration of the 
study and for a month after the end of the study or 
- 
Documented as surgically sterilized  
 
11. For female patient of child-bearing potential: negative urine pregnancy test at inclusion 
12. For male with a child-bearing potential partner (In Italy only): 
- 
Absolute abstention from sexual intercourse during the whole duration of the study and 
for 3 months after the end of the study or 
- 
Use of double barrier contraception method (use of condom for male and effective 
contraception method for the partner) from the entire duration of the study to 3 months 
after the end of the study. 
 
Ethical /legal considerations: 
13. Having signed his/her written informed consent, 
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14. Affiliated to a social security system, or is a beneficiary (if applicable in the national 
regulation) 
5.2. 
NON INCLUSION CRITERIA 
Criteria related to pathologies: 
1. No previous history of first documented episode of persistent Atrial Fibrillation 
2. More than two successful cardioversions (electrical or pharmacological) in the last 6 months, 
3. Secondary Atrial Fibrillation due to alcohol or severe valvular heart disease (grade III to IV), 
4. NYHA class III or IV heart failure at selection or at inclusion 
5. Thyroid disease uncontrolled by treatment: TSH ± T4L ± T3L to be checked in case of 
treatment for thyroid disease  
6. Myocardial infarction or unstable angina or presence of unstable ischemic coronaropathy 
assessed by coronarography or cardiac stress test (Echo stress, exercise stress test, nuclear or 
MR perfusion evaluation methods) within 6 months before selection 
7. Severe chronic kidney disease (creatinine ≥ 25 mg/L or estimated glomerular filtration rate < 
30 ml/min) at selection 
8. Bradycardia (HR ≤ 50 bpm) 
9. Hyperkalemia or hypokalemia (according to the standards of local laboratories) at selection 
10. Cardiac surgery within 3 months before selection or planned during the study duration 
Criteria related to treatments: 
11. Previously ineffective pharmacological or electrical cardioversion 
12. Concomitant treatment with ranolazine or any anti-arrhythmic drug (within 7 days prior to 
selection), except amiodarone, dronedarone and stable dose of digoxin, beta-blockers, 
calcium-blockers. 
13. Concomitant treatment with oral amiodarone or dronedarone from selection  
14. Concomitant treatment with intravenous amiodarone from selection  
15. Patient requiring a cardiac resynchronization therapy (CRT) or having undergone CRT 
implantation within the last 6 months 
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16. Treatment with any Polyunsaturated Fatty Acid within the last 3 months 
17. Dietary supplement with ω3 or ω6 according to investigator’s judgment 
18. Having undergone any form of ablation therapy for AF 
19. Patient treated with oral anticoagulant treatment other than vitamin K antagonist: new oral 
anticoagulants (dabigatran, rivaroxaban, apixaban), or treated with irreversible antiplatelet 
agents P2Y12 inhibitors such as ticlopidine, clopidogrel or prasugrel  
Others criteria:  
20. Patient liable not to comply with protocol instructions and/or with treatment, in the 
investigator’s opinion, 
21. Patient having taken part in a clinical trial in the preceding 2 months or taking part in a trial at 
the time of selection, 
22. Patient linguistically or mentally unable to understand the nature, objectives and possible 
consequences of the trial, or refusing to patient himself / herself to its constraints, 
23. Patient family member or work associate (secretary, nurse, technician…) of the Investigator, 
24. Patient having forfeited his / her freedom by administrative or legal award or being under 
guardianship, 
25. Breastfeeding female patient. 
5.3. 
NUMBER OF PATIENTS 
76 x 2 patients (taking into account 15 % of non evaluable patients). 
5.4. 
RECRUITMENT MODALITIES 
Patients will be recruited within the medical consultation of each centre involved in the study. If 
necessary and when authorized by local and national regulation, some specific supports or tools 
will be used to improve the recruitment (announcement, mailing to general practitioners, leaflet, 
website including ClinicalTrials.gov, CRO…). 
Before implementation, the documents will be submitted to and approved by the Ethics 
Committee. 
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5.5. 
 PATIENT IDENTIFICATION 
Patient's code will contain 7 digits: the 2 first digits corresponding to the country number, the 
following 2 digits corresponding to the centre number and the last 3 digits corresponding to the 
patient's chronological order once having signed the written informed consent. 
5.6. 
WITHDRAWAL CRITERIA 
Reasons for a patient's premature withdrawal from the study may be the following: 
• Patient's decision. A patient who wishes to withdraw from the study for any reason may 
do so at any time but must inform the investigator. In all cases, the Investigator should 
attempt to contact the patient as soon as possible for a final assessment in order to: 
- have the patient's decision written on the consent form 
- obtain the reason(s) for withdrawal and report it/them in the case report form 
- evaluate the patient's clinical condition 
- if necessary, take appropriate therapeutic measures: management of an adverse 
effect or concomitant disease, prescription of another treatment. 
• Investigator's decision in the patient's interest, particularly if a serious adverse event 
occurs and is considered by the Investigator liable to threaten the health of the patient. The 
monitor will be informed by phone or fax and a letter or report explaining the withdrawal 
will be forwarded to the monitor as soon as possible. 
• Erroneous inclusion according to the study protocol. The decision to maintain or not the 
patient in the study will be taken jointly by the investigator and the sponsor. Erroneous 
inclusions will not be paid to the investigator. 
• Patients who could not be treated with VKA for at least 3 weeks before ECV or who will 
experience a VKA intolerance during the study. 
• Patients without dyskalemia who will not have INR values ≥ 2 on the 3 last tests 
performed before ECV should not have an ECV and will be excluded from the study. 
However, if only 2 INR values are ≥ 2 among those 3 last tests, an ECV can be performed 
if the presence of atrial thrombosis can be excluded with an ECHO–TE (transesophageal 
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echocardiography) performed on the same day (before ECV) and the patient can continue 
the study.  
• Patients who will not revert to sinus rhythm (i.e. unsuccessful ECV) or with early AF 
relapse or early atrial flutter emergence within the observation period after ECV will be 
considered to have finished follow-up. 
• Occurrence of AF recurrence or atrial flutter emergence that would require, at the 
investigator’s judgement, a cardioversion or an introduction of an anti-arrhythmic because 
of intolerable and/or uncomfortable clinical symptoms for instance. 
5.7. 
REPLACEMENT OF PATIENTS 
Withdrawn patients will not be replaced. 
5.8. 
POST-STUDY EXCLUSION PERIOD  
Patients will not be allowed to participate in another clinical trial during 3 months following the 
study termination. 
5.9. 
STUDY CARD AND LETTER FOR GENERAL PRACTITIONER(S) 
The patient will receive from the Investigating Centre at Visit 1 - Selection Visit:  
- a personal card to be kept all along the study duration and providing the following information: 
patient's name, sponsor's name, study code, EUDRACT number, start date and expected end date 
of the study, complete address of the Investigating Centre with the name and phone number of the 
Investigator and a sponsor 24H/24 phone contact number in case of emergency (French and 
English languages): 33 (0)5 63 35 25 83. For Italy, this card will be in Italian only, without any 
English mention. 
- in Italy, a letter to be given to his/her general practitioner. This letter intends to inform the 
general practitioner(s) (and any other doctors who take care of the patient) that the patient 
participates to the clinical study. It describes the study treatment and includes some information 
on the forbidden treatment during the study.  
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6. STUDY TREATMENT 
The Clinical Pharmacy Department of the Institut de Recherche Pierre Fabre (IRPF) will supply 
the investigational centres with the treatment necessary for the conduct of the trial.  
6.1. 
SOURCE, PRESENTATION AND COMPOSITION OF 
 
INVESTIGATIONAL PRODUCT 
F373280 and placebo will be prepared in Soft Capsules similar presentation.  
• F373280 
Formulation of F373280, 1 g, Soft Capsules: oral administration, oblong size 20, off-white, Soft 
Capsules containing: Panthenyl ester of DHA, gelatine, glycerol, titanium, dioxide, purified water. 
• Placebo 
Formulation of placebo matching tested product, Soft Capsules: oral administration, oblong size 
20, off-white, Soft Capsules containing: paraffin liquid, fish flavour, gelatine, glycerol, titanium, 
dioxide, purified water. 
 
Placebo and F373280 capsules will be packaged in opaque blisters. 
6.2. 
PACKAGING AND LABELLING 
The treatment units will be packed and labelled by the Clinical Pharmacy Department of the IRPF 
according to European Directive and local requirements. 
6.2.1. Packaging 
Each treatment unit will be composed of 3 cases for a 12-week treatment period. 
Two 12-week treatment units will contain 3 cases, each case of 4-week treatment containing:  
10 blister packs of four 1 g F373280 soft capsules or 1 g placebo soft capsules each. 
6.2.2. Labelling 
Investigational Products will be labelled according to the following rules: 
Labelling should comply with the local requirements for Investigational Medicinal Products. 
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On the treatment units and cases, the labels will bear the following indications:  
a) name and address of the sponsor 
b) protocol number 
c) packaging batch number 
d) treatment number 
e) storage conditions 
f) expiry date 
g) pharmaceutical dose form 
h) route of administration 
i) quantity of dosage units 
j) direction for use 
k) legal statements:  
    -“for clinical trial only”, “keep out of the reach and the sight of children”, “please return to 
your doctor any unused product”, respect the prescribed dose” 
On the treatment unit, another label will be affixed with the mention of the Investigator’s name 
and patient’s code (completed by the Investigator). 
In addition, on each case will be mentioned the case number and a detachable label will bear the 
following indications: 
− Protocol number 
− Packaging batch number 
− Expiry date 
− Case number 
− Treatment number 
On the blister pack, the label will mention the protocol number, the packaging batch number, the 
case number and the treatment number. 
6.3. 
DISTRIBUTION TO CENTRE AND STORAGE 
The Clinical Pharmacy Department of the IRPF will supply the Investigational Centre with the 
treatment units along the study according to the need, upon request triggered by the patient’s 
selection.  
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As soon as the Pharmacist or the Investigator receives the trial medication, he/she will check the 
contents and immediately acknowledges the receipt in the IVRS/IWRS. The copy of the 
acknowledgement will be kept in the Investigator’s or the Pharmacist’s file. The same procedure 
will be applied to all further supplies during the course of the trial. 
At the time of the delivery to the Centre, the following information will be provided: 
• Details of storage conditions that should be respected 
• And, upon request and for the 1st delivery only, a letter of release for the Investigational 
Medicinal Product from the Sponsor's Qualified Person 
The CRA will ensure during the monitoring visits that trial medications have been received in 
good conditions and the acknowledgment of receipt has been performed adequately. 
Treatment units should remain intact until dispensation to the patients. They should be kept at 
temperature below 30°C in an appropriate lockable room only accessible to the person authorised 
to dispense them, under the responsibility of the Pharmacist or the Investigator. 
In the case of undue delay in study execution, the Pharmacist or the Investigator should ensure 
that the expiry date has not been exceeded.  
6.4. 
ALLOCATION OF TREATMENTS AND DISPENSATION TO PATIENT 
A randomisation list will be established by the Clinical Pharmacy Department of the IRPF. This 
list will be computer-generated with internal software. The randomisation methodology is 
validated by the Biometry Department before generation. 
Treatments F373280 or placebo will be balanced in a 1:1 ratio. 
As the treatment units are prepared for 12-week treatment periods, the Investigator will have to 
allocate a treatment number at inclusion visit (V2) and another one at visit 6.  
For each patient, the treatment number given at visit 6 will not be the same that the one given at 
inclusion visit (V2). 
The treatment numbers will be given through the IVRS/IWRS. 
At selection visit (V1), practically, once patient’s eligibility is confirmed:  
• The Investigator: 
− Contacts the IVRS/IWRS 
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− Answers the questions related to the patient  
• The IVRS/IWRS company: 
− Confirms this information by fax/email to the Investigator 
− Fills the “Request for Delivery of Investigational Product” form and sends it by email 
and/or fax to the Clinical Pharmacy Department of the IRPF.  
• The Clinical Pharmacy Department of the IRPF sends the corresponding treatment unit to 
the Investigator within 5 days from reception of the email request form. 
 
At inclusion visit (V2), the treatment number to be allocated for the first 12-week period to the 
patient is given by the IVRS/IWRS.  
At visit 6, the Investigator will contact again the IVRS/IWRS to obtain the treatment number for 
the last 12-week period of treatment. 
The Investigator will dispense to the patient the 4-week treatment cases (one or two according to 
the visit) which label indicates the treatment number and the administration period. 
6.5. 
DRUG ADMINISTRATION 
6.5.1. Duration of Treatment 
For a patient completing the study, the theoretical study treatment exposure to F373280 or 
placebo will be 24 weeks. 
If the ECV is postponed by 1 week to allow INR stabilization, the treatment duration will be 25 
weeks. 
6.5.2. Dose Schedule 
One soft capsule of 1g of F373280 or placebo to be taken each day during 24 weeks. 
6.5.3. Route and Conditions of Administration 
The soft capsules are to be taken orally. One soft capsule is to be taken each evening with the 
dinner during 24 weeks.  
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6.6. 
ACCOUNTABILITY ON SITE AND RETURN/DESTRUCTION OF 
 
INVESTIGATIONAL PRODUCT 
The Investigator should maintain accurate written records of drug received, dispensed, returned 
and any remaining treatment units, on the drug accountability form. These records should be made 
available for Clinical Research Associate (CRA) monitoring. The packaging of the medication 
should remain intact until just before the dispensation. 
At each visit, the Investigator will record the number of soft capsules returned by each patient 
using the appropriate page of the e-CRF. 
At the end of the study, all used and unused treatments including packaging should be noted, and 
return is organised by the CRA to the Clinical Pharmacy Department of the IRPF for destruction. 
A copy of the drug accountability form should be provided by the Investigator to the CRA. 
6.7. 
RECALL OF INVESTIGATIONAL PRODUCTS  
In case of recall of investigational products (decided by the Competent Authorities or the 
Sponsor), the Investigator will immediately be informed by the Sponsor. 
The Investigator in collaboration with the Sponsor’s representatives (Study Manager, CRA) must 
urgently: 
• Stop the delivery of the concerned investigational products to the patients. 
• Inform the concerned patients that they must immediately stop taking these investigational 
products and bring them back. 
The Study Manager/CRA organises the return of the recalled products to the Clinical Pharmacy 
Department of the IRPF according to the Sponsor’s procedures. 
7. CONCOMITANT TREATMENTS 
Any existing concomitant treatment (at selection visit), any new concomitant treatment or change 
in the dosage of an existing concomitant treatment during the course of the study must be noted 
on the electronic Case Report Forms (e-CRF). All treatments should be evaluated by the 
Investigator at patient’s selection, and treatment prolongation or stop during the study should be 
considered. 
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For all concomitant treatments taken during the study, the following information must be noted in 
the relevant section(s) of the e-CRF: 
• The name of the treatment and its form 
• The reason for prescription 
• The route of administration 
• The daily dose 
• The duration of treatment. 
7.1. 
VITAMIN K ANTAGONIST TREATMENT 
VKA should be given for at least 3 weeks before ECV and continued for the whole study 
duration. However, VKA should be stopped in case of occurrence of VKA intolerance during the 
study and the patient should be withdrawn from the study. The VKA used will be left to the 
decision of each Investigator according to his/her local practice. 
7.2. 
PROHIBITED TREATMENTS 
- Class I and class III antiarrhythmic treatments: 
• Class I: 
o Class IA: Disopyramide, Procainamide, Quinidine 
o Class IB: Lidocaine, Mexiletine 
o Class IC: Flecainide, Propafenone 
• Class III: Dofetilide, Ibutilide, Sotalol, Amiodarone, Dronedarone. 
- Ranolazine 
- Any PUFA 
- Any oral anticoagulant treatment other than VKA: new oral anticoagulants (dabigatran, 
rivaroxaban, apixaban), or irreversible antiplatelet agents P2Y12 inhibitors such as ticlopidine, 
clopidogrel or prasugrel 
- Dietary supplement with Omega 3 or Omega 6 
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Prohibited treatments at selection must not be prescribed for the duration of the study except in 
case of occurrence of an adverse event or AF episode that requires a corrective treatment in the 
interest of the patient’s health. 
7.3. 
AUTHORISED TREATMENTS 
Other treatments will be authorised during the study duration. 
However, if medication other than study drugs is administered at any time from the start of the 
study, details must be recorded in the e-CRF. During the study, patients must be asked whether 
they have been on a course of prescribed drug treatment or have taken any OTC or herbal drugs 
since the visit. 
8. EVALUATION CRITERIA 
8.1. 
PRIMARY EFFICACY CRITERION  
8.1.1. Time to the first Atrial Fibrillation Recurrence or Atrial Flutter Emergence 
8.1.1.1. 
Definition 
Time to first AF recurrence or atrial flutter emergence is defined by the time to first episode of AF 
or atrial flutter (symptomatic or not) lasting for at least 10 minutes. 
8.1.1.2. 
Schedule 
The heart rhythm follow up will be performed from the end of ECV visit (visit 3) to the final 
study visit (visit 9).  
For randomised patients with spontaneous cardioversion before ECV, the recurrence of AF or the 
emergence of atrial flutter will be assessed after visit 3 (from week 5). 
8.1.1.3. 
Evaluation Methods 
• 7-day holter monitor: 
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The heart rhythm monitoring will be carried out from visit 3 to visit 4 using a 7-day continuous 
ECG (5-leads/2 or 3 channels) ambulatory recording (holter ECG) fixed after ECV visit.  
Following holter monitoring, the heart rhythm will be documented using Trans Telephonic ECG 
Monitoring (TTEM). 
• Trans Telephonic ECG Monitoring: 
The ECG follow up will be documented using the TTEM: one transmission per week from the day 
of visit 4 (end of week 5) to visit 9 (week 24, end of study). The patient will be requested to 
contact the Central Reading Laboratory for transmission of each stored TTEM.  
Moreover, if patient experiences AF or atrial flutter symptoms during this TTEM period, it should 
be documented using the TTEM. 
In case of AF recurrence or atrial flutter emergence and provided that the patient does not require 
a cardioversion or an introduction of an anti-arrhythmic at Investigator’s judgement, the patient 
could be maintained in the study with the treatment in order to assess a spontaneous 
cardioversion. For that purpose the patient will continue to transmit a TTEM once a week. 
• Process of centralisation of ECG (Holter and TTEM) 
ECG (Holter and TTEM) will be centralized by the Central Reading Laboratory. The ECG will be 
validated by a trained technician, then analysed by a cardiologist. The cardiologist interpretation 
will be emailed to the site (or per fax on request of the site). The investigator will be asked to 
review and sign these documents. 
The Holter and TTEM process will be fully described in separate documents. 
8.2. 
SECONDARY EFFICACY CRITERIA 
8.2.1. Numbers of AF episodes in the first week following visit 3 (ECV visit) 
8.2.1.1. 
Definition 
Number of AF episodes will consist in the assessment of AF episodes with duration at least 10 
minutes (NSup10) and of less than 10 minutes (NInf10), respectively. 
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8.2.1.2. 
Schedule 
The heart rhythm follow up will be performed from the end of successful ECV visit (visit 3) to the 
study visit 4.  
8.2.1.3. 
Evaluation Methods 
• 7-day holter monitor: 
The heart rhythm monitoring will start using a 7-day continuous ECG (5-leads/2 or 3 channels) 
ambulatory recording (holter ECG) after ECV visit from visit 3 to visit 4. 
8.2.2. 
Duration of AF episodes in the first week following visit 3 (ECV visit) 
8.2.2.1. 
Definition 
Duration of AF episodes will consist in the sum of duration of each AF episode. 
8.2.2.2. 
Schedule 
The heart rhythm follow up will be performed from the end of successful ECV visit (visit 3) to the 
follow up study visit (visit 4).  
8.2.2.3. 
Evaluation Methods 
Duration of AF episodes will be assessed using the 7-day continuous ECG (5-leads/2 or 3 
channels) ambulatory recording. 
8.2.3. 
Clinical parameters evaluation 
8.2.3.1. 
EHRA score assessment 
8.2.3.1.1. 
Definition 
AF related symptoms will be evaluated by the EHRA (European Heart Rhythm Association) score 
[20]. The following items “during presumed arrhythmia episodes" are checked to determine the 
score: palpitation, fatigue, dizziness, dyspnea, chest pain and anxiety. 
Classification of AF-related symptoms (EHRA score) are as follows: 
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• EHRA I          - ‘No symptoms’ 
• EHRA II         - ‘Mild symptoms’; normal daily activity not affected 
• EHRA III       - ‘Severe symptoms’; normal daily activity affected 
• EHRA IV       - ‘Disabling symptoms’; normal daily activity discontinued  
This classification relates exclusively to the patient-reported symptoms. 
In addition to this score, the frequency will be classified in three groups, namely occasionally 
(less than once per month), intermediate (1/month to almost daily) and frequent at least daily. 
8.2.3.1.2. 
Schedule 
EHRA evaluation will be performed in case of evocative symptoms of arrhythmia. 
8.2.3.1.3. 
Evaluation Methods 
EHRA evaluation will be collected by Central Reading Laboratory during TTEM period. 
 
8.2.3.2. 
Time to first AF recurrence less than 10 minutes 
Time to first AF recurrence less than 10 minutes will be assessed during TTEM period. 
8.2.3.3. 
Recurrence of symptomatic AF  
Recurrence of symptomatic AF will be assessed during TTEM period. 
The number of recurrences of symptomatic AF consists of the number of AF recurrences 
associated with a symptom (palpitation, fatigue, dizziness, dyspnea, chest pain and anxiety) and 
confirmed by an ECG. 
The time to first symptomatic AF recurrence is defined by the time to first episode of 
symptomatic AF. 
8.2.3.4. 
Number and duration of hospitalizations 
• Number and duration of hospitalizations for cardiovascular events 
− Hospitalization for AF treatment 
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− Hospitalization for worsening of heart failure 
− Hospitalization for myocardial infarction 
− All cause of hospitalization 
• Number and duration of hospitalizations for thromboembolic stroke  
 
8.2.4. 
Cardioversion assessment 
• Assessment of spontaneous cardioversion before visit 3 
• Assessment of successful cardioversion at visit 3 (i.e. return to sinus rhythm) 
• Shocks distribution (1, 2 or 3 shocks) 
• Number of patients needing another cardioversion after initial ECV 
8.2.5. 
Evolution of echocardiographic parameters 
8.2.5.1. 
Definition 
The following echocardiographic parameters will be assessed: Left atrial diameter (mm), LAA 
(cm2), Left atrial volume (ml), Left atrial volume/BSA (ml/m2), LVEF (%), Left ventricular end 
diastolic volume/BSA (ml/m2), Left ventricular end systolic volume/BSA (ml/m2), Left 
ventricular end diastolic diameter (mm), Left ventricular end diastolic volume (ml), Left 
ventricular end systolic diameter (mm) and Left ventricular end systolic volume (ml). 
8.2.5.2. 
 Schedule 
Measurements will be performed at visit 1 and visit 2 to check the eligibility of the patient.  
Measurements performed at visit 4, visit 6 and visit 9 are done to follow the echocardiographic 
evolution of the patients in sinus rhythm. 
8.2.5.3. 
Evaluation method 
The echography evaluations will be carried out according to the recommendations for chamber 
quantification drawn up by the American Society of Echocardiography and the European 
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Association of Echocardiography [23]. So, the recommended method for volume measurements is 
to use the biplane method of discs (modified Simpson’s rule) from 2-D measurement. 
8.3. 
BIOMARKER ASSESSMENT: RED BLOOD CELL 
 
CONCENTRATIONS OF DHA 
8.3.1. Definition 
Because of the limited human tissue accessibility for biopsy, red blood cell DHA contents is a 
marker of tissue DHA concentration [13], [14]. 
8.3.2. Blood samples 
8.3.2.1. 
Collection schedule 
Blood samples will be collected to determine the red blood cells (RBC) concentrations of DHA.  
Blood samples will be performed at visit 2 before treatment, visit 3, visit 6 and visit 9. 
Actual sampling times will be individually reported in the e-CRFs. 
8.3.2.2. 
Technical handling 
Two blood samples (2 x 4 ml) will be collected in EDTA tubes. They will be homogenized slowly 
by inverting the tube without shaking, stored between +2°C/+8°C in a fridge (no freezing will be 
allowed) and sent to Analytical Centre in refrigerated conditions (between +2°C and +8°C). 
Analysis will be performed within 2 weeks following reception at the Analytical Centre. 
8.3.3. DHA concentration measurement 
Analytical determination of RBC concentrations of DHA will be carried out by the Analytical 
Centre. 
Lipids will be extracted from red blood cells samples with a mixture of hexane/isopropanol after 
acidification [17]. Total lipid extracts will be saponified and methylated. The fatty acid methyl 
esters (FAME) will be extracted and analyzed by Gas Chromatography. 
Identification of FAME will be based on retention times obtained for FAME prepared from fatty 
acid standards. The area under peaks will be determined using ChemStation Software (Agilent) 
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and results will be expressed as % of total fatty acids. DHA concentration will be calculated using 
the internal standard and expressed as µg/g for red blood cells samples. Thus, omega-3 index will 
be assessed. The omega-3 index represents the content of EPA plus DHA in red blood cells 
(expressed as a percent of total fatty acids). It is a biomarker considered as a new marker of risk 
for death from coronary disease [18]. 
Results of this analytical determination will be kept confidential by the dosing centre until the end 
of the study, and will be provided only at the end of the study (after database lock) in a separate 
file. 
8.4. 
SAFETY ASSESSMENT 
8.4.1. Adverse Events 
At selection, any concomitant disease will be reported on the e-CRF. At each further visit, the 
occurrence of AEs since the last visit will be based on the patient's spontaneous reporting, the 
Investigator's non-leading questioning and his/her clinical evaluation. All AEs will be reported on 
the e-CRF (see section 10). 
8.4.2. Laboratory Investigations 
8.4.2.1. 
Schedule 
Laboratory investigations will be performed at visit 1 (before treatment) and visit 9 (end of 
treatment) or End of Treatment visit. 
At visit 3 and 6, only a standard haematologic dosage will be performed.  
Furthermore the kalemia will be checked before electrical cardioversion at visit 3. 
The total volume of blood samples taken for haematology and biochemistry analysis should not 
exceed 30 ml. 
8.4.2.2. 
Technical Procedures and Parameters 
The following tests will be performed: 
 
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Haematology: 
haematocrit, haemoglobin, RBC count, white blood cells (WBC) count, WBC 
differential counts (% and/or absolute), reticulocytes, platelets.  
 
Biochemistry: 
sodium, potassium, bicarbonate, chloride, alkaline phosphatase, gamma GT, 
albumin, total bilirubin, conjugated bilirubin, creatinine, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), fasting glucose, 
total cholesterol, cholesterol (HDL, LDL), triglycerides, creatine 
phosphokinase (CPK), fibrinogen. 
Blood samples will be taken in the morning in fasting conditions.  
The estimation of GFR at selection relies on the measurement of serum creatinine and the 
Cockcroft- Gault formula: 
Cockcroft-Gault formula 
- with serum creatinine expressed as mg/L:  
in men: 
GFR (ml/min) = [(140-age) x weight / (7.2 x serum creatinine in mg/L)] 
 
in women: 
GFR (ml/min) = [(140-age) x weight / (7.2 x serum creatinine in mg/L)] x 0.85 
 
- with serum creatinine expressed as μmol/l: 
GFR (ml/min) = [(140-age) x weight / serum creatinine in μmol/l] x k,where k = 1.23 for men, 
1.04 for women. 
 
(weight in kg, age in years) 
Additional tests may be done at the Investigator’s discretion, in the patient’s interest. In case of 
any abnormal and/or clinically significant results, the Investigator should order laboratory control 
tests. 
8.4.3. Global Physical Examination 
A global physical examination including the measurement of body weight will be carried out on 
each body system at visit 1, visit 2, visit 3, visit 6, visit 7, and visit 9. 
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The Body surface area (BSA) will be calculated at the same visits using Mostellers’ formula: 
BSA = [(Weight x Height)/3600]1/2 
(Weight in kg, height in cm) 
The physical examination will be globally evaluated as “normal/abnormal”. Further target 
inspection will be undertaken for any abnormal finding. 
8.4.4. Vital Signs 
Vital signs will consist in blood pressure and heart rate at rest.  
8.4.4.1. 
Schedule 
Vital signs will be measured at each visit. 
8.4.4.2. 
Technical Procedure and Parameters 
Systolic blood pressure (SBP) and diastolic blood pressure (DBP), expressed in mmHg, will be 
measured after at least 5 minutes in supine position and after 2 minutes in standing position.  
The heart rate (HR), expressed in beats per minute (bpm), will be measured by auscultation by 
counting the beats for at least 30 seconds, after at least 5 minutes in supine position and after 2 
minutes in standing position. 
Bodyweight will be measured with patient in underwear and with the same balance at each visit.  
8.4.5. Electrocardiogram (ECG)  
8.4.5.1. 
Schedule 
An ECG will be recorded after at least 10 minutes of rest at visit 1, visit 2, visit 3, visit 6, visit 7, 
and visit 9 using a usual standardised 12-lead cardiograph. 
8.4.5.2. 
Technical Procedure and Parameters 
• Electrocardiogram: 
The global interpretation from manual reading (normality, clinical relevance) and HR (bpm), PR 
(ms), QRS (ms), QT (ms), QTcB (ms), QTcF (ms), repolarisation patterns will be reported in the 
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e-CRF. Each print-out will include the patient’s code, date, time, technician's initials and 
investigator's signature. 
In case of thermic paper ECG print out, a photocopy will be made by the centre to ensure safe 
filing. 
• 24 hour-Holter - ECG 
An ambulatory continuous 24-hour ECG (5-leads/2 or 3 channels) will be recorded at selection 
visit using a holter ECG, in order to confirm persistent AF.  
8.4.6. Coagulation parameters 
Coagulation assessment will be evaluated by the following parameters: 
− Prothrombin Time/INR (PT/INR) 
− Activated Partial Thromboplastin Time (aPTT) 
− Thrombin Clotting Time (TCT) 
The recommendations for the controls of INR are the following [25, 26]: 
1) During the pre-cardioversion period, if the anticoagulation by VKA has to be initiated, the 
treatment must be initiated at least 3 weeks prior to cardioversion then the INR will be monitored 
as follow:  
− The adjustment of the dosage of VKA should be performed stepwise by controlling INR 2 
to 3 times a week until stabilization within the target range (2 - 3) on 2 successive tests. 
− When the INR is within the target range (2 - 3) on 2 successive tests, the dose of VKA 
should be maintained. Then the controls of INR will be progressively spaced within a few 
weeks.  
− When INR is stabilized, at least one test should be performed each week. 
− In all cases, an INR control must be performed within 24 h before ECV. 
2) During the pre-cardioversion period, if the anticoagulation by VKA was already initiated, the 
INR will be monitored as follow: 
− One INR per week up to ECV 
− An INR control must be performed within 24 h before ECV 
3) After cardioversion : one INR every 4 weeks 
4) Throughout the duration of the study if INR > 3 the advocated actions are: 
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− No transesophageal echocardiography before cardioversion 
− For asymptomatic patients:  
- 3 < INR < 4: no omission of VKA (dose adjustment if required), no vitamin K 
- 4 ≤ INR < 6: omit one dose of VKA, no vitamin K 
- 6 ≤ INR < 10: interrupt VKA, vitamin K 2 mg orally 
- INR ≥ 10: interrupt VKA, vitamin K 5 mg orally 
For INR ≥ 6, an adverse event has to be reported (asymptomatic overdose).  
Anti-coagulation by VKA should be given at least 3 weeks before ECV and continued for the 
whole study duration. 
aPTT and TCT will be performed at visit 1, visit 2, visit 3, visit 6, visit 7, and visit 9. 
The quantity of blood samples collected at each time for coagulation parameters will be 2 ml. 
Additional tests may be done at the Investigator’s discretion, in the patient’s interest. In case of 
any abnormal and/or clinically significant results, the Investigator should order laboratory control 
tests. 
8.5. 
CONCOMITANT TREATMENTS 
Concomitant treatments will be evaluated at each study visit. 
Requirements related to patient's concomitant treatments started before selection visit and 
continued throughout the trial, or started during the trial, can be found in section 7.  
8.6. 
COMPLIANCE 
The patient will be reminded at each visit to bring back at the following visit any used or unused 
remaining soft capsule, blister and case. 
At each visit (except at visit 4), the Investigator will record the number of supplied and remaining 
soft capsules in the e-CRF. 
9. STUDY PROCEDURES 
Visit 1 - Selection Visit (Week - 4 to Week -1): 
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The patient considered eligible for selection by the Investigator will be informed of the 
characteristics and the consequences of the trial both verbally and by reviewing the patient's 
information sheet and consent form (see section 14.3). If the patient accepts to participate in the 
study, he/she will sign the informed consent form and will keep a copy. 
The patient will be assessed for the following: 
• Demographic characteristics (gender, age, height, body surface area) 
• Personal and medico-surgical history 
• Habits (Tobacco, alcohol consumption, dietary habits including fish consumption…) 
• Cardiovascular diseases, mainly detailed history of Heart Failure and AF characteristics  
• Echocardiography using a two-dimensional echocardiography 
• 12-lead ECG 
• Concomitant diseases, adverse signs or symptoms (able to be used for treatment emergent 
AE determination) 
• Concomitant treatments (authorised, disallowed) 
• Global physical examination/bodyweight 
• Vital signs 
• Biology: haematology, biochemistry, assessment of coagulation parameters: Prothrombin 
Time/INR (PT/INR), Activated Partial Thromboplastin Time (aPTT), Thrombin Clotting 
Time (TCT) 
• Biology assessment of renal function: creatinine or estimated glomerular filtration rate 
If the results of the above assessments are compatible with the selection criteria: 
• A 24-hour continuous ECG ambulatory recording (Holter ECG) device will be installed 
on the patient to monitor the patient heart rhythm. The patient will be requested to bring 
back the device after the termination of 24 hours recording. The recording will be 
transmitted from the Investigational site to the Central Reading Laboratory. The Central 
Reading Laboratory will send his/her assessment regarding the confirmation of persistent 
AF within 2 working days to the Investigator. 
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• The patient will enter the selection and pre-cardioversion periods in which anticoagulant 
(VKA) will be adjusted to achieve ideally an International Normalized Ratio (INR)  in the 
range of 2 to 3 before ECV.  
At the end of the visit, the Investigator will contact the IVRS/IWRS to confirm the patient 
selection (which will automatically order the treatment delivery) and organise the appointment for 
the next visit.  
The patient will receive from the investigational centre the participant card to be kept for all the 
duration of the study. 
Visit 2 - Inclusion Visit (Day 1):  
If the patient's behaviour during the selection period and/or the result of complementary 
examinations, particularly the confirmation of the presence of persistent AF by the Central 
Reading Laboratory during this period and the laboratory tests, are compatible with the inclusion 
criteria, the patient will be assessed for the following: 
• Adverse events 
• Concomitant treatments (authorised, disallowed) 
• Laboratory examination: red blood cell concentrations of DHA and coagulation 
parameters Prothrombin Time/INR (PT/INR), Activated Partial Thromboplastin Time 
(aPTT), Thrombin Clotting Time (TCT) 
• Global Physical examination/bodyweight 
• Vital signs 
• Echocardiography using a two-dimensional echocardiography 
• 12-lead ECG 
• Urine pregnancy test for women of child bearing potential 
If the results of the above assessments are compatible with the inclusion criteria, the patient will 
be included and the investigator will contact the IVRS/IWRS to obtain the treatment unit number 
to be dispensed at visit 2 for the first 12-week period. 
Between this Inclusion visit and the next visit (V3), the INR will be closely monitored (refer to 
paragraph 8.4.6) in order to fulfil the ECV conditions (refer to paragraph 3).  
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At the end of the visit, the Investigator will organise the appointment for the next visit and will 
give the treatment for the next 4-week period (one case of treatment). 
Visit 3 (Week 4: D28 -2/+7 days) cardioversion: 
Patient will be assessed for the following criteria: 
• Adverse events 
• Concomitant treatments (authorised, disallowed) 
• Laboratory examination: Haematology, RBC concentrations of DHA, Prothrombin 
Time/INR (PT/INR), Activated Partial Thromboplastin Time (aPTT), Thrombin Clotting 
Time (TCT) 
• Global Physical examination /bodyweight 
• Vital signs  
• 12-lead ECG 
• Electrocardioversion (ECV): ECV has to be performed 4 weeks after randomization in 
patients with AF. ECV will be performed in the morning, with the patient in the fasting 
state and without dyskalemia. An INR value control must be performed within 24h before 
ECV. INR values ≥ 2 on the 3 last tests performed before ECV are required. However, if 
only 2 INR values are ≥ 2 among those 3 last tests, an ECV can be performed if the 
presence of atrial thrombosis can be excluded with an ECHO–TE (transesophageal 
echocardiography) performed on the same day (before ECV) and the patient can continue 
the study. Anesthesia will be induced and patients will be cardioverted with administration 
of a synchronized, biphasic current. The initial shock will be set at 100 J if the body 
weight is less than 70 kg and at 150 J for higher body weights. Successful cardioversion 
will be defined as recovery of sinus rhythm lasting at least 1 minute after the shock. If 
unsuccessful, a second 200-J shock, and eventually a third 200-J shock, will be 
administered. Failure of ECV is defined as the persistence of AF after the third attempt at 
cardioversion. After the procedure, patients will be monitored on telemetry for at least 6 
hours before discharge.  
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Patients who will not revert to sinus rhythm or with early AF relapse or early atrial flutter 
emergence within the observation period after ECV will be withdrawn from the study and will 
be considered to have finished their follow-up. 
 
At the end of the visit, a 7-day continuous ECG (5-leads/2 or 3 channels) ambulatory recording 
(holter ECG) will be installed on the patient in order to monitor the patient heart rhythm after 
ECV.  
The Investigator will collect all unused cases, blisters and soft capsules, and will count the unused 
capsules for each 4-week treatment period. 
At the end of the visit, the Investigator will organise the appointment for the next visit and give 
the treatment to be taken during the next 8-week period (two cases of treatment). 
Visit 4 (Week 5: D35 -2/+7 days): 
After removal of the continuous ECG ambulatory device, the patient will be assessed for the 
following criteria: 
• Assessment of AE 
• Concomitant treatments (authorised, disallowed) 
• Bodyweight (bodyweight measured at V3 to be used) 
• Vitals Signs 
• Echocardiography using a two-dimensional echocardiography 
At the end of the visit, the patient will be given the TTEM device for cardiac monitoring. The 
patient will be clearly instructed on the frequency and modalities of transmission. The patient will 
be requested to perform one transmission per week from this visit (initial call to perform with the 
patient) to the visit 9 (week 24 – end of study). Moreover, in case of AF or atrial flutter 
symptoms, additional transmissions may be performed.  
Visit 6* (Week 12: D84 ± 7 days) - Visit 7 (Week 16: D112 ± 7 days) : 
*see amendment PA05 dated 22OCT2014 
Patient will be assessed for the following criteria: 
• Adverse events 
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• Concomitant treatments (authorised, disallowed) 
• Laboratory 
examination: 
Prothrombin 
Time/INR 
(PT/INR), 
Activated 
Partial 
Thromboplastin Time (aPTT), Thrombin Clotting Time (TCT). However, in case of 
discontinuation of anticoagulation after ECV due to occurrence of VKA intolerance, the 
monitoring of INR, aPTT and TCT should be stopped. 
• Global Physical examination/bodyweight  
• Vital signs  
• 12-lead ECG 
• The cardiac monitoring will be continued using the TTEM device through one 
transmission per week from the day of visit 4 (end of week 5) to visit 9 (week 24, end of 
study). Moreover, in case of AF or atrial flutter symptoms, additional transmissions may 
be performed. 
The Investigator will collect all unused cases, blisters and soft capsules, and will count the unused 
capsules for each 4-week treatment period. 
In addition, at visit 6: 
• the investigator will contact the IVRS/IWRS to obtain the treatment unit number to be 
dispensed at visit 6 for the last 12-week period. 
• an echocardiography will be performed, an haematology examination will be done and the 
RBC concentration of DHA will be measured.  
At the end of each visit, the Investigator will organise the appointment for the next visit and give 
the treatment to be taken during the next treatment period: one case at visit 6 and two cases at visit 
7. 
Visit 9* - End-of-Study Visit (Week 24: D168 ± 7 days):  
*see amendment PA05 dated 22OCT2014 
Patient will be assessed for the following: 
• Adverse events 
• Concomitant treatments (authorised, disallowed) 
• Global Physical examination/bodyweight 
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• Vital signs 
• 12-lead ECG 
• Laboratory examination: haematology, biochemistry, assessment of coagulation 
parameters: Prothrombin Time/INR (PT/INR), Activated Partial Thromboplastin Time 
(aPTT), Thrombin Clotting Time (TCT), Red blood cell concentration of DHA. 
• Urine pregnancy test for women of childbearing potential 
• Echocardiography using a two-dimensional echocardiography 
The Investigator will collect all unused cases, blisters and soft capsules, and will count the unused 
soft capsules. 
 
The total volume of blood collected should be about 90 ml for the study duration (30 ml for the 
total volume of haematology and biochemistry, 2 ml for each blood samples for coagulations 
parameters and 4 ml for each blood samples of DHA). 
10. ADVERSE EVENTS: DEFINITION AND REPORTING 
10.1. ADVERSE EVENTS 
10.1.1. Definition of Adverse Events 
An AE is any adverse change from the patient's baseline condition, i.e. any subjective signs and 
symptoms or change in a concomitant disease present at the Selection Visit considered or not 
related to the treatment. 
AE includes intercurrent signs, symptoms, illnesses and significant deviations from baseline for 
vital signs and laboratory values which may occur during the course of the clinical study. 
All laboratory tests for which abnormal results are collected after study treatment initiation should 
be repeated until the values return to normal or to a stable status. Abnormal results are defined as 
those falling out of the laboratory normal ranges and that are clinically significant. The frequency 
of such checks should be defined by the Investigator according to the degree of abnormality. 
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In all cases, the aetiology should, as much as possible, be identified and Pierre Fabre Médicament 
notified. 
10.1.2. Grading of Adverse Events 
Adverse or intercurrent events are graded as follows: 
• Mild: awareness of signs or symptoms, but easily tolerated 
• Moderate: uncomfortable enough to cause interference with usual activity 
• Severe: incapacity with inability to work or do usual activity 
10.1.3. Reporting of Adverse Events 
The records of AE in the e-CRF describe the nature (diagnosis, signs and symptoms), severity, 
onset date, stop date, outcome and actions taken, and relationship to study treatment (in the 
Investigator's opinion). It must be specified whether the event is serious or not. 
10.2. SERIOUS ADVERSE EVENTS (SAE) 
10.2.1. Definition 
A SAE includes, but is not necessarily restricted to, any event which: 
• Results in death (whatever may be the cause) 
• Is life-threatening 
• Results in persistent or significant disability/incapacity 
• Requires the patient's hospitalisation or prolongation of current hospitalisation * 
• Is a congenital anomaly or birth defect 
Other events such as cancer and any additional adverse experience or abnormal laboratory values 
occurring during the study period, defined by the protocol as serious or which the Investigator 
considers significant enough or that suggest a significant hazard, contra-indications, side effect or 
precaution, must be handled as serious adverse events. 
Any overdosage meeting a seriousness criteria should be reported as a SAE (see section 10.3). 
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Any pregnancy occurring during/after exposure to the study drug(s) should be reported on the 
SAE notification form (see section 10.4). 
* any hospitalisation, or prolongation of hospitalisation due to the circumstances listed below: 
− planned (as per protocol) medical/surgical procedure 
− preparation for routine health assessment/procedure (e.g. routine colonoscopy) 
− planned medical/surgical admission (planned prior to entry into study trial, appropriate 
documentation required) 
− administrative or social reasons (e.g. lack of housing, economic inadequacy, care-giver 
respite, family circumstances) 
will not be reported as a SAE. 
10.2.2. Reporting of SAE 
All Serious Adverse Events, according to the above-mentioned definitions and regardless of 
treatment or relationship to study drug, and occurring once the informed consent form has been 
signed, must be reported by the Investigator as soon as he/she is informed of the event. 
The Investigator must notify the Sponsor of this event by sending, within 24 hours, the 
"Notification of serious adverse event" form ("first notification") with all the available 
information about the event (see appendix 17.2), to the Sponsor's Corporate Vigilances e-mail 
dedicated box: 
HQ.pharmacovigilance@pierre-fabre.com 
 
 In case it is not possible to send the report by e-mail it can be sent by FAX at the 
following number: 
+ 33 1 49 10 80 90 
In case of non-inclusion, the reporting period ends when the non-inclusion is documented. 
10.2.3. Follow-up of SAE 
The Investigator must draw-up a specific clinical report and use the "Notification of serious 
adverse event" form ("follow-up") (see appendix 17.2) and collect the results of the carried out 
examinations and the reports of hospitalisation. 
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The serious adverse events must be followed up until resolution or stabilisation. 
10.2.4. SAE Occurring After the Study 
Any SAE occurring during 30 days following the end of the study for the patient should be 
notified to the Sponsor. 
Must also be notified to the Sponsor any event occurring at any time after the end of the study for 
the patient which may be related to the study treatment in the Investigator's opinion. 
10.3. REPORTING OF OVERDOSAGE TO THE SPONSOR 
For the purpose of this trial, an overdosage will be defined as any dose exceeding the planned 
prescribed dose of the study drug or the administration of any dose of an associated product that is 
considered both excessive and medically important. 
In the absence of seriousness criteria, the overdosage and associated adverse event if any, are 
reported only on the Adverse Event page of the e-CRF. If the definition of seriousness criteria is 
met, the SAE notification form must also be transmitted to the Sponsor. 
10.4. REPORTING OF PREGNANCY TO THE SPONSOR 
Pregnancies discovered in the period in between the informed consent form signed but before any 
study drug exposure are not to be reported to the Sponsor unless associated to a seriousness 
criteria (e.g. serious adverse event study-protocol related procedure). If pregnancy is confirmed, 
the women must not be administered the study drug and must be withdrawn immediately from the 
study.  
If pregnancy is suspected while the patient is receiving study treatment, the study drug should be 
discontinued immediately until the result of the pregnancy testing is known. If pregnancy is 
confirmed, then the study treatment is permanently discontinued in an appropriate manner and the 
patient is withdrawn from the study.  
The Investigator must report to the Sponsor any pregnancy which occurs during or after the 
patient has been exposed to the study drug and until 30 days after the last study drug 
administration. The Investigator must immediately notify the Sponsor using the SAE notification 
form and also report the pregnancy on the AE page of the e-CRF. 
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Women who become pregnant after exposure to the study drug must be followed by the 
Investigator until the completion/termination of the pregnancy. If the pregnancy goes to term, the 
outcome will have to be reported to the Sponsor (baby's healthy status). 
10.5. SPONSOR'S RESPONSIBILITIES FOR SAFETY REPORTING 
 
PURPOSES 
Sponsor will submit expedited and periodic reports to both Competent Authorities and Ethics 
Committees per corporate standard operating procedures as regards to the EU directive 
2001/20/EC taking into account local specific requirements. 
11. DATA COLLECTION AND STUDY MONITORING 
11.1. DATA COLLECTION 
11.1.1. Case Report Form 
An e-CRF will be used to record all patient data required by the protocol except the central ECG 
(Holter ECG, TTEM) and DHA data which will be transferred from vendors to the subcontractor 
as electronic data files that will be loaded into the study database.  
The e-CRF should be fully validated, compliant with ICH-GCP requirements and European 
regulations and should include a traceability system for data corrections and deletions (audit trail). 
Prior to the start of the study, the Investigator will complete a "Delegation of significant study-
related duties" form. The signature and initials of all personal in charge of e-CRF completion 
should be recorded on this form. Each person involved in e-CRF completion, review, correction 
and / or validation will be trained and will have an individual login and access code to the e-CRF. 
Training sessions will be held by the subcontractor for all participants using this tool. An e-CRF 
user manual will be available for investigators and CRAs.  
All the information included into the e-CRF will be recorded from source documents onto the e-
CRF by an authorised person. 
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The Investigator is responsible for the management and accuracy of the information on the e-
CRF. At each monitoring visit, the e-CRF(s) should be at the CRA's disposition for review and 
validation.  
At the end of the study, a CD-ROM containing the pdf version of all e-CRFs (including audit-
trail) will be sent by the subcontractor to the Sponsor and to the investigational sites for archiving. 
The subcontractor must store all study data for at least 15 years after the end of the study and 
ensure their legibility and accessibility during all the storage period. 
11.1.2. Source Documents 
A source document is an original record or certified copy of an original record of clinical findings, 
observations or any other medical or paramedical activities performed during the clinical trial, 
necessary for the transcription and the verification of the collected data. 
Source documents along with all other trial-related documents (copies of all "informed consent" 
forms, e-CRFs CD-ROM, drug inventories and any correspondence related to the study) must be 
kept in the investigator's file throughout the study, and then, must be stored in the study centre's 
archives for a period of at least 15 years or as per local legal requirements, whatever is the 
longest.  
For further details see section 15.2. 
11.2. STUDY MONITORING 
11.2.1. Monitoring visits 
On-site visits will be carried out by a representative of the Sponsor's staff (Study Manager or 
CRA) prior to study initiation and at regular intervals (every 4 to 6 weeks) throughout the study. 
Additional visits and communication by telephone fax or meeting may be performed if necessary. 
Any site visit performed by the Sponsor's representatives will be recorded in the Investigator's 
study file. 
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11.2.1.1. Site Preselection Visit 
Before selecting a centre for the study, a visit will be carried out by the CRA and/or the Study 
Manager to ensure that the Investigator has the necessary capacities (availability, patient's 
recruitment, environment), technical means and staff to carry out the study. 
11.2.1.2. Initiation Visit 
Before the start of the study at all investigational sites, an initiation visit will be carried out by the 
CRA to check at the latest that: 
• The Investigator: 
− has received the technical protocol, administrative and financial agreement signed by all 
parties 
− has received the written statement of the Ethics Committee approval and the list of its 
members and their functions 
• The original dated and signed curriculum vitae of the investigator(s) has been collected 
• Laboratory normal ranges have been collected  
• All study materials are available on the study site 
• All participants agree with the monitoring procedures and know the study procedures 
• All participants are aware of a possible audit or inspection 
The CRA has also to provide training on the study protocol requirements and study specific 
procedures. 
11.2.1.3. Follow-up Visits 
Throughout the study, regular follow-up visits will be carried out by the CRA to check 
compliance with GCP, patient’s informed consents, strict application of the protocol, conformity 
of the data entered on the e-CRF with the source documents and ensure its correct completion, 
adverse events reporting, proper retention, storage and management of the study medication, as 
well as the source and other trial-related documents. 
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11.2.1.4. Closing Visit 
At the end of the study, a final visit will be carried out by the CRA to: 
• Verify that the e-CRFs CD-ROM with pdf files are correctly stored 
• Control the accountability of intact and used treatment units and return them to the 
Clinical Pharmacy Department of the IRPF for destruction 
• Obtain the last data clarifications and/or solutions if any 
• Collect the patient's consent forms in sealed envelopes (except in case of specific country 
requirements),  
• Make an on-site review of all study documentation and complete it if necessary 
• And finally, remind the Investigator of his regulatory obligations, study document 
archiving process and duration. 
11.2.2. Direct Access to Source Documents 
In accordance to the requirements of the GCP, all Sponsor representatives (Study Manager, CRA 
and Auditors) have to be given a direct access to all source and study data to perform quality 
monitoring/audit, thus ensuring accuracy and completeness of data).  
Investigators are reminded that all Sponsor representatives keep professional confidentiality with 
regards to the patient data. 
11.3. INDEPENDENT DATA MONITORING COMMITTEE 
An Independent Data Monitoring Committee (IDMC) will be established to assess at intervals the 
progress of the clinical trial, the compliance with the inclusion criteria, the quality of follow up, 
the quality of primary end point measures, the safety data. The IDMC will thereafter recommend 
to the Sponsor whether to continue, modify, or stop the study.  
The IDMC operating procedures will be described in an independent document.  
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12. DATA MANAGEMENT  
All clinical data related to the study will be collected and saved in a computerised database by the 
Data Management Department of the subcontractor and under the supervision of the Data 
Manager of Pierre Fabre Biometry (PFB) according to the following procedures.  
12.1. DATA ENTRY 
All required data will be collected by the Investigator or authorised designee (duly identified into 
the delegation task list) on the e-CRFs.  
The e-CRFs used for this study will be developed and maintained by the Data Management 
Department of the subcontractor and approved by the Sponsor.  
Electronic data (Holter ECG, TTEM and DHA) will be transferred by the 3rd party vendor 
according to the specifications given by the Data Manager of the subcontractor. These data will be 
captured and handled in accordance with the European GCP ICH E6 guideline. 
12.2. DATA CLEANING 
The subcontractor will define in the Data Validation Plan for reviewing and querying data, 
descriptions of both manual and electronic edit checks. Upon Sponsor approval, the subcontractor 
will program the checks.  
The subcontractor will review the data over the course of the study, working with the Sponsor to 
identify data inconsistencies. The Investigator will be asked to resolve queries by making changes 
directly into the e-CRF.  
12.3. DATA CODING 
Adverse events, concomitant diseases, medical/surgical histories will be coded by the 
subcontractor using the MedDRA dictionary (latest version in use). 
Concomitant medication will be coded by the subcontractor using the WHO-DRUG dictionary 
(latest version in use).  
The Sponsor Clinical Development Physician will validate the coding. 
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12.4. DATA STORAGE 
Computer data files as well as their modifications will be archived by the subcontractor and kept 
available upon request of the Sponsor. 
12.5. DATABASE LOCK 
The validated database will be locked by the subcontractor upon request of the Data Manager of 
PFB following the completion of all steps required, i.e. data entry and check of all data, resolution 
of all queries, validation of the coding, Clinical and Products Safety databases reconciliation and 
validation committee.  
Then, the subcontractor will transfer the locked database in SAS format to the Data Manager of 
PFB who assume storage on the PFB secured server. 
13. STATISTICAL ANALYSIS 
After the database lock and the randomisation code release, the statistical analysis will be 
performed by PFB or under the supervision of the statistician of PFB using SAS® software, 
according to the Statistical Analysis Plan approved by the Validation Committee. 
13.1. GENERAL CONSIDERATIONS 
The main objective of the study is to assess the efficacy of F373280 versus placebo on the 
maintenance of sinus rhythm after direct ECV in patients with persistent AF and chronic heart 
failure. 
Only the primary analysis of the primary efficacy criterion, on which is based the sample size 
justification, may lead to a causal interpretation. All other statistical results are to be regarded 
within a descriptive perspective. 
The statistical significance level of the various two sided tests of all analyses will be 5 %. 
13.2. SAMPLE SIZE 
Assuming an AF recurrence or atrial flutter emergence rate of 85% under placebo and 65% under 
active group, i.e. a clinically relevant difference ∆ of 20%, a sample size of 64 assessable patients 
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per group is required, using a log-rank test of survival curves with a 80 % power and a 5 % two-
sided significance level. 
According to the previous assumptions and assuming a rate of not assessable patients of 15%, a 
minimum of 76 patients will have to be randomised per group. 
13.3. PROTOCOL DEVIATIONS 
Prior to the database lock and the randomisation code release, the Validation Committee members 
will review the protocol deviations and will classify them as either minor or major. A protocol 
deviation will be considered major when it is likely to bias significantly the treatment effect 
estimate based on the primary efficacy criterion. 
Patients with major deviation(s) will be excluded from the Per Protocol data set (see section 13.4). 
A listing of all protocol deviations will be provided for all randomised patients, including the type 
(major/minor) of protocol deviations according to the decisions made by the members of the 
Validation Committee. 
The number and percentage of patients with major protocol deviations will be tabulated by 
treatment group and type of major protocol deviations on the Full Analysis Set defined in section 
13.4. 
13.4. DATA SETS ANALYSED 
The following 3 data sets will be analysed (as defined by the Validation Committee):  
 
• The Safety Set composed of all randomised patients having received at least one dose of 
the study treatment. This data set will be used to perform analyses of Safety. 
• The Full Analysis Set (FAS) composed of all randomised patients having received at least 
one dose of the study treatment and with a successful cardioversion observed at visit 3. 
This data set will be used to perform analyses of Efficacy.  
• The Per Protocol Set (PP) which is the subset of the Full Analysis Set composed of all 
patients with a primary efficacy criteria available and without any major protocol 
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deviation or other source of bias for primary criteria analyses. This data set will be used to 
perform the supportive analysis of the primary efficacy criterion. 
13.5. HANDLING OF DROPOUTS AND MISSING DATA 
13.5.1. Dropouts 
The number of patients who withdraw from the study after their randomisation will be provided 
by treatment group for all treated patients (Safety Set). All withdrawn patients will be further 
described regarding their time to dropout and reasons for withdrawal. 
13.5.2. Repositioning of Visits 
No repositioning of visits will be done. 
13.5.3. Missing Data 
Missing values will not be substituted by estimated values, but considered as missing in statistical 
analysis. 
13.6. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Before the first trial drug intake, patient’s background, medical and surgical history, demographic 
data and disease characteristics will be described by treatment group on the Safety Set. 
- Quantitative parameters will be described by treatment group and overall using the 
following: number of patients, number of missing data, mean, standard deviation, 
minimum, median and maximum values. 
- Qualitative parameters will be described by treatment group and overall using 
frequencies. 
Concomitant diseases, as well as medical and surgical histories will be tabulated descriptively by 
treatment group and overall using the MedDRA codes of System Organ Classes and preferred 
terms. 
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If more than 10% of patients are excluded from the FAS and PP set, the description of patients by 
treatment group at selection and inclusion will be repeated on the FAS and PP set for all 
parameters. 
No statistical test of comparability of treatment groups at baseline will be performed.  
13.7. EFFICACY ANALYSIS  
13.7.1. Primary Criterion  
13.7.1.1. Primary Analysis 
The primary criteria, time to first recurrence of AF or atrial flutter emergence, will be analysed 
using the Kaplan Meier method and compared with the Log rank test. Hazard ratios and 95% 
confidence intervals will be estimated with the Cox regression model. 
The primary analysis will be performed on the FAS. 
13.7.1.2. Supportive Analysis 
The primary analysis will be repeated on the PP set. 
13.7.2. Secondary Criteria 
All secondary analyses will be performed on the FAS. If more than 10% of patients are excluded 
from the PP set, the secondary analyses will be repeated on the PP set.  
13.7.2.1. Numbers of Atrial Fibrillation Episodes in the first week following V3 
Both the numbers of AF episodes (symptomatic or not) lasting for at least 10 minutes and with 
duration less than 10 minutes (NSup10 and NInf10) will be described by treatment group and 
compared by the chi-square test (or CMH test adjusted for centre) or Fisher’s exact Test. 
13.7.2.2. Duration of Atrial Fibrillation Episodes in the first week following V3 
The duration of all AF Episodes will be described by treatment group and compared using the 
Student t (or using an ANOVA with treatment and centres effects) or Wilcoxon test. 
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13.7.2.3. Time to first AF recurrence less than 10 minutes or symtomatic 
The time to the first AF recurrence less than 10 minutes and the time to the first symptomatic AF 
recurrence will be analysed as the primary analysis.  
13.7.2.4. Clinical parameters evaluation 
The EHRA score will be described by treatment group and analysed using a chi-squared test (or 
CMH test adjusted for centre) or Fisher’s exact Test.  
The frequency of presumed arrhythmia will be described by treatment group. 
The number of recurrence of symptomatic AF, of hospitalizations (for cardiovascular events, for 
thromboembolic stroke and for all causes), of spontaneous cardioversion, of successful 
cardioversion (including number of shocks distribution) and the number of patients needing 
cardioversion after initial ECV will be described by treatment group and compared using a chi-
square test or a Fisher Test (if the numbers are relevant).  
The duration of hospitalizations for cardiovascular events, for thromboembolic stroke and for any 
cause will be described by treatment group and compared using the Student t (or using an 
ANOVA with treatment and centre effects) or Wilcoxon test. 
The echocardiographic parameters values will be described at each time (V1, V2, V4, V6 and V9) 
and changes described from V4 to V9 and from V2 to V9. 
13.7.2.5. Biomarker analysis: red blood cell concentrations of DHA 
Values and changes from baseline for red blood cell concentration of DHA will be performed by 
treatment group and assessment time. 
13.8. SAFETY ANALYSIS 
The Safety Set will be used to perform all analyses of the safety criteria. 
13.8.1. Adverse Events 
Any adverse event having been reported during the study for a given patient will be classified by 
preferred term and corresponding system organ class using the MedDRA terminology. 
Adverse events will be classified as: 
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• Treatment emergent adverse events, i.e., any adverse event which occurs or worsens on 
study treatment during the randomised period. 
• Or non treatment emergent adverse events, i.e., any adverse event which occurs during the 
run-in period (before V2) or is reported as concomitant disease with the same intensity. 
For each study period, any patient with at least one reported adverse event will be classified as a 
patient: 
• With at least one adverse event 
• With at least one treatment emergent adverse event 
• With one TEAE 
• With two TEAEs 
• With at least three TEAEs 
• With at least one related TEAE 
• With an adverse event leading to the study treatment discontinuation (definitive or 
temporary) 
• With an adverse event leading to withdrawal 
• With at least one serious adverse event. 
Numbers and percentages of patient with at least one reported treatment emergent adverse event 
will be tabulated by treatment group: 
• By system organ class 
• By system organ class and preferred term 
• By system organ class and preferred term, taking into consideration its most severe 
intensity 
• And by system organ class and preferred term, taking into consideration the most severe 
relationship to the study treatment. 
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Recurring adverse events (i.e., adverse events classified with the same preferred term) for a given 
patient will only be counted once and only their most severe intensity or most severe relationship 
to the study treatment will be tabulated. 
The number and percentage of patient with at least one most common (reported in 1% patients in 
any group) drug related TEAE ("not excluded or unassessable") will be tabulated by Preferred 
Term and Treatment group in decreasing order for the treatment group (for all patients). 
The number and percentage of patients with at least one reported most common treatment 
emergent adverse event will also be plotted by treatment group. This graphical representation will 
highlight the frequencies of the most severe intensities reported by system organ class and 
preferred term. 
SAE will also be described on an individual basis: treatment group, patient's code, sex and age, 
Investigator's reported term, preferred term, time of onset according to the time of the first study 
treatment administration, duration, action taken regarding the study treatment administration, use 
of a corrective treatment, outcome and relationship to the study treatment in the Investigator’s 
opinion. 
13.8.2. Clinical Laboratory Evaluation  
For each laboratory parameter, data will be tabulated by treatment group and assessment time. 
The absolute changes post-trial drug administration - baseline (the baseline value being the value 
measured on the last blood sample collected before the first trial drug administration) will be 
calculated and tabulated by parameter, treatment group and post-trial drug administration 
assessment time. Results of retests performed post-trial drug administration will not be analysed 
and tabulated. They will only be displayed in individual data listings. 
For all biochemistry parameters, scatter plots highlighting individual results will display the 
baseline and week 24 of the laboratory measurements for each patient by locating the point 
defined by the baseline value on the abscissa and respectively week 24 value in the ordinate.  
For all haematology parameters, scatter plots highlighting individual results will display the 
baseline and week 4, week 12 and week 24 of the laboratory measurements for each patient by 
locating the point defined by the baseline value on the abscissa and respectively week 4, week 12 
and week 24 value in the ordinate.  
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Each treatment group will be differently identified. The first bisecting line (45° line), the lines of 
lower and upper normal range, the lines of Potentially Clinically Significant Change (PSC) range 
and Clinically noteworthy abnormal laboratory value (CNALV) range added on the plots (see 
Appendix 17.3). 
For all blood laboratory parameters, shift tables will be provided to depict the numbers of  patients 
with post-trial drug administration variations at each assessment time as compared to the baseline 
values (measured on the last blood sample collected before the first trial drug administration) by 
treatment group. A 3-point scale (low, normal, high) will be used as defined by the normal ranges 
in use in the laboratory in charge of the assays. 
CNALV (see in Appendix 17.3) will be identified and described on an individual basis. If 
relevant, five separate individual data listings by treatment group will be provided: 
• CNALV for haemoglobin (including corresponding individual results of erythrocytes and 
haematocrit) 
• CNALV for neutrophils or leucocytes (including corresponding individual results of 
basophils, eosinophils, lymphocytes and monocytes) 
• CNALV for platelets (including corresponding individual results of erythrocytes and 
leucocytes) 
• CNALV for liver function parameters (including corresponding individual results of 
gamma-GT) 
• CNALV for serum creatinine  
13.8.3. Global Physical Examination 
Recorded data of the global physical examination performed will not be tabulated as any 
abnormal findings post-randomisation should be reported as AEs (if clinically significant). 
Physical examination assessments will be provided in the listings of individual data. 
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13.8.4. Vital Signs, Physical Findings and Other Observations Related to Safety 
13.8.4.1. Vital Sign Measurements Over Time 
For each parameter (systolic blood pressure, diastolic blood pressure and HR in supine and 
standing positions), descriptive statistics over time of values and changes from baseline will be 
tabulated by treatment group and assessment time. 
13.8.4.2. Body weight 
Descriptive statistics over time of values and changes from baseline will be tabulated by treatment 
group and assessment time. 
13.8.4.3. Individual Patient Changes 
The number and percentage of patient with at least one Predefined Potentially Clinically 
Significant Change (PSC) and with at least one PSC Leading to Clinically Significant Value 
(PSCV) will be tabulated by treatment group (see Table 1 in Appendix 17.3).  
According to the pharmacological drug profile mentioned previously in this Protocol, the changes 
from baseline to the maximum and/or minimum post-baseline value could be categorized and 
tabulated by treatment group with frequencies and decreasing cumulative percentages. 
If there is a signal of a drug effect toward one direction rather than the other, additionally shift 
tables of variations from baseline to the maximum or minimum post-baseline value could be also 
provided (see Table 2 to 4 in Appendix 17.3). 
An individual data listing of patients with symptomatic or asymptomatic orthostatic hypotension 
will be provided by treatment group (see Table 5 in Appendix 17.3). 
13.8.5. ECG 
Frequencies on the clinical interpretation (normal, abnormal CS or NCS) will be presented by 
treatment group and assessment time. Individual tabulated data for ECG abnormalities will be also 
displayed. 
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13.8.6. Coagulation parameters 
Scatter plots highlighting individual results for coagulation parameters (prothrombin time/INR, 
activated partial thromboplastin time and thrombin clotting time) before and after study treatment 
administration will be produced. 
13.9. CONCOMITANT TREATMENTS 
Concomitant treatments will be tabulated by treatment group within a descriptive perspective. 
They will be classified by therapeutic area according to the WHO-DRUG dictionary using the 
"anatomical therapeutic chemical" classification on the safety set. 
13.10. COMPLIANCE 
 
The percentage of compliance will be described by treatment group using the quantity 
 
100
_
_
_
(%)
×
=
n
consumptio
l
Theoretica
n
consumptio
actual
Estimated
Compliance
 
 
 
with: Estimated actual consumption = number of tablets provided at the start of study (Visit 2) 
minus number of tablets returned at the end of study (Visit 9) 
Theoretical consumption = number of days of treatment intake planned between the start and the 
end of study (168 days ± 7days) 
 
13.11. INTERIM ANALYSIS AND DATA MONITORING 
No analyses of efficacy data are planned for IDMC that ensures that the overall probability of type 
I error is controlled. No Type I error and sample size adjustments are necessary. Any 
recommendations of the IDMC to alter study conduct will be based on safety, so IDMC 
monitoring of the study will not affect the statistical operating characteristics of the final analysis. 
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The IDMC will review, three times during the study period (after the first 30 subjects will have 
been randomized, when the first 80 subjects will have terminated their study participation and 
when 130 subjects will have terminated their study participation), safety data results across 
treatment groups and judges whether the overall safety and feasibility (not futility) of the trial 
remain acceptable.  
14. GENERAL ETHICAL CONSIDERATIONS  
14.1. ETHICAL CONDITIONS 
This study is performed in accordance with the principles stated in the Declaration of Helsinki 
(1964) and subsequent amendments and in accordance with the Good Clinical Practice Guideline 
(CPMP/ICH/135/95). 
14.2. ETHICS COMMITTEE AND LEGAL REQUIREMENTS 
All the documents required by National Regulations and any other informative documents that 
may be requested are submitted for review to an Ethics Committee whose procedures and 
operations meet the GCP and National Legal Requirements. 
Depending on National Regulations, the application is submitted to the Ethics Committee by the 
Sponsor (or representative) or by the Investigator. 
A copy of the formal written approval from the Ethics Committee is provided to the Sponsor 
(directly by the Ethics Committee or via the Investigator) with a list of names and qualifications 
of its members. 
The request for authorisation by the Competent Authority or its notification if required (depending 
on National Regulations) is carried out by the Sponsor. 
The screening of patients does not start before the approval of the Ethics Committee has been 
obtained and the study authorised by the Competent Authority or notified to the Competent 
Authority (depending on National Regulations). 
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14.3. PATIENT'S INFORMATION LEAFLET AND INFORMED CONSENT 
 
FORM 
An information must be given to the patients before their decision to participate or abstain from 
participation. 
This information is based on the elements set out in the Declaration of Helsinki and the ICH GCP 
Guidelines. It must also describe the measures taken to safeguard patient’s privacy and protection 
of personal data, according to European Directive 95/46 EC or other local regulation. 
Restraints and risks must be explained, as well as the right to discontinue participation in the 
study at any stage, without affecting their further relationship with the Investigator and/or their 
future care. 
The written information and consent form must be submitted to the patient with an oral 
explanation. It must be agreed and signed by the patient before any study-related procedure starts. 
This information and consent procedure is under the Investigator’s responsibility. 
The information and consent document are made in triplicate: the original copy is kept by the 
Investigator, one copy is given to the patient and the last copy is kept by the Clinical Quality 
Assurance Unit of the Sponsor in a sealed envelope at the end of study (except in case of specific 
country requirement). 
Specific areas of the Sponsor’s copy are not triplicated to avoid the reading of the patient’s 
surname (except the first 3 letters), first name, address and signature.  
If any information becomes available during the trial that may be relevant to the patient’s 
willingness to keep on participating in the trial, an updated written informed consent must be 
submitted to the patient to confirm  agreement to continue participating. 
14.4. PERSONAL DATA PROTECTION 
All information from this study (excluding data from the informed consent) is entered into a 
computer under the Sponsor’s responsibility in accordance with the French law, "Loi 
Informatique et Libertés" (January 6, 1978, and subsequent amendments) and with the European 
Directive 95/46/CE. 
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14.5. INSURANCE POLICY 
In accordance with the provisions of the law and the GCP, the Sponsor Pierre Fabre Médicament, 
has an insurance policy intended to guarantee against possible damage resulting from the research. 
The studies and/or experiments performed on behalf of the Sponsor Pierre Fabre Médicament are 
specifically and expressly guaranteed. 
It is advisable to underline that non compliance with the Research Legal Conditions is a cause for 
guarantee exclusion. 
15. ADMINISTRATIVE PROCEDURES 
15.1. PROTOCOL AMENDMENT 
Neither the Investigator nor the Sponsor may alter the protocol without the authorisation of the 
other party.  
All changes to the protocol are subject to an amendment which must be dated and signed by both 
parties and must appear as an amendment to the protocol. 
Substantial amendments are submitted for approval / authorisation to the Ethics Committees and 
Competent Authorities. 
Urgent amendments are submitted for approval / authorisation to the Ethics Committees and 
Competent Authorities, but could be implemented immediately under specific conditions defined 
with the Sponsor. 
15.2. SOURCE DOCUMENTS, INVESTIGATOR'S FILE STORAGE 
The Investigator: 
• Keeps all trial-related documents in appropriate file folders. Records of patient, original 
informed consent forms, source documents, a CD Rom containing a pdf copy of e-CRF, 
drug inventory, Ethics Committees and Sponsor correspondence pertaining to the study 
must be kept on file. 
• Retains all documents relating to the screening (consent and investigation results) of all 
patients included in the trial or not. 
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• Retains a list of the patient’s names, addresses (and/or number of medical file), code 
numbers to allow checking of data reported on e-CRFs with those from source documents. 
• Authorises direct access to source documents for monitoring, audits and inspections. 
• The trial-related documents must be retained as strictly confidential at the Investigator’s 
site for at least 15 years or according to local requirements, whatever is the longest after 
the completion or discontinuation of the trial (European Directive 2003/63/EC). 
15.3. END OF THE STUDY 
15.3.1. Definition of the End of Study 
The end of study is the last visit of the last patient undergoing the trial. 
Any change to this definition during the study, for whatever reason, must be notified as a 
substantial amendment. 
15.3.2. Early Study Termination 
15.3.2.1. Early Study Termination Decided by the Sponsor 
The Sponsor may discontinue the study at any time for any of the following reasons: 
• Lack of recruitment 
• Deviations from good clinical practice and/or regulations 
• Poor product safety 
• New information that could jeopardise the patient’s safety 
• Stopping of the development … 
15.3.2.2. Early Study Termination Decided by the Competent Authorities 
The Competent Authorities may suspend or prohibit a study if they consider that either the 
conditions of authorisation are not being met or has doubt about the safety or scientific validity of 
the study. 
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15.4. AUDIT 
The Sponsor is responsible for making sure that both its representatives (Study Manager, CRA...) 
and the Investigator fulfil the requirements as specified by the GCP Guideline.  
An audit can be organised internally at Pierre Fabre Médicament and at the investigational site 
where the e-CRFs are matched against source documents. 
All study documentation must be directly accessible to auditors. 
The practical conditions for the audit are discussed between the Investigator and the Clinical 
Quality Assurance Department. 
Oral information about the audit results are given to the Investigator. 
15.5. INSPECTION 
The Health Authorities may inspect any investigation site or the Sponsor in the course of the study 
or after its completion, to verify the conduct of the study and quality of the data. The Investigator 
must provide to the inspectors direct access to study documents. 
15.6. CONFIDENTIALITY 
The present materials (protocol and related documentation, e-CRF, Investigator's Brochure) 
contain confidential information.  
Except if agreed in writing with the Study Manager, the Investigators must hold such information 
confidential, and must not disclose it to others (except where required by Applicable Law). 
15.7. CLINICAL STUDY REPORT 
Data analysis and clinical study report writing are under the Sponsor’s responsibility.  
Upon data analysis completion, a final report including a review of the objectives and methods, a 
presentation and a discussion of the results is drawn up according to ICH Guidelines (Structure 
and Content of Clinical Study Reports, ICH-E3, CPMP/ICH/137/95). 
The report is a clinical and statistical integrated report. It must be signed by the Sponsor's 
representative(s) and the Coordinating Investigator. 
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15.8. STUDY RESULTS COMMUNICATION 
Upon completion of the study, the global results of the Research are communicated to the 
Investigator. According to the Local Regulation, the patient can ask the Investigator for the 
results. 
15.9. STUDY RESULTS PUBLICATION 
The information and data collected during the conduct of this clinical study are considered 
confidential and are used by the Sponsor in connection with the development of the study drug. 
This information may be disclosed if deemed necessary by the Sponsor. 
To allow the use of the information derived from this clinical study and to insure compliance with 
Current Regulations, the Investigator must provide the Sponsor with complete test results and all 
data collected during the study.  
Only the Sponsor may make study information available to physicians and to Regulatory 
Agencies, except as required by Current Regulations. 
All the results of this study including data, reports, discoveries and inventions resulting from the 
study, are the property of the Sponsor. 
In the event the Sponsor chooses to publish study data, the manuscript must be provided to the 
author(s) at least 30 days prior to the expected date of submission to the intended publisher. 
The Investigator(s) can reserve the right to publish or present study data; if so, the manuscript or 
abstract must be provided to the Sponsor for review at least 30 days prior to the expected date of 
submission to the intended publisher or of planned presentation. 
In addition, if necessary, (the) Investigator(s) shall withhold publication for an additional 60 days, 
to allow the filing of a patent application, or to allow the Sponsor to take any measures he deems 
appropriate to establish and preserve his proprietary rights. 
It is agreed that publication of study results by each site shall be made only as part of a 
publication of the study results obtained by all sites performing the protocol, once the study is 
completed and finalised.  
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The authors list is agreed by all Investigators prior to publication. The names of the authors are 
provided according to their participation in the design of the protocol as well as their recruitment 
of eligible and analysable patients. 
 
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16. REFERENCES 
 
[1]. 
F373280 INVESTIGATOR'S BROCHURE, version October 2013 
 
[2]. 
NODARI S., TRIGGIONAI M., CAMPIA U., MANERBA A., MILESI G., CESANA 
M.B., GHEORGHIADE M., DEI CAS L. 
n-3 Polyunsaturated Fatty Acids in the prevention of atrial Fibrillation Recurrences after 
electrical cardioversion. A prospective, Randomised study 
Circulation, 2011; 124:1100-1106 
 
[3]. 
NODARI S., TRIGGIANI M., CAMPIA U., MANERBA A., MILESI G., CESANA 
M B., GHEORGHIADE M., DEI CAS L. 
Effects of n-3 polyunsaturated fatty acids on left ventricular function and functional 
capacity in patients with dilated cardiomyopathy 
J. Am. Coll. Cardiol. 2011;57;870-879 
 
[4]. 
MOERTL D., HAMMER A., STEINER S., HUTULEAC R., VONBANK K., 
BERGER R. 
Dose-dependant effects of omega-3-polyunsaturated fatty acids on systolic left ventricular 
function, endothelial function, and markers of inflammation in chronic heart failure of non 
ischemic origin: A double-blind, placebo-controlled, 3-arm study  
American Heart Journal 2011; 161:915.e1-915.e9 - volume 161, number 5 
 
[5]. 
GISSI-HF INVESTIGATORS 
Effects of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GSSI-
HF Trial): a randomised, double-blind, placebo-controlled trial 
The lancet on line - August 2008 
 
[6]. 
CAMM A.J., KIRCHHOF P., LIP G.Y., SCHOTTEN U., SAVELIEVA I., ERNST 
S., VAN GELDER I.C., AL-ATTAR N., HINDRICKS G., PRENDERGAST B., 
HEIDBUCHEL H., ALFIERI O., ANGELINI A., ATAR D., COLONNA P., DE 
CATERINA R., DE SUTTER J., GOETTE A., GORENEK B., HELDAL M., 
HOHLOSER S.H., KOLH P., LE HEUZEY J.Y., PONIKOWSKI P., RUTTEN F.H. 
Guidelines for the management of atrial fibrillation: the Task Force for the Management of 
Atrial Fibrillation of the European Society of Cardiology (ESC). 
European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery, 
Eur Heart J. 2010 Oct;31(19):2369-429 
 
 
[7]. 
KOWEY PR, REIFFEL JA, ELLENBOGEN KA, NACCARELLI GV, PRATT CM. 
Efficacy and safety of prescription omega-3 fatty acids for the prevention of recurrent 
symptomatic atrial fibrillation: a randomised controlled trial. 
JAMA. 2010;304:2363–2372. 
 
 
 
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[8]. 
BIANCONI L., CALO L., MENNUNI M., SANTINI L., MOROSETTI P., 
AZZOLINI P., BARBATO G., BISCIONE F., ROMANO P., SANTINI M.  
N-3 polyunsaturated fatty acids for the prevention of arrhythmia recurrence after electrical 
cardioversion of chronic persistent atrial fibrillation: a randomised, double-blind, 
multicentre study  
Europace (2011) 13, 174-181 
 
[9]. 
OMACOR® SUMMARY PRODUCT CARACTERISTICS (SPC) dated 17/02/2012 
 
[10]. 
BEPANTHENE ® SUMMARY PRODUCT CARACTERISTICS (SPC) 
 
[11]. 
TOUBOUL P, BRUGADA J, CAPUCCI A, CRIJNS HJ, EDVARDSSON N, 
HOHNLOSER SH.  
Dronedarone for prevention of atrial fibrillation: a dose-ranging study.  
Eur Heart J 2003;24(16):1481-7. 
 
[12]. 
LE HEUZEY JY AND ALL.  
A Short-Term, Randomised, Double-Blind, Parallel-Group Study to Evaluate the Efficacy 
and Safety of Dronedarone versus Amiodarone in Patients with Persistent Atrial 
Fibrillation: The DIONYSOS Study. 
J Cardiovasc Electrophysiol. 
 
[13]. 
METCALF G.R., JAMES J.M., GIBSON A.R., EDWARDS J., STUBBERFIELD J., 
STUKLIS R., YOUNG D.G., ROBERTS-THOMSON K. & CLELAND G.L.M.L. & 
OKEN H. 
Effects of fish-oil supplementation on myocardial fatty acids in humans.  
Am J Clin Nutr (2007); 85 : 1225. 
 
[14]. 
ARTERBURN M.L. & OKEN H. 
Distribution, interconversion and dose response of n-3 fatty acids in humans.  
Am J Clin Nutr (2006);83 : 1469-1473S. 
 
[15]. 
TIELEMAN RG, VAN GELDER IC, CRIJNS HJ, DE KAM PJ, VAN DEN BERG 
MP, HAAKSMA J, VAN DER WOUDE HJ, AND ALLESSIE MA. 
Early recurrences of atrial fibrillation after electrical cardioversion: a result of 
fibrillation-induced electrical remodelling of the atria? 
J. Am. Coll. Cardiol. 1998;31;167-173 
 
[16]. 
SALM P, TAYLOR PJ, KOSTNER K 
Simultaneous quantification of total eicosapentaenoic acid, docosahexaenoic acid and 
arachidonic acid in plasma by high-performance liquid chromatography-tandem mass 
spectrometry.  
Biomed Chromatogr 2011 Jun;25(6):652-9. 
 
[17]. 
LEGRAND P., SCHMITT B., MOUROT J., CATHELINE D., CHESNEAU G., 
MIREAUX M., KERHOAS N., WEILL P. 
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The consumption of food products from linseed-fed animals maintains erythrocyte omega-
3 fatty acids in obese human.  
Lipids, 2010, 45, 11-19. 
 
[18]. 
HARRIS WS, VON SCHACKY C. 
The Omega-3 Index: a new risk factor for death from coronary heart disease? 
 Prev Med. 2004 Jul; 39(1):212-20 
 
[19]. 
ABSTRACT: P5161.  
NODARI S, MANERBA A., MADURERI A., BERLINGHIERI N., PULCINI E., 
FRATTINI S., METRA M, DEI CAS L. 
Effects of Polyunsaturated Fatty Acids n-3 (PUFA n-3) in the prophylaxis of atrial 
fibrillation relapses after external electric cardioversion 
World Congress of Cardiology 2006, 2-6 September, Barcelona – Spain 
[20]. 
KIRCHHOF P., AURICCHIO A., BAX J., CRIJNS H., CAMM J., DIENER HC., 
GOETTE A., HINDRICKS G., HOHNLOSER S., KAPPENBERGER L., KUCK 
KH., LIP HYG., OLSSON B., MEINERTZ T., PRIORI S., RAVENS U., 
STEINBECK G., SVERHAGE E., TIJSSEN J., VINCENT A., BREITHARDT G. 
Outcome parameters from a consensus conference organized by the German Atrial Fibrillation 
Competence NETwork and the European Heart Rhythm Association. 
Europace 2007, 9, 1006-1023 
[21]. 
EUROPEAN MEDICINES AGENCY 
Addendum to the guideline on antiarrhythmics on atrial fibrillation and atrial flutter. 
EMA/CHMA/EWP/213056/2010 
[22]. 
OWEN AJ, PETER-PRZYBOROWSKA BA, HOY AJ, MCLENNAN PL. 
Dietary fish oil dose- and time-response effects on cardiac phospholipid fatty acid composition. 
Lipids. 2004;39:955–961 
[23]. 
ROBERTO M. LANG, MICHELLE BIERIG, RICHARD B. DEVEREUX, FRANK 
A. FLACHSKAMPF*, ELYSE FOSTER, PATRICIA A. PELLIKKA, MICHAEL H. 
PICARD, MARY J. ROMAN, JAMES SEWARD, JACK SHANEWISE, SCOTT 
SOLOMON, KIRK T. SPENCER, MARTIN ST. JOHN SUTTON, WILLIAM 
STEWART. 
 
Recommendations for chamber quantification 
 
Eur J Echocardiography (2006) 7, 79-108 
[24]. 
JOHN J.V. MCMURRAY, STAMATIS ADAMOPOULOS, STEFAN D. ANKER, 
ANGELO 
AURICCHIO, 
MICHAEL 
BÖHM, 
KENNETH 
DICKSTEIN, 
VOLKMAR FALK, GERASIMOS FILIPPATOS, CÂNDIDA FONSECA, MIGUEL 
ANGEL GOMEZ-SANCHEZ, TINY JAARSMA, LARS KØBER, GREGORY Y.H. 
LIP, ALDO PIETRO MAGGIONI, ALEXANDER PARKHOMENKO, BURKERT 
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M. PIESKE, BOGDAN A. POPESCU, PER K. RØNNEVIK, FRANS H. RUTTEN, 
JUERG SCHWITTER, PETAR SEFEROVIC, JANINA STEPINSKA, PEDRO T. 
TRINDADE, ADRIAAN A. VOORS, FAIEZ ZANNAD, ANDREAS ZEIHER 
ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012 
European Heart Journal (2012) 33, 1787–1847 
[25]. 
AGENCE NATIONALE DE SECURITE DU MEDICAMENT ET DES PRODUITS 
DE SANTE (ANSM). 
 
Bon usage des médicaments antivitamine K (AVK) 
 
Actualisation – Juillet 2012 
[26]. 
GILLES PERNOD, ANNE GODIER, CLAIRE GOZALO, BENJAMIN TREMEY, 
PIERRE SIE 
French clinical practice guidelines on the management of patients on vitamin K 
antagonists in at-risk situations (overdose, risk of bleeding, and active bleeding) 
Thrombosis Research 126 (2010) e167–e174 
 
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17. APPENDICES 
 
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17.1. DECLARATION OF HELSINKI 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
ETHICAL PRINCIPLES FOR MEDICAL RESEARCH INVOLVING 
HUMAN SUBJECTS 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 29th WMA 
General Assembly, Tokyo, Japan, October 1975 35th WMA General Assembly, Venice, Italy, October 1983 41st 
WMA General Assembly, Hong Kong, September 1989 48th WMA General Assembly, Somerset West, Republic of 
South Africa, October 1996 52nd WMA General Assembly, Edinburgh, Scotland, October 2000 53th WMA General 
Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 55th WMA General Assembly, Tokyo 
2004 (Note of Clarification on Paragraph 30 added) 59th WMA General Assembly, Seoul, October 2008 
 
A. INTRODUCTION  
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of 
ethical principles for medical research involving human subjects, including research on identifiable 
human material and data. The Declaration is intended to be read as a whole and each of its constituent 
paragraphs should not be applied without consideration of all other relevant paragraphs.  
2. Although the Declaration is addressed primarily to physicians, the WMA encourages other participants 
in medical research involving human subjects to adopt these principles.  
3. It is the duty of the physician to promote and safeguard the health of patients, including those who are 
involved in medical research. The physician's knowledge and conscience are dedicated to the fulfilment 
of this duty.   
4. The Declaration of Geneva of the WMA binds the physician with the words, “The health of my patient 
will be my first consideration,” and the International Code of Medical Ethics declares that, “A physician 
shall act in the patient's best interest when providing medical care.”  
5. Medical progress is based on research that ultimately must include studies involving human subjects. 
Populations that are underrepresented in medical research should be provided appropriate access to 
participation in research.  
6. In medical research involving human subjects, the well-being of the individual research subject must 
take precedence over all other interests.  
7. The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic interventions 
(methods, procedures and treatments). Even the best current interventions must be evaluated continually 
through research for their safety, effectiveness, efficiency, accessibility and quality.  
8. In medical practice and in medical research, most interventions involve risks and burdens.  
9. Medical research is subject to ethical standards that promote respect for all human subjects and protect 
their health and rights. Some research populations are particularly vulnerable and need special 
protection. These include those who cannot give or refuse consent for themselves and those who may be 
vulnerable to coercion or undue influence.  
10. Physicians should consider the ethical, legal and regulatory norms and standards for research involving 
human subjects in their own countries as well as applicable international norms and standards. No 
national or international ethical, legal or regulatory requirement should reduce or eliminate any of the 
protections for research subjects set forth in this Declaration.  
 
B. PRINCIPLES FOR ALL MEDICAL RESEARCH  
11. It is the duty of physicians who participate in medical research to protect the life, health, dignity, 
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integrity, right to self-determination, privacy, and confidentiality of personal information of research 
subjects.  
12. Medical research involving human subjects must conform to generally accepted scientific principles, be 
based on a thorough knowledge of the scientific literature, other relevant sources of information, and 
adequate laboratory and, as appropriate, animal experimentation. The welfare of animals used for 
research must be respected.   
13. Appropriate caution must be exercised in the conduct of medical research that may harm the 
environment.  
14. The design and performance of each research study involving human subjects must be clearly described 
in a research protocol. The protocol should contain a statement of the ethical considerations involved 
and should indicate how the principles in this Declaration have been addressed. The protocol should 
include information regarding funding, sponsors, institutional affiliations, other potential conflicts of 
interest, incentives for subjects and provisions for treating and/or compensating subjects who are 
harmed as a consequence of participation in the research study. The protocol should describe 
arrangements for post-study access by study subjects to interventions identified as beneficial in the 
study or access to other appropriate care or benefits.   
15. The research protocol must be submitted for consideration, comment, guidance and approval to a 
research ethics committee before the study begins. This committee must be independent of the 
researcher, the sponsor and any other undue influence. It must take into consideration the laws and 
regulations of the country or countries in which the research is to be performed as well as applicable 
international norms and standards but these must not be allowed to reduce or eliminate any of the 
protections for research subjects set forth in this Declaration. The committee must have the right to 
monitor ongoing studies. The researcher must provide monitoring information to the committee, 
especially information about any serious adverse events. No change to the protocol may be made 
without consideration and approval by the committee.  
16. Medical research involving human subjects must be conducted only by individuals with the appropriate 
scientific training and qualifications. Research on patients or healthy volunteers requires the 
supervision of a competent and appropriately qualified physician or other health care professional. The 
responsibility for the protection of research subjects must always rest with the physician or other health 
care professional and never the research subjects, even though they have given consent.  
17. Medical research involving a disadvantaged or vulnerable population or community is only justified if 
the research is responsive to the health needs and priorities of this population or community and if 
there is a reasonable likelihood that this population or community stands to benefit from the results of 
the research.   
18. Every medical research study involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and communities involved in the research in 
comparison with foreseeable benefits to them and to other individuals or communities affected by the 
condition under investigation.  
19. Every clinical trial must be registered in a publicly accessible database before recruitment of the first 
subject.  
20. Physicians may not participate in a research study involving human subjects unless they are confident 
that the risks involved have been adequately assessed and can be satisfactorily managed. Physicians 
must immediately stop a study when the risks are found to outweigh the potential benefits or when 
there is conclusive proof of positive and beneficial results.  
21. Medical research involving human subjects may only be conducted if the importance of the objective 
outweighs the inherent risks and burdens to the research subjects.  
22. Participation by competent individuals as subjects in medical research must be voluntary. Although it 
may be appropriate to consult family members or community leaders, no competent individual may be 
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enrolled in a research study unless he or she freely agrees.  
23. Every precaution must be taken to protect the privacy of research subjects and the confidentiality of 
their personal information and to minimize the impact of the study on their physical, mental and social 
integrity.   
24. In medical research involving competent human subjects, each potential subject must be adequately 
informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional 
affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort 
it may entail, and any other relevant aspects of the study. The potential subject must be informed of the 
right to refuse to participate in the study or to withdraw consent to participate at any time without 
reprisal. Special attention should be given to the specific information needs of individual potential 
subjects as well as to the methods used to deliver the information. After ensuring that the potential 
subject has understood the information, the physician or another appropriately qualified individual 
must then seek the potential subject’s freely-given informed consent, preferably in writing. If the 
consent cannot be expressed in writing, the non-written consent must be formally documented and 
witnessed.  
25. For medical research using identifiable human material or data, physicians must normally seek consent 
for the collection, analysis, storage and/or reuse. There may be situations where consent would be 
impossible or impractical to obtain for such research or would pose a threat to the validity of the 
research. In such situations the research may be done only after consideration and approval of a 
research ethics committee.   
26. When seeking informed consent for participation in a research study the physician should be 
particularly cautious if the potential subject is in a dependent relationship with the physician or may 
consent under duress. In such situations the informed consent should be sought by an appropriately 
qualified individual who is completely independent of this relationship.  
27. For a potential research subject who is incompetent, the physician must seek informed consent from the 
legally authorized representative. These individuals must not be included in a research study that has 
no likelihood of benefit for them unless it is intended to promote the health of the population 
represented by the potential subject, the research cannot instead be performed with competent persons, 
and the research entails only minimal risk and minimal burden.   
28. When a potential research subject who is deemed incompetent is able to give assent to decisions about 
participation in research, the physician must seek that assent in addition to the consent of the legally 
authorized representative. The potential subject’s dissent should be respected.  
29. Research involving subjects who are physically or mentally incapable of giving consent, for example, 
unconscious patients, may be done only if the physical or mental condition that prevents giving 
informed consent is a necessary characteristic of the research population. In such circumstances the 
physician should seek informed consent from the legally authorized representative. If no such 
representative is available and if the research cannot be delayed, the study may proceed without 
informed consent provided that the specific reasons for involving subjects with a condition that renders 
them unable to give informed consent have been stated in the research protocol and the study has been 
approved by a research ethics committee. Consent to remain in the research should be obtained as soon 
as possible from the subject or a legally authorized representative.  
30. Authors, editors and publishers all have ethical obligations with regard to the publication of the results 
of research. Authors have a duty to make publicly available the results of their research on human 
subjects and are accountable for the completeness and accuracy of their reports. They should adhere to 
accepted guidelines for ethical reporting. Negative and inconclusive as well as positive results should 
be published or otherwise made publicly available. Sources of funding, institutional affiliations and 
conflicts of interest should be declared in the publication. Reports of research not in accordance with 
the principles of this Declaration should not be accepted for publication.  
 
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C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE  
31. The physician may combine medical research with medical care only to the extent that the research is 
justified by its potential preventive, diagnostic or therapeutic value and if the physician has good 
reason to believe that participation in the research study will not adversely affect the health of the 
patients who serve as research subjects.   
32. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the 
best current proven intervention, except in the following circumstances:  
• 
The use of placebo, or no treatment, is acceptable in studies where no current proven intervention 
exists; or  
• 
Where for compelling and scientifically sound methodological reasons the use of placebo is 
necessary to determine the efficacy or safety of an intervention and the patients who receive 
placebo or no treatment will not be subject to any risk of serious or irreversible harm.  Extreme 
care must be taken to avoid abuse of this option.  
33. At the conclusion of the study, patients entered into the study are entitled to be informed about the 
outcome of the study and to share any benefits that result from it, for example, access to interventions 
identified as beneficial in the study or to other appropriate care or benefits.  
34. The physician must fully inform the patient which aspects of the care are related to the research. The 
refusal of a patient to participate in a study or the patient’s decision to withdraw from the study must 
never interfere with the patient-physician relationship.  
35. In the treatment of a patient, where proven interventions do not exist or have been ineffective, the 
physician, after seeking expert advice, with informed consent from the patient or a legally authorized 
representative, may use an unproven intervention if in the physician's judgement it offers hope of 
saving life, re-establishing health or alleviating suffering. Where possible, this intervention should be 
made the object of research, designed to evaluate its safety and efficacy. In all cases, new information 
should be recorded and, where appropriate, made publicly available.  
 
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17.2. SAE REPORT FORM 
 
 
 
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N O T I F I C A T I O N  O F  S E R I O U S  A D V E R S E  E V E N T  ( S A E )  O R  P R E G N A N C Y   
T O  P I E R R E  F A B R E  C O R P O R A T E  V I G I L A N C E S  D I V I S I O N   
 
TO 
BE 
TRANSMITTED 
TO 
THE 
CORPORATE 
VIGILANCES 
DIVISION 
BY 
E-MAIL 
WITHIN 
24H 
TO 
HQ.pharmacovigilance@pierre-fabre.com OR BY FAX WITHIN 24H – Fax N°: 33 (0) 1.49.10.80.90 
Transmission date  
 
 
  
 
  
 
 
 
(ddmmyyyy) 
Country :  
........................................
 
 
 
   SAE N° 
 
 
 
                      FIRST NOTIFICATION           FOLLOW-UP   N° 
 
 SUBJECT CHARACTERISTICS  
 
 
 
 
 
 
 
 
Birth date  
 
 
 
 
 
 
 
 
  
 
 
Gender 
 
1=M,    2=F 
   Height 
 
 
 
cm 
 Weight 
 
 
 
 
 
kg 
 
 
 DESCRIPTION OF THE EVENT 
The serious adverse event resulted in : 
 Death (whatever may be the cause) 
 Hospitalisation (*) or extension thereof 
 Life threatening 
 Invalidity or disability 
 
 Congenital abnormality or abnormal pregnancy outcome 
 Cancer 
 Other  (any other serious clinical or laboratory event 
     according to the investigator or the protocol, overdosage 
      meeting seriousness criteria, suicide attempts) 
Other fact to be notified : 
 Pregnancy exposure 
Nature of the event (if clinical nature, indicate the diagnosis or the major symptom) : 
........................................................................................................................................................................................................... 
........................................................................................................................................................................................................... 
........................................................................................................................................................................................................... 
AE onset date  |__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
 
Seriousness onset date  |__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
 
Summary description (if clinical cause, significant history, progression of event, available laboratory results, etc...) : 
 
 
 
 
 
 
(*) Except hospitalisations with durations and goals planned in the protocol 
 
 THE SAE IN RELATION TO THE TRIAL 
                                                      TREATMENT NUMBER         |___|___|___|___|___|___| 
• Time of occurrence of SAE 
 
 During the selection or run-in period 
 
 During the administration phase of the study treatment 
 
 After the administration phase of the study treatment 
• Date of first study treatment administration 
• Date of last study treatment administration 
   before the occurence of SAE 
|__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
 
|__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
• Was the blind broken ?       Yes         No          Not applicable 
   If yes, or if this is an open study, drug(s) administered : 
 
 
 
 
 
  Conditions of administration (cycles(s), daily dose(s), route(s) of administration, etc..) :  
 
 
 
 
 
 
 
 
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Transmission date 
 
 
 
 
 
 
 
 
 
 
  (ddmmyyyy) 
Country : ............................................ 
 
 
 
  SAE N° 
 
 
 
                     FIRST NOTIFICATION           FOLLOW-UP   N° 
 
 CONCOMITANT MEDICATION SINCE TRIAL INITIATION and UP UNTIL THE OCCURRENCE OF THE SAE 
     (EXCEPT THE TREATMENTS GIVEN FOR THE SAE)  
 
Trade name  
(or INN) 
 
Daily dose 
 
Start date 
(dd/mm/yy) 
Ongoing at 
occurence of the 
event 
 
Stop date 
(dd/mm/yy) 
Route of 
admin. 
 
Indication 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 MEASURES TAKEN FOLLOWING THE SAE 
• Study treatment 
 
 No change 
 
 Dosage modification, specify :……………………………..….      Modification Date : 
 
 Temporarily discontinued                                                       Readministration date : 
 
 Withdrawn                                                                                                  End date : 
 
 Not applicable 
 
____/____/_____ 
 ____/____/_____ 
 ____/____/_____ 
• The event led to : 
 
 Prescription of corrective or symptomatic treatments: 
 
 
Trade name  
(or INN) 
 
Daily dose 
 
Start date 
(dd/mm/yy) 
Ongoing at 
occurence of the 
event 
 
Stop date 
(dd/mm/yy) 
Route of 
admin. 
 
Indication 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 Discontinuation of concomitant treatments: 
 
 
Trade name  
(or INN) 
 
Daily dose 
 
Start date 
(dd/mm/yy) 
Ongoing at 
occurence of the 
event 
 
Stop date 
(dd/mm/yy) 
Route of 
admin. 
 
Indication 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
 Others, specify : 
 
 
 OUTCOME 
         Not recovered/Not resolved                  Recovering/Resolving               Recovered/Resolved 
         Recovered/Resolved with sequelae     Fatal                                          Unknown 
 
                In case of death, has an autopsy been conducted ?       Yes         No 
 
 INVESTIGATOR CAUSALITY ASSESSMENT (investigator’s assessment to be done as soon as possible) 
Study drug:                                                                         Related to study protocol: 
 Not Suspected                 Suspected                             Not Suspected                          Suspected                   
Comments: ............................................................................................................................................................. 
 
Enclose in the notification the results of carried out examinations, reports of hospitalisation, etc... 
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17.3. PREDEFINED LIMITS OF LABORATORY AND VITAL SIGN 
POTENTIALLY CLINICALLY SIGNIFICANT CHANGES AND VALUES  
List of Predefined Potentially Clinically Significant Change For Laboratory Values(¤) 
 
 
PARAMETERS 
UNIT 
PSC 
 
 
 
Decrease 
Increase 
MUSCLE 
Creatine  Phosphokinase 
U / l 
- 
236 
KIDNEY 
Creatinine 
Urea 
Uric acid 
Phosphate 
Calcium 
µmol/l 
mmol/l 
µmol/l 
mmol/l 
mmol/l 
- 
- 
- 
0.39 
0.30 
35 
3.2 
119 
0.39 
0.30 
ELECTROLYTES 
Sodium 
Potassium 
Chloride 
Bicarbonate 
mmol/l 
mmol/l 
mmol/l 
mmol/l 
8 
1.1 
8 
7 
8 
1.1 
7 
8 
METABOLISM/ 
NUTRITIONAL 
Glucose (random) 
Albumin 
Protein 
Cholesterol 
HDL cholesterol 
LDL cholesterol 
Triglycerides 
mmol/l 
g/l 
g/l 
mmol/l 
mmol/l 
mmol/l 
mmol/l 
3 
6 
11 
- 
0.91 
2.17 
- 
3.7 
6 
10 
1.97 
0.85 
2.04 
2.91 
ERYTHROCYTES 
Erythrocyte count 
Haemoglobin 
Haematocrit 
MCV  
MCH (Fe) 
MCHC (Fe) 
T/l 
g/l 
1 
fl 
fmol 
mmol/l 
0.7 
20 
0.06 
7 
0.19 
2 
0.7 
- 
0.06 
7 
0.19 
2 
LEUKOCYTES 
Leukocyte count 
G/l 
4.2 
3.8 
DIFFERENTIAL 
COUNT 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
G/l 
G/l 
G/l 
G/l 
G/l 
3.47 
1.76 
- 
- 
- 
3.19 
1.63 
0.49 
0.41 
0.14 
URINE 
Specific gravity 
pH 
- 
- 
0.017 
2 
0.015 
2 
LIVER 
Total bilirubin 
ASAT (SGOT) 
ALAT (SGPT) 
Gamma GT 
Alkaline phosphatase 
µmol/l 
U/l 
U/l 
U/l 
U/l 
- 
- 
- 
- 
-- 
10 
N x (23/36) 
N x (28/45) 
N x (25/38) 
N x (30/95) 
 
N = upper limit of normal range 
 
(¤) Delta-limits from « Routine Laboratory Tests in Clinical Trials » W. Leigh Thompson, Rocco 
L. Brunelle, Gregory G. Enas, Patrick J. Simpson and Randy L. Walker Lilly Research 
Laboratories, Lilly Corporate Centre, Indianapolis, Indiana in « Clinical Trials and Tribulations » 
1988. 
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Definition of Clinically Noteworthy Abnormal Laboratory Values (CNALV) 
 
 
PARAMETERS 
CNALV 
HAEMOGLOBIN 
 
• Decrease of at least 2g/dl and value < 10 g/dl whatever the baseline 
value 
• If missing baseline : value <10g/dl 
NEUTROPHILS 
• < 1 500/mm3 whatever the baseline value 
WBC 
(if missing value for neutrophils) 
• < 3 000/mm3 whatever the baseline value 
PLATELETS 
• < 100 000/mm3 whatever the baseline value 
SERUM CREATININE 
• Increase of at least 30 % as compared to baseline value and 
value > 150 µmol/l whatever the baseline value 
• If missing baseline : value > 150 µmol/l 
LIVER FUNCTION TESTS 
 
 
ALAT 
 
 If normal baseline :  
 
 
•ALAT > 2 N 
 If abnormal baseline : 
→if baseline value ≤ 2.5 N : 
  
• increase of at least 100 % as compared to baseline value 
→ if baseline value > 2.5 N :  
 
 
• value > 5 N 
and/or 
ASAT 
 
  If normal baseline :  
 
 
• ASAT > 2 N 
  If abnormal baseline : 
→ if baseline value ≤ 2.5 N : 
  
• increase of at least 100 % as compared to baseline value 
→ if baseline value > 2.5 N :  
 
 
• value > 5 N 
and/or 
Alkaline phosphatase (AP) 
 
  If normal baseline :  
 
 
• AP > 1.25 N 
  If abnormal baseline :  
 
 
• AP > 2 N 
and/or 
Total bilirubin (TB) 
  If normal baseline :  
 
 
• TB > 1.5 N 
  If abnormal baseline :  
 
 
• TB > 2 N 
N=upper limit of normal range 
International consensus Meeting. International Journal of Clinical Pharmacology, Therapy and Toxicology, 1990;28:317-322 
Standardisation of definitions and criteria of causality assessment of adverse drug reactions: drugs-induced liver disorders: report 
of an Standardisation of definitions and criteria of causality assessment of adverse drug reactions: drugs-induced cytopenia. 
International Journal of Clinical Pharmacology, Therapy and Toxicology, 1991;29:75-81 
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Cardiovascular Safety 
 
Table 1: Predefined Limits for Potentially Clinically Significant Changes (PSC) and PSC 
Leading to Clinically Significant Values (PSCV) 
 
Parameter 
PSC 
PSCV 
SBP 
Increase ≥ 20 mmHg 
Decrease ≥ 20 mmHg 
SBP ≥ 160 mmHg and increase ≥ 20 mmHg 
SBP ≤ 90 mmHg and decrease ≥ 20 mmHg 
DBP 
Increase ≥ 10 mmHg 
Decrease ≥ 10 mmHg 
DBP ≥ 100 mmHg and increase ≥ 10 mmHg 
DBP ≤ 50 mmHg and decrease ≥ 10 mmHg 
HR 
Increase ≥ 10 bpm 
Decrease ≥ 10 bpm 
HR ≥ 110 bpm and increase ≥ 10 bpm 
HR ≤ 50 bpm and decrease ≥ 10 bpm 
 
Table 2: Predefined Classes for changes from Baseline to the Maximum (and/ or Minimum) 
Post-baseline Value 
Classes of Change from Baseline to the Maximum 
Post-baseline Value 
Classes of Change from Baseline to the 
Minimum Post-baseline Value 
SBP  mmHg 
DBP  mmHg 
HR bpm 
SBP  mmHg 
DBP  mmHg 
HR bpm 
All 
All 
All 
All 
All 
All 
≥  0 
≥  0 
≥  0 
≤  0 
≤  0 
≤  0 
>  0 
>  0 
>  0 
<  0 
<  0 
<  0 
≥ 10 
≥  5 
≥ 10 
≤ -10 
≤ - 5 
≤ -10 
≥ 20 
≥ 10 
≥ 20 
≤ -20 
≤ -10 
≤ -20 
≥ 30 
≥ 15 
≥ 30 
≤ -30 
≤ -15 
≤ -30 
≥ 40 
≥ 20 
 
≤ -40 
≤ -20 
 
 
≥ 25 
 
 
≤ -25 
 
 
≥ 30 
 
 
≤ -30 
 
 
Table 3: Classes for Vital Signs Maximum or Minimum Values 
Classes  for  the Maximum Post-baseline Value 
for each parameter 
Classes  for  the Minimum Post-baseline Value 
for each parameter 
SBP  mmHg 
DBP  mmHg 
HR bpm 
SBP  mmHg 
DBP  mmHg 
HR bpm 
< 120 
< 80 
≤ 50 
≤ 90 
≤ 50 
≤ 50 
[120 ;140[ 
[80;90[ 
]50 ;75[ 
[90 ;120[ 
[50;80[ 
]50 ;75[ 
[140;160[ 
 [90;100[ 
[75;100[ 
[120;140[ 
 [80;90[ 
[75;100[ 
≥ 160 
≥ 100 
≥ 100 
≥ 140 
≥ 90 
≥ 100 
 
Table 4: Classes for Maximum or Minimum of BP in its entirety 
Classification of Maximum Values for Blood 
Pressure (mmHg) 
Classification of Minimum Values Blood 
Pressure (mmHg) 
SBP < 140 and DBP < 90 
SBP > 90 and DBP > 50 
SBP [140;160[ and DBP < 100 
or DBP [90;100[ and SBP < 160 
SBP ≤  90 or DBP ≤  50 
SBP ≥ 160 or DBP ≥ 100 
 
 
Table 5: Definition of orthostatic hypotension 
Orthostatic Hypotension * 
SBP Decrease ≥ 20 mmHg or DBP Decrease ≥ 10 mmHg between supine and standing positions 
* Consensus Committee of the American Autonomic Society and the American Academy of Neurolog :Consensus statement on the definition of 
orthostatic hypotension, pure autonomic failure and multiple system atrophy. Neurology 1996;46:1470-3. 
 
 
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16.1.1.9. 
Protocol amendment n° PA06  
General and non-substantial dated on 06 June 2016) 
 
 
 
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CLINICAL STUDY PROTOCOL AMENDMENT n° PA06 
(GENERAL – Non Substantial) 
 
 
 
 
 
 
 
 
 
 
 
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Pierre Fabre Médicament 
Represented by: Institut de Recherche Pierre Fabre 
45, Place Abel Gance 
F-92100 Boulogne, France 
 
 
CLINICAL STUDY PROTOCOL AMENDMENT n° PA06  
 
(GENERAL – Non-Substantial) 
 
 
Efficacy and safety study of F373280 for maintenance of sinus rhythm after electrical 
cardioversion in patients with persistent Atrial Fibrillation and Chronic Heart Failure. 
 
International, multicentric, randomised, double-blind, placebo controlled study 
 
Pierre Fabre Study Code: 
F373280 CA 2 01  
EudraCT Number or equivalent: 2012-003487-48 
Sponsor’s Representative: 
 
Karim KEDDAD 
INSTITUT DE RECHERCHE PIERRE FABRE   
Centre de R&D Pierre Fabre - BP 13562  
3 avenue Hubert Curien  
31035 TOULOUSE Cedex 1, FRANCE 
 
Study Coordinating Investigator: 
Pr Savina NODARI 
Department of Clinical and Surgical Specialities, Radiological Science 
and Public Health 
Section of Cardiovascular Diseases 
University Medical School and Spedali Civili Hospital of Brescia 
c/o Spedali Civili di Brescia 
Piazzale Spedali Civili, 1 
25123 - BRESCIA, ITALY 
 
Date of amendment PA06: 
06JUN2016 
 
 
 
 
 
 
 
The information contained in this document is confidential and is the property of the sponsor Pierre Fabre Médicament. This 
information is given for the needs of the trial and must not be disclosed without prior written consent of the sponsor Pierre 
Fabre Médicament. Persons to whom this information is given for the needs of the trial must be informed that it is 
confidential and must be disclosed. 
 
Final version
952/1185


Final version
953/1185


Final version
954/1185


 
INVESTIGATOR SIGNATURE FORM  
STUDY: Efficacy and safety study of F373280 for maintenance of sinus rhythm after 
electrical cardioversion in patients with persistent Atrial Fibrillation and Chronic Heart 
Failure. 
 
International, multicentric, randomised, double-blind, placebo controlled study 
 
Clinical Study Protocol Amendment n° PA06  
(GENERAL – Non-Substantial) 
Dated:  06JUN2016 
 
 
By my signature below, I, Dr _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _, hereby confirm that I have read, 
taken note of (and will apply) the modifications brought by the protocol amendment n° PA06 and I 
will conduct the trial according to these new modalities. 
 
 
Date: 
Signature: 
 
 
 
Final version
955/1185


HISTORY OF AMENDMENTS  
N° 
TYPE 
APPLICATION 
AREA 
DATE 
MODIFICATIONS 
NA 
NA 
General 
NA 
Corresponding to Protocol Version 2:  
Following French CA request (ANSM) and leading 
to protocol version 2: 
- Add of a non inclusion criteria: “Breast-feeding 
female patient” 
- Add of haematology examination at visit 3 and 6 
 
PA01 
Substantial 
Local (Italy) 
01MAR2013 
Corresponding to Protocol Version 3: 
- Integration of the modification included in the 
protocol version 2 
- Harmonisation of the protocol and the Informed 
Consent Form: 
• 
adjustment of the selection criteria n°10 
related to the contraception method  
• 
addition of a letter that is given by the 
patient to his/her GENERAL practitioner 
(GP) 
• 
precision that the sponsor can not collect a 
copy of the Informed Consent Form  
• 
precision that the patient card is in Italian 
language only (without any English 
mention)   
PA02 
Non 
Substantial 
General 
28MAR2013 
Corresponding to Protocol Version 4 : 
- change of Sponsor’s Representative (Clinical 
Study Manager),  
- modification of the technical handling of the blood 
samples for determination of red blood cells 
concentration of DHA: the centrifugation is no more 
needed, 
- precision on the function and address of the 
International Study Coordinator Pr Nodari,  
- add of address and contacts details of two CRO 
newly involved in the study: Theradis (in charge of 
transportation of blood samples to the Analytical 
centre and material supply) and “Clinact” (in charge 
of refund of patients expenses linked to the study), 
 - adjustment of the wording, in agreement with the 
commitment to the French Ethics Committee. In the 
paragraphe 8.3.2.1, the wording "hematology 
examination” is replaced by "standard hematologic 
dosage", 
  - precision of the full title in the study synopsis (in 
agreement with the commitment to the Spanish 
Ethics Committee),  
- correction of a mistake in section 8.1.1.3 (related 
to TTEM transmission) and sections 3, 9 and study 
synopsis (related to the definition of INR not 
stabilized). 
- addition of the changes included in the local italian 
Final version
956/1185


N° 
TYPE 
APPLICATION 
AREA 
DATE 
MODIFICATIONS 
substantial protocol amendment (i.e: contraception 
method, letter to GENERAL Practionner, patient 
card in Italian and no collection of the consent form 
by the sponsor in Italy). 
 
PA03 
Substantial 
General 
23OCT2013 
Corresponding to Protocol Version 5:  
- Fax modification of the sponsor’s representatives 
- Planned end of study postponed to January 2015. 
- The authorized history of the first documented 
persistent atrial fibrillation is less than 3 years. 
- At selection a hyperkalemia or a hypokalemia is 
better defined by the standards of the local 
laboratories.  
- Regarding previous treatments by amiodarone the 
non inclusion criteria of the protocol are adapted as 
follow: 
• 
Previous treatment with oral amiodarone 
within 4 months prior to inclusion 
• 
Intake of oral amiodarone for more than 1 
month within 4 to 12 months before 
inclusion 
• 
Previous 
treatment 
with 
intravenous 
amiodarone within 4 weeks prior to 
inclusion. 
- For male with a child-bearing potential partner (in 
Italy only): taking into account the duration of 
spermatogenesis the absolute abstention from 
sexual intercourse or the use of double barrier 
contraception method are extended to 3 months 
after the end of the study. 
- Ranolazine is an antiarrhythmic treatment added 
to the prohibited treatments. 
- Update of Serious Adverse Events (SAEs) form: 
Main change is the SAE sending: SAEs have to be 
reported to the Corporate Vigilance Department, 
and not anymore to the clinical study manager. Also 
SAEs can be sent by e-mail and by fax. 
- Addition of Alpha Bioresearch as CRO involved 
for Feasibility, Monitoring and Regulatory issues in 
Spain. 
- Correction of some minor typographic errors  
 
PA04 
Non 
Substantial 
General 
03JUN2014 
Corresponding to protocol V7: 
- Precision on the temperature storage of DHA 
samples 
- Precision on the BSA formula 
- Addition of QTcB and QTcF 
- Precision on TTEM recording timelines 
- Clarification of the section Interim analysis 
and data monitoring (13.11) 
- Clarifications and specifications on some 
Final version
957/1185


N° 
TYPE 
APPLICATION 
AREA 
DATE 
MODIFICATIONS 
minor points 
PA05 
Substantial 
General 
22OCT2014 
Corresponding to protocol V8: 
 
- Planned end of study postponed to April 2016 
- Clarifications regarding the management of VKA 
treatment 
- Precision regarding the primary efficacy criterion 
(the time to the first Atrial Fibrillation recurrence or 
Atrial Flutter emergence) 
- Deletion of Visit 5 and Visit 8 
- Previous history of a first documented persistent 
Atrial Fibrillation without limitation in time instead of 
no longer than 3 years 
- Patients must have a systolic heart failure defined 
by a reduced ventricular ejection fraction and or 
defined also through other echocardiographic 
parameters mentioned in the ESC guidelines for the 
diagnosis and treatment of acute and chronic heart 
failure (2012) 
- Regarding previous prohibited treatments by 
amiodarone or droderanone, the non inclusion 
criteria of the protocol are adapted as follow: 
• 
Concomitant 
treatment 
with 
oral 
amiodarone or dronedarone from selection 
• 
Concomitant treatment with intravenous 
amiodarone from selection 
 
 
Final version
958/1185


 
1. AMENDMENT RATIONALE 
 
This amendment is written to update the Sponsor Personnel list following changes in the Clinical team 
and to extend the planned end date of the study: 
 
- 
The previous Clinical Study Manager left the team: Gaëlle Alcaraz, and one new Clinical 
Study Manager has joined the team: Marine Fagard 
- 
Dr Richard Roche (Medical Director) is replaced by Dr Karim Keddad (Head of medical Unit) 
- 
Due to a recruitment rate lower than expected the planned end of study is postponed to 
September 2017. 
 
 
2. CHANGES DESCRIPTION 
 
 
PREVIOUS VERSION 
MODIFIED VERSION 
Sponsor Personnel, page 2 & page 3 
 
Clinical Study Manager (Monitor) 
Gaëlle ALCARAZ 
 
Institut de Recherche Pierre Fabre 
Centre de R&D Pierre Fabre 
BP 13 562 
3, Avenue Hubert Curien 
31035 TOULOUSE Cedex 1, France 
Phone: +33 5 34 50 62 16  
Fax: + 33 5 34 50 69 69 
E-mail: gaelle.alcaraz@pierre-fabre.com 
Sponsor Personnel, page 2, page 3 & page 5 
Medical Director 
Richard ROCHE, MD 
 
Institut de Recherche Pierre Fabre 
Centre de R&D Pierre Fabre 
BP 13 562 
3, Avenue Hubert Curien 
31035 TOULOUSE Cedex 1, France 
Phone: +33 5 34 50 61 94 
Fax: +33 5 34 50 69 69 
 
 
 
Clinical Study Manager (Monitor) 
Marine FAGARD 
Institut de Recherche Pierre Fabre 
Centre de R&D Pierre Fabre 
BP 13 562 
3, Avenue Hubert Curien 
31035 TOULOUSE Cedex 1, France  
Phone: +33 (0)5 34 50 63 54 
Fax: +33 (0)5 34 50 65 92 
E-mail: marine.fagard@pierre-fabre.com 
 
 
 
Head of Medical Unit 
 
Karim KEDDAD, MD, PhD 
Institut de Recherche Pierre Fabre 
Centre de R&D Pierre Fabre 
BP 13 562 
3, Avenue Hubert Curien 
31035 TOULOUSE Cedex 1, France 
Phone: +33 5 34 50 61 69 
Fax: +33 (0)5 34 50 65 92 
Final version
959/1185


PREVIOUS VERSION 
MODIFIED VERSION 
E-mail: richard.roche@pierre-fabre.com 
 
SYNOPSIS, page 13 
Planned Study Period: January 2013 –  April 2016 
 
 
E-mail: karim.keddad@pierre-fabre.com 
 
 
Planned Study Period: January 2013 –  September 
2017 
 
Final version
960/1185


 
 
 
 
 
 
 
 
16.1.1.10. Protocol amendment n° PA07  
General and substantial dated on 28 September 2016 
linked to Protocol and appendices  
(version 9: 28 September 2016) 
 
 
Final version
961/1185


 
CLINICAL STUDY PROTOCOL AMENDMENT n° PA07 
(GENERAL –SUBSTANTIAL) 
 
 
 
 
 
 
 
 
 
 
 
Final version
962/1185


Pierre Fabre Médicament 
Represented by: Institut de Recherche Pierre Fabre 
45, Place Abel Gance 
F-92100 Boulogne, France 
 
 
CLINICAL STUDY PROTOCOL AMENDMENT n° PA07  
 
(GENERAL – SUBSTANTIAL) 
 
 
Efficacy and safety study of F373280 for maintenance of sinus rhythm after electrical 
cardioversion in patients with persistent Atrial Fibrillation and Chronic Heart Failure. 
 
International, multicentric, randomised, double-blind, placebo controlled study 
 
Pierre Fabre Study Code: 
F373280 CA 2 01  
EudraCT Number or equivalent: 2012-003487-48 
Sponsor’s Representative: 
 
Karim KEDDAD 
INSTITUT DE RECHERCHE PIERRE FABRE   
Centre de R&D Pierre Fabre - BP 13562  
3 avenue Hubert Curien  
31035 TOULOUSE Cedex 1, FRANCE 
 
 
 
Study Coordinating Investigator: 
Pr Savina NODARI 
Department of Clinical and Surgical Specialities, Radiological Science 
and Public Health 
Section of Cardiovascular Diseases 
University Medical School and Spedali Civili Hospital of Brescia 
c/o Spedali Civili di Brescia 
Piazzale Spedali Civili, 1 
25123 - BRESCIA, ITALY 
 
Date of amendment PA07: 
28SEP16 
 
 
 
 
 
The information contained in this document is confidential and is the property of the sponsor Pierre Fabre Médicament. This 
information is given for the needs of the trial and must not be disclosed without prior written consent of the sponsor Pierre 
Fabre Médicament. Persons to whom this information is given for the needs of the trial must be informed that it is 
confidential and must be disclosed. 
 
Final version
963/1185


Final version
964/1185


Final version
965/1185


 
INVESTIGATOR SIGNATURE FORM  
STUDY: Efficacy and safety study of F373280 for maintenance of sinus rhythm after 
electrical cardioversion in patients with persistent Atrial Fibrillation and Chronic Heart 
Failure. 
 
International, multicentric, randomised, double-blind, placebo controlled study 
 
Clinical Study Protocol Amendment n° PA07  
(GENERAL –SUBSTANTIAL) 
Dated:  28SEP16 
 
 
By my signature below, I, Dr _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _, hereby confirm that I have read, 
taken note of (and will apply) the modifications brought by the protocol amendment n° PA07 and I 
will conduct the trial according to these new modalities. 
 
 
Date: 
Signature: 
 
 
 
Final version
966/1185


HISTORY OF AMENDMENTS  
N° 
TYPE 
APPLICATION 
AREA 
DATE 
MODIFICATIONS 
NA 
NA 
General 
NA 
Corresponding to Protocol Version 2:  
Following French CA request (ANSM) and leading 
to protocol version 2: 
- Add of a non inclusion criteria: “Breast-feeding 
female patient” 
- Add of haematology examination at visit 3 and 6 
 
PA01 
Substantial 
Local (Italy) 
01MAR2013 
Corresponding to Protocol Version 3: 
- Integration of the modification included in the 
protocol version 2 
- Harmonisation of the protocol and the Informed 
Consent Form: 
• 
adjustment of the selection criteria n°10 
related to the contraception method  
• 
addition of a letter that is given by the 
patient to his/her GENERAL practitioner 
(GP) 
• 
precision that the sponsor can not collect a 
copy of the Informed Consent Form  
• 
precision that the patient card is in Italian 
language only (without any English 
mention)   
PA02 
Non 
Substantial 
General 
28MAR2013 
Corresponding to Protocol Version 4 : 
- change of Sponsor’s Representative (Clinical 
Study Manager),  
- modification of the technical handling of the blood 
samples for determination of red blood cells 
concentration of DHA: the centrifugation is no more 
needed, 
- precision on the function and address of the 
International Study Coordinator Pr Nodari,  
- add of address and contacts details of two CRO 
newly involved in the study: Theradis (in charge of 
transportation of blood samples to the Analytical 
centre and material supply) and “Clinact” (in charge 
of refund of patients expenses linked to the study), 
 - adjustment of the wording, in agreement with the 
commitment to the French Ethics Committee. In the 
paragraphe 8.3.2.1, the wording "hematology 
examination” is replaced by "standard hematologic 
dosage", 
  - precision of the full title in the study synopsis (in 
agreement with the commitment to the Spanish 
Ethics Committee),  
- correction of a mistake in section 8.1.1.3 (related 
to TTEM transmission) and sections 3, 9 and study 
synopsis (related to the definition of INR not 
stabilized). 
- addition of the changes included in the local italian 
Final version
967/1185


N° 
TYPE 
APPLICATION 
AREA 
DATE 
MODIFICATIONS 
substantial protocol amendment (i.e: contraception 
method, letter to GENERAL Practionner, patient 
card in Italian and no collection of the consent form 
by the sponsor in Italy). 
 
PA03 
Substantial 
General 
23OCT2013 
Corresponding to Protocol Version 5:  
- Fax modification of the sponsor’s representatives 
- Planned end of study postponed to January 2015. 
- The authorized history of the first documented 
persistent atrial fibrillation is less than 3 years. 
- At selection a hyperkalemia or a hypokalemia is 
better defined by the standards of the local 
laboratories.  
- Regarding previous treatments by amiodarone the 
non inclusion criteria of the protocol are adapted as 
follow: 
• 
Previous treatment with oral amiodarone 
within 4 months prior to inclusion 
• 
Intake of oral amiodarone for more than 1 
month within 4 to 12 months before 
inclusion 
• 
Previous 
treatment 
with 
intravenous 
amiodarone within 4 weeks prior to 
inclusion. 
- For male with a child-bearing potential partner (in 
Italy only): taking into account the duration of 
spermatogenesis the absolute abstention from 
sexual intercourse or the use of double barrier 
contraception method are extended to 3 months 
after the end of the study. 
- Ranolazine is an antiarrhythmic treatment added 
to the prohibited treatments. 
- Update of Serious Adverse Events (SAEs) form: 
Main change is the SAE sending: SAEs have to be 
reported to the Corporate Vigilance Department, 
and not anymore to the clinical study manager. Also 
SAEs can be sent by e-mail and by fax. 
- Addition of Alpha Bioresearch as CRO involved 
for Feasibility, Monitoring and Regulatory issues in 
Spain. 
- Correction of some minor typographic errors  
 
PA04 
Non 
Substantial 
General 
03JUN2014 
Corresponding to protocol V7: 
- Precision on the temperature storage of DHA 
samples 
- Precision on the BSA formula 
- Addition of QTcB and QTcF 
- Precision on TTEM recording timelines 
- Clarification of the section Interim analysis 
and data monitoring (13.11) 
- Clarifications and specifications on some 
Final version
968/1185


N° 
TYPE 
APPLICATION 
AREA 
DATE 
MODIFICATIONS 
minor points 
PA05 
Substantial 
General 
22OCT2014 
Corresponding to protocol V8: 
 
- Planned end of study postponed to April 2016 
- Clarifications regarding the management of VKA 
treatment 
- Precision regarding the primary efficacy criterion 
(the time to the first Atrial Fibrillation recurrence or 
Atrial Flutter emergence) 
- Deletion of Visit 5 and Visit 8 
- Previous history of a first documented persistent 
Atrial Fibrillation without limitation in time instead of 
no longer than 3 years 
- Patients must have a systolic heart failure defined 
by a reduced ventricular ejection fraction and or 
defined also through other echocardiographic 
parameters mentioned in the ESC guidelines for the 
diagnosis and treatment of acute and chronic heart 
failure (2012) 
- Regarding previous prohibited treatments by 
amiodarone or droderanone, the non inclusion 
criteria of the protocol are adapted as follow: 
• 
Concomitant 
treatment 
with 
oral 
amiodarone or dronedarone from selection 
• 
Concomitant treatment with intravenous 
amiodarone from selection 
 
PA06 
Non 
substantial 
General 
06JUN2016 
Corresponding to protocol V8 
- 
Change of sponsor Clinical Study Manager and 
Clinical Development Physician  
- 
Planned end of study postponed to September 
2017 
 
 
Final version
969/1185


 
1. AMENDMENT RATIONALE 
 
The F373280 CA 201 planned initially to recruit 152 patients over 6 months across 50 
sites in Europe.  
Since May 2013, only 134 patients have been randomised and 1 patient is currently 
enrolled. Due to very slow recruitment over more than 3 years, and, in the absence of 
any possibility to plan a reliable date for completion of recruitment, the Sponsor has 
decided to stop the recruitment of patients as of September 23, 2016. This population of 
maximum 135 randomised patients will be taken into account for efficacy and safety 
analyses. Despite the loss of power, statistical analyses planned in the protocol are 
maintained. 
There is no unexpected safety signal on the current population, therefore, enrolled 
patients may continue receiving treatment and participate in the study, as planned by the 
protocol.  
In this context, the purpose of this amendment is limited to the change of the number of 
patients, the number of IDMC meetings and the planned study period. 
This change does apply to all relevant sections of the protocol. Furthermore, all enrolled 
patients will be informed of this change of recruited patient number.   
 
 
Final version
970/1185


2. CHANGES DESCRIPTION 
 
 
PREVIOUS VERSION 
MODIFIED VERSION 
Synopsis 
Planned Study Period: January 2013 –  September 2017 
(according to amendment PA06) 
Number of Patients: 76 x 2 patients 
 
 
13.11 INTERIM ANALYSIS AND DATA MONITORING 
The IDMC will review, three times during the study period 
(after the first 30 subjects will have been randomized, when 
the first 80 subjects will have terminated their study 
participation and when 130 subjects will have terminated their 
study participation), safety data results across treatment groups 
and judges whether the overall safety and feasibility (not 
futility) of the trial remain acceptable. 
 
Synopsis 
Planned Study Period: January 2013 – April 2017 
Number of Patients: maximum 135 patients 
 
13.11 INTERIM ANALYSIS AND DATA 
MONITORING 
The IDMC will review, two times during the study period 
(after the first 30 subjects will have been randomized and 
when the first 80 subjects will have terminated their study 
participation), safety data results across treatment groups 
and judges whether the overall safety and feasibility (not 
futility) of the trial remain acceptable. 
 
 
Final version
971/1185


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
F 373280 CA 2 01 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Final version
972/1185


 
 
Pierre Fabre Médicament 
Represented by: Institut de Recherche Pierre Fabre 
45, Place Abel Gance 
F-92100 Boulogne 
CLINICAL STUDY PROTOCOL 
 
Efficacy and safety study of F373280 for maintenance of sinus rhythm after 
electrical cardioversion in patients with persistent Atrial Fibrillation and 
Chronic Heart Failure. 
International, multicentric, randomised, double-blind, placebo controlled study 
F373280 / Soft Capsules / 1g  
Pierre Fabre Study Code: 
EudraCT Number: 
 
Sponsor's Representative: 
 
 
 
 
 
 
 
 
Study Coordinating Investigator 
F 373280 CA 2 01  
2012 – 003487 - 48 
 
Marine FAGARD  
INSTITUT DE RECHERCHE PIERRE FABRE - 
Centre de R&D Pierre Fabre - BP 13562  
3 avenue Hubert Curien  
31035 TOULOUSE Cédex 1, FRANCE 
Phone: +33 5 34 50 63 54  
Fax:+33 5 34 50 65 92  
E-mail:marine.fagard@pierre-fabre.com  
 
Pr Savina NODARI 
Associate Professor of Cardiology 
Department of Clinical and Surgical Specialities, 
Radiological Science and Public Health 
Section of Cardiovascular Diseases 
University Medical School and Spedali Civili Hospital of 
Brescia 
c/o Spedali Civili di Brescia 
Piazzale Spedali Civili, 1 
25123 - BRESCIA, ITALY 
Phone: +39 030 3996 587 – +39 030 393849 
Fax: +39 030 3700 359 
E-mail: savinanodari@gmail.com; nodari@med.unibs.it 
 
Version 9 – 28SEP2016 
The information contained in this document is confidential and is the property of the Sponsor, Pierre Fabre 
Medicament. This information is given for the needs of the study and must not be disclosed without prior written 
consent of the Sponsor Pierre Fabre Medicament. Persons to whom this information is given for the needs of the 
study must be informed that it is confidential and must not be disclosed. 
Final version
973/1185


 
SPONSOR PERSONNEL 
PIERRE FABRE MEDICAMENT 
represented by 
Institut de Recherche Pierre Fabre 
 
Clinical Study Manager (Monitor) 
Marine FAGARD  
 
Phone: +33 5 34 50 63 54  
Fax: + 33 5 34 50 65 92 
E-mail: marine.fagard@pierre-
fabre.com 
Institut de Recherche Pierre Fabre 
Centre de R&D Pierre Fabre 
BP 13 562 
3, Avenue Hubert Curien 
31035 TOULOUSE Cedex 1, FRANCE 
 
 
Head of Medical Unit 
Karim KEDDAD, MD, PhD 
 
Phone: +33 5 34 50 61 69 
Fax: +33 5 34 50 65 29 
E-mail: karim.keddad@pierre-
fabre.com 
Institut de Recherche Pierre Fabre 
Centre de R&D Pierre Fabre 
BP 13 562 
3, Avenue Hubert Curien 
31035 TOULOUSE Cedex 1, FRANCE 
 
 
Final version
974/1185


 
CONTRACT RESEARCH ORGANISATIONS 
 
For Feasibility, Monitoring and Regulatory issues (in Hungary, Czech Republic and Italy): 
Pharmaceutical Service Network (PSN) 
Rufino Gonzalez 
28 037 Madrid - SPAIN 
Phone: +34 91 375 6930 - Fax: +34 91 375 6931 
E-mail:  rzurita@psnglobal.org 
 
For Feasibility, Monitoring and Regulatory issues (in Spain): 
Alpha Bioresearch 
Paseo de la Castellana, 163 - 2º Izquierda 
28 046 Madrid - SPAIN 
Phone: +34 91 745 2520 - Fax: +34 91 745 0653 
E-mail: teresa.bricio@alphabioresearch.com 
 
For Centralised Randomisation and Electronic Case Report Form 
S-Clinica 
6, Chaussée de Boondael 
B-1050 Brussels - BELGIUM 
Phone: +32 2 645 0567 - Fax: +32 2 645 0569 
E-mail: irena.seredina@s-clinica.com 
 
For Centralised Reading of Holder ECG and TTEM and equipment supply: 
Biomedical System 
1945 Chaussée de Wavre 
B-1160 Brussels - BELGIUM 
Phone: +32 2 661 20 70 - Fax: +32 2 661 20 71 
E-mail: sjacobs@biomedsys.com 
 
For intra erythrocyte DHA dosage: 
Agrocampus Ouest 
Laboratoire de Biochimie 
65 rue de Saint Brieuc – CS 84215 
35042 RENNES Cedex - FRANCE 
Phone: +33 2 23 48 55 49 - Fax: +33 2 23 48 55 50 
E-mail: daniel.catheline@agrocampus-ouest.fr 
 
For transportation of blood sample to the Analytical centre (Agrocampus) and material 
supply: 
Theradis Pharma 
41, chemin des Presses 
06800 CAGNES-SUR-MER – FRANCE 
Phone: +33 (0)4 97 02 07 07 - Fax: +33 (0)4 97 10 08 78 
E-mail: chantal.raffy@theradis.pharma.com 
Final version
975/1185


Final version
976/1185


Final version
977/1185


 
 
Protocol F 373280 CA 2 01 
INVESTIGATOR SIGNATURE FORM 
Protocol Version 9 – 28SEP2016 
 
 
 
By my signature below, I, Dr / Pr "                                         ", hereby confirm that I agree: 
♦ to conduct the trial described in the protocol F 373280 CA 2 01, dated 28SEP2016 in 
compliance with GCP, with applicable regulatory requirements and with the protocol 
agreed upon by the Sponsor Pierre Fabre Médicament and given approval / favourable* 
opinion by the Ethics Committee; 
♦ to document the delegation of significant study-related tasks and to notify the Sponsor of 
changes in site personnel involved in the study; 
♦ to comply with the procedure for data recording and reporting; 
♦ to allow monitoring, auditing and inspection; 
♦ to retain the trial-related essential documents until the Sponsor informs that these documents 
are no longer needed. 
Furthermore, I hereby confirm that I will have and will use the available adequate resources, 
personnel and facilities for conduct this trial. 
 
I have been informed that certain regulatory authorities require the Sponsor Pierre Fabre 
Médicament to obtain and supply details about the investigator’s ownership interest in the 
Sponsor or the study drug, and more generally about his/her financial relationships with the 
Sponsor. The Sponsor will use and disclose the information solely for the purpose of complying 
with regulatory requirements. 
Hence I agree: 
♦ to supply the Sponsor with any information regarding ownership interest and financial 
relationships with the Sponsor (including those of my spouse and dependent children); 
♦ to promptly update this information if any relevant changes occur during the course of the 
study and for 1 year following completion of the study; 
♦ that the Sponsor may disclose this information about such ownership interests and financial 
relationships to regulatory authorities. 
* To be adapted  
 
Date:  
Signature:  
 
 
Final version
978/1185


TABLE OF CONTENTS OF CLINICAL STUDY PROTOCOL 
 
1. 
INTRODUCTION AND STUDY RATIONALE ................................................................ 22 
1.1. 
TARGET PATHOLOGY AND THERAPY ........................................................................ 22 
1.2. 
INFORMATION ON THE TEST PRODUCT .................................................................... 24 
1.2.1. 
Chemical and pharmaceutical characteristics .................................................................... 25 
1.2.1.1. 
Nomenclature and structure ............................................................................................ 25 
1.2.1.2. 
Physical and chemical general properties ...................................................................... 25 
1.2.2. 
Non-clinical Data .............................................................................................................. 25 
1.2.2.1. 
Pharmacological profile ................................................................................................. 26 
1.2.2.2. 
Safety pharmacology ...................................................................................................... 27 
1.2.2.3. 
Toxicology profile .......................................................................................................... 27 
1.2.2.4. 
Pharmacokinetic data ..................................................................................................... 27 
1.2.3. 
Clinical data ....................................................................................................................... 27 
1.3. 
STUDY RATIONALE ......................................................................................................... 29 
1.4. 
OVERALL RISK AND BENEFIT ASSESSMENT ............................................................ 30 
2. 
STUDY OBJECTIVES ......................................................................................................... 32 
2.1. 
PRIMARY OBJECTIVE ..................................................................................................... 32 
2.2. 
SECONDARY OBJECTIVES ............................................................................................. 32 
3. 
ETHICAL CONSIDERATIONS RELATING TO THE STUDY .................................... 33 
4. 
STUDY DESIGN ................................................................................................................... 34 
4.1. 
OVERALL DESCRIPTION ................................................................................................ 34 
4.2. 
DISCUSSION OF THE STUDY DESIGN .......................................................................... 35 
4.2.1. 
Choice of the Study Population ......................................................................................... 35 
4.2.2. 
Choice of the Study Design ............................................................................................... 36 
4.2.3. 
Choice of the Dose ............................................................................................................ 37 
4.2.4. 
Choice of the Sample Size ................................................................................................. 38 
5. 
STUDY POPULATION ........................................................................................................ 38 
5.1. 
INCLUSION CRITERIA ..................................................................................................... 38 
5.2. 
NON INCLUSION CRITERIA ........................................................................................... 40 
5.3. 
NUMBER OF PATIENTS ................................................................................................... 41 
5.4. 
RECRUITMENT MODALITIES ........................................................................................ 41 
5.5. 
PATIENT IDENTIFICATION ............................................................................................ 42 
5.6. 
WITHDRAWAL CRITERIA ............................................................................................... 42 
5.7. 
REPLACEMENT OF PATIENTS ....................................................................................... 43 
5.8. 
POST-STUDY EXCLUSION PERIOD .............................................................................. 43 
5.9. 
STUDY CARD AND LETTER FOR GENERAL PRACTITIONER(S) ............................ 43 
6. 
STUDY TREATMENT ......................................................................................................... 44 
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6.1. 
SOURCE, PRESENTATION AND COMPOSITION OF  INVESTIGATIONAL 
PRODUCT ........................................................................................................................... 44 
6.2. 
PACKAGING AND LABELLING ..................................................................................... 44 
6.2.1. 
Packaging .......................................................................................................................... 44 
6.2.2. 
Labelling ............................................................................................................................ 44 
6.3. 
DISTRIBUTION TO CENTRE AND STORAGE .............................................................. 45 
6.4. 
ALLOCATION OF TREATMENTS AND DISPENSATION TO PATIENT ................... 46 
6.5. 
DRUG ADMINISTRATION ............................................................................................... 47 
6.5.1. 
Duration of Treatment ....................................................................................................... 47 
6.5.2. 
Dose Schedule ................................................................................................................... 47 
6.5.3. 
Route and Conditions of Administration ........................................................................... 47 
6.6. 
ACCOUNTABILITY ON SITE AND RETURN/DESTRUCTION OF  
INVESTIGATIONAL PRODUCT ...................................................................................... 48 
6.7. 
RECALL OF INVESTIGATIONAL PRODUCTS ............................................................. 48 
7. 
CONCOMITANT TREATMENTS ..................................................................................... 48 
7.1. 
VITAMIN K ANTAGONIST TREATMENT ..................................................................... 49 
7.2. 
PROHIBITED TREATMENTS ........................................................................................... 49 
7.3. 
AUTHORISED TREATMENTS ......................................................................................... 50 
8. 
EVALUATION CRITERIA ................................................................................................. 50 
8.1. 
PRIMARY EFFICACY CRITERION ................................................................................. 50 
8.1.1. 
Time to the first Atrial Fibrillation Recurrence or Atrial Flutter Emergence ................... 50 
8.1.1.1. 
Definition ........................................................................................................................ 50 
8.1.1.2. 
Schedule ......................................................................................................................... 50 
8.1.1.3. 
Evaluation Methods ........................................................................................................ 50 
8.2. 
SECONDARY EFFICACY CRITERIA .............................................................................. 51 
8.2.1. 
Numbers of AF episodes in the first week following visit 3 (ECV visit) ......................... 51 
8.2.1.1. 
Definition ........................................................................................................................ 51 
8.2.1.2. 
Schedule ......................................................................................................................... 52 
8.2.1.3. 
Evaluation Methods ........................................................................................................ 52 
8.2.2. 
Duration of AF episodes in the first week following visit 3 (ECV visit) .......................... 52 
8.2.2.1. 
Definition ........................................................................................................................ 52 
8.2.2.2. 
Schedule ......................................................................................................................... 52 
8.2.2.3. 
Evaluation Methods ........................................................................................................ 52 
8.2.3. 
Clinical parameters evaluation .......................................................................................... 52 
8.2.3.1. 
EHRA score assessment ................................................................................................. 52 
8.2.3.2. 
Time to first AF recurrence less than 10 minutes .......................................................... 53 
8.2.3.3. 
Recurrence of symptomatic AF ...................................................................................... 53 
8.2.3.4. 
Number and duration of hospitalizations ....................................................................... 53 
8.2.4. 
Cardioversion assessment .................................................................................................. 54 
8.2.5. 
Evolution of echocardiographic parameters ...................................................................... 54 
8.2.5.1. 
Definition ........................................................................................................................ 54 
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8.2.5.2. 
Schedule ......................................................................................................................... 54 
8.2.5.3. 
Evaluation method .......................................................................................................... 54 
8.3. 
BIOMARKER ASSESSMENT: RED BLOOD CELL  CONCENTRATIONS OF 
DHA ..................................................................................................................................... 55 
8.3.1. 
Definition ........................................................................................................................... 55 
8.3.2. 
Blood samples ................................................................................................................... 55 
8.3.2.1. 
Collection schedule ........................................................................................................ 55 
8.3.2.2. 
Technical handling ......................................................................................................... 55 
8.3.3. 
DHA concentration measurement ..................................................................................... 55 
8.4. 
SAFETY ASSESSMENT .................................................................................................... 56 
8.4.1. 
Adverse Events .................................................................................................................. 56 
8.4.2. 
Laboratory Investigations .................................................................................................. 56 
8.4.2.1. 
Schedule ......................................................................................................................... 56 
8.4.2.2. 
Technical Procedures and Parameters ............................................................................ 56 
8.4.3. 
Global Physical Examination ............................................................................................ 57 
8.4.4. 
Vital Signs ......................................................................................................................... 58 
8.4.4.1. 
Schedule ......................................................................................................................... 58 
8.4.4.2. 
Technical Procedure and Parameters.............................................................................. 58 
8.4.5. 
Electrocardiogram (ECG) .................................................................................................. 58 
8.4.5.1. 
Schedule ......................................................................................................................... 58 
8.4.5.2. 
Technical Procedure and Parameters.............................................................................. 58 
8.4.6. 
Coagulation parameters ..................................................................................................... 59 
8.5. 
CONCOMITANT TREATMENTS ..................................................................................... 60 
8.6. 
COMPLIANCE .................................................................................................................... 60 
9. 
STUDY PROCEDURES ....................................................................................................... 60 
10. ADVERSE EVENTS: DEFINITION AND REPORTING ............................................... 66 
10.1. ADVERSE EVENTS ........................................................................................................... 66 
10.1.1. Definition of Adverse Events ............................................................................................ 66 
10.1.2. Grading of Adverse Events ............................................................................................... 67 
10.1.3. Reporting of Adverse Events ............................................................................................ 67 
10.2. SERIOUS ADVERSE EVENTS (SAE) .............................................................................. 67 
10.2.1. Definition ........................................................................................................................... 67 
10.2.2. Reporting of SAE .............................................................................................................. 68 
10.2.3. Follow-up of SAE ............................................................................................................. 68 
10.2.4. SAE Occurring After the Study ......................................................................................... 69 
10.3. REPORTING OF OVERDOSAGE TO THE SPONSOR ................................................... 69 
10.4. REPORTING OF PREGNANCY TO THE SPONSOR ...................................................... 69 
10.5. SPONSOR'S RESPONSIBILITIES FOR SAFETY REPORTING  PURPOSES ............... 70 
11. DATA COLLECTION AND STUDY MONITORING ..................................................... 70 
11.1. DATA COLLECTION ......................................................................................................... 70 
11.1.1. Case Report Form .............................................................................................................. 70 
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11.1.2. Source Documents ............................................................................................................. 71 
11.2. STUDY MONITORING ...................................................................................................... 71 
11.2.1. Monitoring visits ............................................................................................................... 71 
11.2.1.1. Site Preselection Visit .................................................................................................... 72 
11.2.1.2. Initiation Visit ................................................................................................................. 72 
11.2.1.3. Follow-up Visits ............................................................................................................. 72 
11.2.1.4. Closing Visit ................................................................................................................... 73 
11.2.2. Direct Access to Source Documents ................................................................................. 73 
11.3. INDEPENDENT DATA MONITORING COMMITTEE ................................................... 73 
12. DATA MANAGEMENT ...................................................................................................... 74 
12.1. DATA ENTRY ..................................................................................................................... 74 
12.2. DATA CLEANING ............................................................................................................. 74 
12.3. DATA CODING .................................................................................................................. 74 
12.4. DATA STORAGE ............................................................................................................... 75 
12.5. DATABASE LOCK ............................................................................................................. 75 
13. STATISTICAL ANALYSIS ................................................................................................. 75 
13.1. GENERAL CONSIDERATIONS ........................................................................................ 75 
13.2. SAMPLE SIZE ..................................................................................................................... 75 
13.3. PROTOCOL DEVIATIONS ................................................................................................ 76 
13.4. DATA SETS ANALYSED .................................................................................................. 76 
13.5. HANDLING OF DROPOUTS AND MISSING DATA ..................................................... 77 
13.5.1. Dropouts ............................................................................................................................ 77 
13.5.2. Repositioning of Visits ...................................................................................................... 77 
13.5.3. Missing Data ...................................................................................................................... 77 
13.6. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ............................... 77 
13.7. EFFICACY ANALYSIS ...................................................................................................... 78 
13.7.1. Primary Criterion ............................................................................................................... 78 
13.7.1.1. Primary Analysis ............................................................................................................ 78 
13.7.1.2. Supportive Analysis ....................................................................................................... 78 
13.7.2. Secondary Criteria ............................................................................................................. 78 
13.7.2.1. Numbers of Atrial Fibrillation Episodes in the first week following V3 ....................... 78 
13.7.2.2. Duration of Atrial Fibrillation Episodes in the first week following V3 ....................... 78 
13.7.2.3. Time to first AF recurrence less than 10 minutes or symtomatic .................................. 79 
13.7.2.4. Clinical parameters evaluation ....................................................................................... 79 
13.7.2.5. Biomarker analysis: red blood cell concentrations of DHA ........................................... 79 
13.8. SAFETY ANALYSIS .......................................................................................................... 79 
13.8.1. Adverse Events .................................................................................................................. 79 
13.8.2. Clinical Laboratory Evaluation ......................................................................................... 81 
13.8.3. Global Physical Examination ............................................................................................ 82 
13.8.4. Vital Signs, Physical Findings and Other Observations Related to Safety ....................... 83 
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13.8.4.1. Vital Sign Measurements Over Time ............................................................................. 83 
13.8.4.2. Body weight ................................................................................................................... 83 
13.8.4.3. Individual Patient Changes ............................................................................................. 83 
13.8.5. ECG ................................................................................................................................... 83 
13.8.6. Coagulation parameters ..................................................................................................... 84 
13.9. CONCOMITANT TREATMENTS ..................................................................................... 84 
13.10. COMPLIANCE .................................................................................................................... 84 
13.11. INTERIM ANALYSIS AND DATA MONITORING ........................................................ 84 
14. GENERAL ETHICAL CONSIDERATIONS .................................................................... 85 
14.1. ETHICAL CONDITIONS ................................................................................................... 85 
14.2. ETHICS COMMITTEE AND LEGAL REQUIREMENTS ................................................ 85 
14.3. PATIENT'S INFORMATION LEAFLET AND INFORMED CONSENT  FORM ........... 86 
14.4. PERSONAL DATA PROTECTION ................................................................................... 86 
14.5. INSURANCE POLICY ........................................................................................................ 87 
15. ADMINISTRATIVE PROCEDURES ................................................................................ 87 
15.1. PROTOCOL AMENDMENT .............................................................................................. 87 
15.2. SOURCE DOCUMENTS, INVESTIGATOR'S FILE STORAGE ..................................... 87 
15.3. END OF THE STUDY ......................................................................................................... 88 
15.3.1. Definition of the End of Study .......................................................................................... 88 
15.3.2. Early Study Termination ................................................................................................... 88 
15.3.2.1. Early Study Termination Decided by the Sponsor ......................................................... 88 
15.3.2.2. Early Study Termination Decided by the Competent Authorities.................................. 88 
15.4. AUDIT .................................................................................................................................. 89 
15.5. INSPECTION ....................................................................................................................... 89 
15.6. CONFIDENTIALITY .......................................................................................................... 89 
15.7. CLINICAL STUDY REPORT ............................................................................................. 89 
15.8. STUDY RESULTS COMMUNICATION .......................................................................... 90 
15.9. STUDY RESULTS PUBLICATION ................................................................................... 90 
16. REFERENCES ...................................................................................................................... 92 
17. APPENDICES ....................................................................................................................... 96 
17.1. DECLARATION OF HELSINKI ........................................................................................ 97 
17.2. SAE REPORT FORM ........................................................................................................ 101 
17.3. PREDEFINED LIMITS OF LABORATORY AND VITAL SIGN POTENTIALLY 
CLINICALLY SIGNIFICANT CHANGES AND VALUES ............................................ 104 
 
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SYNOPSIS 
 
Name of Sponsor: 
Pierre Fabre Médicament represented by the Institut de Recherche Pierre Fabre (IRPF) 
Name of Finished Product: 
Not applicable 
Name of Active Substance:  
F373280 (Panthenyl-Ester of DHA) 
Title of the Study: 
Efficacy and safety study of F373280 for maintenance of sinus rhythm after electrical 
cardioversion in patients with persistent Atrial Fibrillation and Chronic Heart Failure. 
International, multicentric, randomised, double-blind, placebo controlled study 
Abbreviated Title: 
Not applicable 
Study Coordinating Investigator: 
Pr Savina NODARI 
Study Centres: 
International, multicentric 
Publication / Rationale: 
F373280 is a new therapy based on DHA delivery (pro-drug) developed for the maintenance 
of sinus rhythm after electrical cardioversion in persistent atrial fibrillation (AF) patients with 
chronic heart failure. 
The results of a pharmacological study performed in animals evidenced that DHA reduces the 
duration of AF induced by burst pacing.[1] 
Moreover, the effectiveness of PolyUnsaturated Fatty Acid (PUFA) has been proven in the 
following conditions: 
− 
prevention of AF recurrence in patients with persistent AF, in co-administration 
with amiodarone (add on therapy) [2]  
− 
Improvement of ventricular functional parameters, morbi-mortality and duration of 
hospitalisation in patients with heart failure [3, 4, 5] 
Taking into account these studies, it seems that DHA might be of therapeutic interest in the 
treatment of patients with both persistent atrial fibrillation and chronic heart failure. 
This phase IIa study is designed to assess the efficacy and the safety of the investigational 
product (F373280) for maintenance of sinus rhythm after electrical cardioversion (ECV) in 
patients with persistent atrial fibrillation and chronic heart failure. 
Planned Study Period: 
January 2013 –  April 2017 
Clinical Phase: IIa 
Objectives: 
Primary: 
- Efficacy of F373280 on the maintenance of sinus rhythm after direct electrical 
cardioversion in patients with persistent atrial fibrillation and chronic heart failure 
Secondary: 
- Efficacy of F373280 on the efficiency of direct electrical cardioversion 
- Effect of F373280 on echocardiographic parameters 
- Safety and tolerability of F373280 
Methodology: 
- International, multicentre, randomised, double-blind, placebo-controlled 
- Selection period 
- Start of treatment 4 weeks before ECV 
• 
Condition to ECV:  
− 
Ideally INR 2-3 (vitamin K antagonist should be given at least 3 weeks before 
ECV) 
− 
No spontaneous cardioversion before ECV 
- Follow-up 20 weeks after visit 3 (ECV visit) 
• 
Condition: successful ECV or spontaneous CV 
- Cardiac monitoring: 
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• 
7-days continuous ECG ambulatory recording (Holter ECG) between visit 3 (ECV 
visit) and visit 4 (week 5) in patients with sinusal rhythm 
• 
TTEM: one transmission per week from the day of visit 4 (end of week 5) to visit 9 
(week 24) and at any time in case of AF or atrial flutter symptoms. 
- Treatment duration: 24 weeks 
Study Schedule: 
 7 visits will be scheduled: 
- V1/ W-4 to W-1: selection visit (7 to 28 days before the inclusion visit)  
- V2/ D1: Inclusion visit (start of study treatment) 
- V3/ W4 (D28 -2/+7 days): cardioversion visit (outpatient or hospitalization according to 
clinical practice of the centre) (installation of the Holter device) 
- V4/ W5 (D35 -2/+7 days): follow-up visit (removing of the Holter device and 
installation of the TTEM) 
- V6/ W12* (D84 ± 7 days): follow-up visit    
 *see amendment PA05 dated 22OCT2014 
- V7/ W16 (D112 ± 7 days): follow-up visit     
- V9/ W24* (D168 ± 7 days): final study visit    
 *see amendment PA05 dated 22OCT2014 
Number of  Patients: 
Maximum 135  patients  
Diagnosis and Criteria for Inclusion: 
Inclusion Criteria: 
 
Demographic Characteristics and Other Baseline Characteristics: 
1. 
Men or women aged more than 18 years (inclusive) 
2. 
Patients with current episode of persistent AF between 7 days and 6 months duration for 
whom electrical cardioversion is warranted 
3. 
Previous history of first documented episode of persistent AF. 
4. 
Previous history of ischemic or non ischemic heart failure  
5. 
NYHA class I or II chronic heart failure at selection and at inclusion 
6. 
Left ventricular systolic dysfunction defined at selection and at inclusion by a reduced 
left ventricular ejection fraction (LVEF) ≥ 30% and ≤ 45% or for patients with a LVEF 
> 45%: 
• an increased left ventricular end-diastolic size  
(diameter ≥ 60 mm and/or > 32 mm/m² and/or volume > 97 ml/m²) 
• and/or an increased left ventricular end-systolic size 
(diameter > 45 mm and/or > 25 mm/m² and/or volume > 43 ml/m²) 
• and/or a reduced left ventricular outflow tract velocity time integral < 15 cm 
7. 
On appropriate, stable medical treatments for heart failure, including a diuretic and/or 
angiotensin-converting enzyme, and/or angiotensin-receptor blocker and/or 
mineralocorticoid receptor (MR) antagonists, and/or betablockers 
8. 
Left atrial area ≤ 40 cm² at selection and at inclusion 
9. 
Patients treated or having to be treated by vitamin K antagonist 
10. For female patient of child-bearing potential:  
• 
In all the countries except Italy:  
- Use of an effective method of contraception (hormonal contraception or intra-
uterine device) assessed by the investigator, for at least 2 months before the 
selection in the study, and agreement to go on using it during the whole duration of 
the study and up to 1 month after the last dose of the study treatment 
- Documented as surgically sterilized 
• 
In Italy only:  
- Absolute abstention from sexual intercourse during the whole duration of the study 
and for a month after the end of the study or 
- Use of double barrier contraception method (use of effective medical contraception 
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method) from at least 2 months before the start of the study to the entire duration of 
the study and for a month after the end of the study or 
- Documented as surgically sterilized 
11. For female patient of child-bearing potential: negative urine pregnancy test at inclusion 
12. For male with a child-bearing potential partner (In Italy only): 
- Absolute abstention from sexual intercourse during the whole duration of the study 
and for 3 months after the end of the study or 
- Use of double barrier contraception method (use of condom for male and effective 
contraception method for the partner) from the entire duration of the study to 3 
months after the end of the study. 
Ethical / legal considerations: 
13. Having signed his/her written informed consent, 
14. Affiliated to a social security system, or is beneficiary (if applicable in the national 
regulation) 
 
Non-Inclusion Criteria: 
Criteria related to pathologies: 
1. 
No previous history of first documented episode of persistent AF  
2. 
More than two successful cardioversions (electrical or pharmacological) in the last 6 
months 
3. 
Secondary Atrial Fibrillation due to alcohol or severe valvular heart disease (grade III to 
IV) 
4. 
NYHA class III or IV heart failure at selection or at inclusion 
5. 
Thyroid disease uncontrolled by treatment: TSH ± T4L ± T3L to be checked in case of 
treatment for thyroid disease 
6. 
Myocardial infarction or unstable angina or presence of unstable ischemic 
coronaropathy assessed by coronarography or cardiac stress test (Echo stress, exercise 
stress test, nuclear or MR perfusion evaluation methods) within 6 months before 
selection 
7. 
Severe chronic kidney disease (creatinine ≥ 25 mg/L or estimated glomerular filtration 
rate < 30 ml/min) at selection 
8. 
Bradycardia (HR ≤ 50 bpm) 
9. 
Hyperkalemia or hypokalemia (according to the standards of local laboratories) at 
selection  
10. Cardiac surgery within 3 months before selection or planned during the study duration 
Criteria related to treatments: 
11. Previously ineffective pharmacological or electrical cardioversion 
12. Concomitant treatment with ranolazine or any antiarrhythmic drug (within 7 days prior 
to selection), except amiodarone, dronedarone and stable dose of digoxin, betablockers, 
calcium-blockers 
13. Concomitant treatment with oral amiodarone or dronedarone from selection  
14. Concomitant treatment with intravenous amiodarone from selection  
15. Patient requiring a cardiac resynchronization therapy (CRT) or having undergone CRT 
implantation within the last 6 months  
16. Treatment with any Polyunsaturated Fatty Acid (PUFA) within the last 3 months 
17. Dietary supplement with ω 3 or ω 6 according to investigator’s judgement 
18. Having undergone any form of ablation therapy for AF 
19. Patient treated with oral anticoagulant treatment other than vitamin K antagonist: new 
oral anticoagulants (dabigatran, rivaroxaban, apixaban), or treated with irreversible 
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antiplatelet agents P2Y12 inhibitors such as ticlopidine, clopidogrel or prasugrel 
 
Other criteria: 
20. Patient liable not to comply with protocol instructions and/or with treatment, in the 
investigator’s opinion 
21. Patient having taken part in a clinical trial in the preceding 2 months or taking part in a 
trial at the time of selection 
22. Patient linguistically or mentally unable to understand the nature, objectives and 
possible consequences of the trial, or refusing to patient himself/herself to its constraints 
23. Patient family member or work associate (secretary, nurse, technician,..) of the 
Investigator 
24. Patient having forfeited his / her freedom by administrative or legal award or being 
under guardianship 
25. Breastfeeding female patient 
 
Exclusion criteria before V3: 
Patients without dyskalemia who will not have INR values ≥ 2 on the 3 last tests performed 
before ECV should not have an ECV and will be excluded from the study. 
However, if only 2 INR values are ≥ 2 among those 3 last tests, an ECV can be performed if 
the presence of atrial thrombosis can be excluded with an ECHO–TE (transesophageal 
echocardiography) performed on the same day (before ECV) and the patient can continue the 
study. 
If necessary, for meeting these INR conditions, the ECV (and following visits) could be 
postponed by 7 days. 
Test Product:  
F373280  
Soft Capsules  
Dose: 
Arm with 1g of F373280 
Mode of Administration: 
Oral, one capsule each evening with dinner. 
Duration of Treatment: 
24 weeks of treatment exposure with F373280 (25 weeks if ECV postponed by 1 week) 
Reference Therapy 
Placebo soft capsules 
Placebo will be administered in the same conditions as the tested product. 
Mode of Administration: 
Oral, one capsule each evening with dinner 
Evaluation Criteria: 
Efficacy evaluation variables: 
Primary evaluation variable: 
- Time to first Atrial Fibrillation recurrence or atrial flutter emergence defined by the time to 
first episode of AF or atrial flutter lasting for at least 10 minutes (Follow up of 20 weeks 
after visit 3 – ECV visit). 
Handling of AF recurrences or atrial flutter emergences: 7-day continuous ECG (5-leads/2 
or 3 channels) ambulatory recording (holter ECG) between visit 3 (ECV visit) and visit 4 
(week 5). Then, the follow up will be documented using the TTEM: one transmission per 
week from the day of visit 4 (end of week 5) to visit 9 (week 24). 
For randomised patients with spontaneous cardioversion before ECV, the recurrence of AF 
or the emergence of atrial flutter will be assessed after visit 3 (from week 5).  
Moreover, during this TTEM period, if patient experiences any AF or atrial flutter 
symptoms, it should be recorded and documented using the TTEM.  
All ECG (Holter and TTEM) will be evaluated by a Central Reading Laboratory. 
Secondary evaluation variables: 
During the 7-day continuous ECG monitoring, 
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• 
Numbers of AF episodes 
• 
Duration of AF episodes 
Clinical parameters: 
During the whole study: 
• 
Number of recurrence of symptomatic AF episodes 
• 
EHRA score 
• 
Hospitalization for cardiovascular events 
• 
Hospitalization for thromboembolic stroke 
• 
All causes of hospitalization 
Cardioversion: 
• 
Assessment of spontaneous cardioversion 
• 
Assessment of successful cardioversion 
• 
Shocks distribution (1, 2 or 3 shocks) 
• 
Number of patients needing an other cardioversion after the initial ECV 
 
Other: 
• 
Evolution of echocardiographic parameters (at V4,  V6 and V9) (Left atrial 
diameter (mm), Left atrial area (cm²), Left atrial volume (ml), Left atrial 
volume/BSA (ml/m2), Left ventricular ejection fraction (%), Left ventricular end 
diastolic volume/BSA (ml/m2), Left ventricular end systolic volume/BSA(ml/m2), 
Left ventricular end diastolic diameter (mm), Left ventricular end diastolic volume 
(ml) Left ventricular end systolic diameter (mm), Left ventricular end systolic 
volume (ml)) 
• 
Evolution of omega 3 index and intra erythrocyte DHA (For this assessment 
samples will be centralized). 
 
Safety criteria: 
• 
Adverse events (observed and / or spontaneously reported) 
• 
Vital signs (Blood pressure (supine and standing), heart rate) 
• 
Physical examination (body weight, body surface area)  
• 
Standard 12-lead ECG: heart rate (bpm), PR (ms), QRS (ms), QT (ms), QTcB 
(ms), QTcF (ms), repolarisation patterns (ECG not centralized) 
• 
Haematology: haematocrit, haemoglobin, red blood cell (RBC) count, white blood 
cell (WBC) count, WBC differential count, reticulocytes, platelets 
• 
Biochemistry: sodium, potassium, bicarbonate, chloride, alkaline phosphatase, 
gamma GT, albumin, total bilirubin, conjugated bilirubin, creatinine, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), fasting glucose, total 
cholesterol, cholesterol (HDL, LDL), triglycerides, creatin phosphokinase (CPK) 
fibrinogen (local laboratory) 
• 
Coagulation parameters: Activated partial thromboplastin time (aPTT), thrombin 
clotting time (TCT), INR (local laboratory), Prothrombine Time (PT). 
 
Concomitant treatments 
 
Compliance 
 
Statistical Methods: 
Sample Size: 
Assuming an AF recurrence or atrial flutter emergence rate under placebo of 85%, a power of 
80%, an alpha risk of 5% and a rate of not assessable patients of 15%, 76 randomised patients 
per group will be necessary, using a log-rank test of survival curves, a difference between 
groups of 20%.  
Primary Efficacy Analysis 
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The primary analysis, performed on the Full Analysis Set (FAS: all randomised patients with 
at least one dose of treatment and with a successful cardioversion observed at visit 3), will be 
a survival analysis using the Kaplan Meier method and Cox regression model. 
Secondary Analyses  
All secondary efficacy criteria will be described and compared using appropriate tests on the 
FAS. 
Safety Analyses 
Descriptive statistics will be performed on the Safety Set (all randomised patients with at 
least one dose of treatment).  
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STUDY FLOW-CHART 
F373280 CA 201 
V1 
V2 
V3 
V4 
 
V6 
V7 
 
V9 
Weeks 
W-4 to W-1 
D1 
W4 
(28 -2D/+7 D) 
W5 
(35 -2D/+7 D) 
 
W12 
(84+/-7D) 
W16 
(112+/-7D) 
 
W24 
(168+/-7D) 
  
  
  
  
  
  
  
  
  
  
Outpatient or Hospitalization (1) 
  
  
X 
  
 
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
  
  
  
  
  
  
  
  
Demographic characteristics 
X 
  
  
  
  
  
  
  
  
Medico-surgical history 
X 
  
  
  
  
  
  
  
  
Concomitant disease 
X 
  
  
  
  
  
  
  
  
Concomitant treatment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Habits 
X 
  
  
  
  
  
  
  
  
Global physical examination (body weight) 
X 
X 
X 
 
X 
X 
X 
X 
X 
Echocardiography 
X 
X 
  
X 
  
X 
  
  
X 
Eligibility criteria check 
X 
X 
  
  
  
  
  
  
  
Blood pressure, heart rate  
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead  ECG Recording 
X 
X 
X 
  
X 
X 
X 
X 
X 
INR  
 
 
                   
  
X 
 
 
X 
                     (2) 
aPTT, TCT  
X 
X 
X 
  
X 
X 
X 
X 
X 
Biochemistry 
X 
  
  
  
  
  
  
  
X 
Haematology  
X 
  
X 
  
  
X 
  
  
X 
Urinary pregnancy test 
  
X 
  
  
  
  
  
  
X 
Red Blood Cell concentrations of DHA  
  
X 
X 
  
  
X 
  
  
X 
Treatment number allocation 
  
X 
  
  
  
X 
  
  
  
IVRS/IWRS 
X 
X 
  
  
 
X 
  
  
  
ECV (3) 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Drug administration  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Adverse events recording 
  
X 
X 
X 
X 
X 
X 
X 
X 
Holter ECG 
                (4) 
  
 
                (5) 
 
 
 
 
 
TTEM (6) 
  
  
 
 
 
  
  
  
  
(1) Outpatient or hospitalization according to clinical practice of the centre (less or more than 24 hours) 
(2) In case of VKA introduction: INR 2 to 3 times a week until stabilization, then weekly until the ECV, then every 4 weeks after ECV 
(3) In patients with AF 
(4) 24-hour Holter ECG 
(5) 7-day Holter ECG 
(6) TTEM: one transmission per week from the day of visit 4 (end of week 5) to visit 9 (week 24) and at any time in case of AF or atrial flutter symptoms. 
TTEM once a week even in case of AF recurrence or atrial flutter emergence for at least 10 minutes. 
 
 
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LIST OF ABBREVIATIONS 
 
aPTT 
: 
Activated partial thromboplastin time 
AE 
: 
Adverse event 
AF 
: 
Atrial fibrillation 
ALA 
: 
Alpha-linoleic acid 
ALT 
: 
Alanine aminotransferase 
AST 
: 
Aspartate aminotransferase 
AUC 
: 
Area under the plasma concentration versus time curve 
AUCinf 
: 
Total area under the curve extrapolated to infinity 
βHCG 
: 
beta human chorionic gonadotrophin 
BLQ 
: 
Below the limit of quantification 
BMI 
: 
Body mass index 
BP 
: 
Blood pressure 
BSA 
: 
Body Surface Area 
CEP 
: 
Protocol evaluation committee 
CHMP 
: 
Committee for medicinal products for human use 
Cmax 
: 
Maximum concentration 
Cmin 
: 
Minimum concentration 
CNALV 
: 
Clinically noteworthy abnormal laboratory value 
CPK 
: 
Creatin phosphokinase 
CPP 
: 
Comité de protection des personnes  
CRA 
: 
Clinical research associate 
CRT 
: 
Cardiac resynchronization therapy 
CSC 
: 
“Clinically Significant Change”, i.e., Predefined potentially clinically significant 
change leading to a potentially clinically significant value (vital signs) 
CV 
: 
Coefficient of variation 
DBP 
: 
Diastolic blood pressure 
DHA 
: 
Docosahexaenoic acid 
EC 
: 
Ethics committee 
ECG 
: 
Electrocardiogram 
ECHO –TE : 
Transesophageal echocardiograph 
ECV 
: 
Electrical cardioversion 
EHRA 
: 
European heart rhythm association 
EPA 
: 
Eicosapentaenoic acid 
e-CRF 
: 
Electronic case report form 
FAS 
: 
Full analysis set 
Fe 
: 
Fraction of the administered drug excreted in urine 
GCP 
: 
Good clinical practice 
GFR 
:  Glomerular Filtration Rate 
HBs 
: 
Hepatitis B antigen 
HCV 
: 
Hepatitis C virus 
HDL 
: 
High density lipoprotein 
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HF 
: 
Heart failure 
HIV 
: 
Human immunodeficiency virus 
HR 
: 
Heart rate 
ICH 
: 
International conference on harmonisation of technical requirements for 
registration of pharmaceuticals for human use 
IDMC 
: 
Independent data monitoring committee 
INR 
: 
International normalized ratio 
IRPF 
: 
Institut de Recherche Pierre Fabre 
IVRS 
: 
Interactive voice response system 
LAA 
: 
Left atrial area 
LC/MS-MS : 
Liquid chromatography with tandem mass spectrometry 
LDL 
: 
Low density lipoprotein 
LOQ 
: 
Limit of quantification 
LVEF 
: 
Left ventricular ejection fraction 
MedDRA 
: 
Medical dictionary for regulatory activities 
MR 
: 
Mineralocorticoid receptor 
MR perfusion : 
Magnetic Resonance perfusion 
MTD 
: 
Maximum tolerated dose 
N 
: 
Number of determinations or replicates 
NOAEL 
: 
No observed adverse effect level 
NYHA 
: 
New York heart association 
od 
: 
Once a day 
PC 
: 
“Predefined Change”, i.e., Predefined potentially clinically significant change (lab 
or vital signs) 
PCA 
: 
PC leading to an out-of-range value (lab values) 
PFB 
: 
Pierre Fabre Biométrie 
PSC 
: 
Potentially Clinically Significant Change 
PSCV 
: 
Potentially Clinically Significant Value 
PUFA 
: 
PolyUnsaturated fatty acid 
p.o. 
: 
Per os 
PP 
: 
Per protocol data set 
QTcB 
: 
QT interval using Bazett’s correction formula 
QTcF 
: 
QT interval using Fridericia’s correction formula 
RBC 
: 
Red blood cells 
SAE 
: 
Serious adverse event 
SBP 
: 
Systolic blood pressure 
SD 
: 
Standard deviation 
T1/2 
: 
Terminal half-life 
T0 
: 
Time of drug administration 
Tmax 
: 
Time to reach the maximal concentration 
TCT 
: 
Thrombin clotting time 
TEAEs 
: 
Treatment emergent adverse events 
TTEM 
: 
TransTelephonic ECG monitoring 
VKA 
: 
Vitamin K Antagonist 
WBC 
: 
White blood cells 
WHO-DRUG : 
World health organization drug reference list 
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1. INTRODUCTION AND STUDY RATIONALE 
1.1. 
TARGET PATHOLOGY AND THERAPY 
 
Atrial Fibrillation (AF) is a supraventricular arrhythmia characterized by uncoordinated atrial 
electric activity with consequent deterioration of atrial mechanical function. It is the most 
common sustained cardiac rhythm disorder, increasing in prevalence with age. Haemodynamic 
impairment and thromboembolic events related to AF result in significant morbidity and mortality 
[7]. 
In 2009, Decision Resources estimated that there were 7.8 million diagnosed prevalent cases of 
AF in US, Europe and Japan. This age-related pathology should increase to 9.4 million cases in 
2019.  
Except for the conventional class I and class III anti-arrhythmic agents, the Polyunsaturated Fatty 
Acids (PUFAs) constitute one emerging antiarrhythmic therapy. These compounds potently 
address the AF substrate by directly targeting both the electrical and the structural remodelling of 
the deficient atria. The n-3 PUFAs, essential for human, are alpha-linoleic acid (ALA), 
eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). First, PUFAs specifically 
modulate ionic channels by fastening their inactivating mode which renders these compounds 
selective for pathological situations (such as AF) without any major effect in normal conditions. 
PUFAs are “open Kv1.5 channel blockers” leading to a lengthening of atrial action potential 
duration and are “persistent Nav1.5 channel blockers” leading to hyperpolarization of diastolic 
resting potential. Second, PUFAs influence structural remodelling through their anti-inflammatory 
effects as they directly compete with arachidonic acid in the production of inflammatory 
eicosanoids. In summary, PUFAs share unique, well-tolerated antiarrhythmic potential by 
interacting with the electrical and structural remodelling during sustained AF. In animal studies, it 
was recently demonstrated that DHA is particularly effective in pathologic conditions such as 
ischemia and/or AF. 
The potential anti-arrythmic effects of a PUFA were previously developed in AF: nicotinyl ester 
of DHA (pro-drug based on DHA delivery) was assessed in a two-week ventricular tachypaced 
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canine model. Dogs were subjected to 4 weeks of medication prior to undergoing an 
electrophysiology study, and received either placebo or nicotinyl ester of DHA. Dogs were 
tachypaced at 240 beats per min for the final two weeks of the treatment plan. The results showed 
that the tested PUFA reduced the duration of AF induced by burst pacing, and the incidence of 
sustained AF, compared to dogs treated with the placebo [1]. 
In clinical practice, Nodari and coll [2] assessed n-3 PUFAs in the prevention of AF recurrences 
after electrical cardioversion (ECV). All included patients were treated with amiodarone and a 
renin-angiotensin-aldosterone system inhibitor. The 199 patients were assigned either to placebo 
or n-3 PUFAs 2 g/d and then underwent direct ECV 4 weeks later. The primary end point was the 
maintenance of sinus rhythm at 1 year after cardioversion. At the 1-year follow up, the 
maintenance of sinus rhythm was significantly higher in the n-3 PUFAs treated patients compared 
with the placebo group (hazard ratio, 0.62 [95% confidence interval, 0.52 to 0.72] and 0.36 [95% 
confidence interval, 0.26 to 0.46], respectively; p = 0.0001). The study concludes that in patients 
with persistent AF on amiodarone and a renin-angiotensin-aldosterone system inhibitor, the 
addition of n-3 PUFAs 2 g/d improves the probability of the maintenance of sinus rhythm after 
direct current cardioversion. Previously, during the World Congress of Cardiology in 2006, an 
abstract reported the effectiveness of PUFAs on top of traditional treatment (amiodarone, beta 
blockers, renin-angiotensin-aldosterone system inhibitor) in the prevention of AF relapses in 
patients having undergone ECV. In the PUFA group, AF relapses were significantly lower than in 
the placebo group at 1 month (3.3% vs 10%; p = 0.043), at 3 months (10% vs 25%; p = 0.004) and 
at 6 months (13.3% vs 40%; p < 0.0001) [19]. 
In contrast, in the general AF population (paroxystic atrial fibrillation and persistent atrial 
fibrillation), PUFAs failed to prove their efficacy [7] because of the absence of cardiac 
remodelling or because of a short pre-treatment duration before ECV (1 week) [8]. The effects of 
PUFAs were only observed in patients with persistent AF on add on therapy and after a sufficient 
pre-treatment before ECV. Persistent AF is commonly associated to heart failure. Previous studies 
performed in heart failure population demonstrated the benefit of PUFAs on the improvement of 
functional ventricular parameters and morbi-mortality, and on the reduction of hospitalisation [3, 
4, 5]. 
Nodari and coll [3] performed a trial in patients with chronic heart failure (NYHA I to III and 
LVEF< 45%). After a treatment of 133 patients with PUFAs (n=67) or placebo (n=66) at a dosage 
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of 5 g/day for 1 month, then 2 g/day for 11 months, the n-3 PUFAs group and the placebo group 
differed significantly (p <0.001) in regard to:  
− LVEF (increased by 10.4% and decreased by 5.0%, respectively) 
− peak VO2 (increased by 6.2% and decreased by 4.5%, respectively) 
− exercise duration (increased by 7.5% and decreased by 4.8%, respectively) 
− mean New York Heart Association functional class (decreased from 1.88+/- 0.33 to 1.61 
+/- 0.49 and increased from 1.83+/- 0.38 to 2.14 +/- 0.65, respectively).  
The hospitalization rates for patients with HF were 6% in the n-3 PUFAs and 30% in the placebo 
group (p <0.0002). 
Moertl and coll [4] performed a dose-ranging study in patients with a more severe chronic heart 
failure (NYHA III and IV and LVEF < 35%). It was a double-blind, randomised, controlled pilot 
trial in 43 patients treated with PUFAs or placebo for 3 months (1 g/d n3-PUFA (n = 14), 4 g/d 
n3-PUFA (n = 13), or placebo (n = 16)). After treatment, left ventricular ejection fraction 
increased in a dose-dependent manner (p = 0.01 for linear trend) in the 4 g/d (baseline vs 3 
months [mean ± SD]: 24% ± 7% vs 29% ± 8%, p = 0.005) and 1 g/d treatment groups (24% ± 8% 
vs 27% ± 8%, p = 0.02). 
No changes in any investigated parameters were noted with placebo. 
Taking into account these studies performed with PUFAs, it seems that the best target for DHA is 
persistent AF in patients with heart failure. The aim of this proof of concept study is to assess in 
stand alone therapy (without association of other anti-arrhythmic treatments), the effect of 
F373280 in patients with persistent AF and heart failure in the maintenance of sinus rhythm after 
ECV. 
1.2. 
INFORMATION ON THE TEST PRODUCT 
F373280 or panthenyl ester of DHA is the mono-ester of panthotenic alcohol and DHA, selected 
to be developed for the management of AF.  
F373280 is a prodrug of DHA. 
A brief summary of F373280 known characteristics is presented in this section. For further details, 
please refer to the F373280 Investigator’s Brochure. [1] 
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1.2.1. Chemical and pharmaceutical characteristics 
1.2.1.1. 
Nomenclature and structure 
Chemical name (IUPAC):  
(4Z,7Z,10Z,13Z,16Z,19Z)-3-((R)-2,4-dihydroxy-3,3-diméthylbutanamido) 
propyl 
docosa-
4,7,10,13,16,19-hexaenoate 
Structural formula: 
O
O
O
O
NNHH
O
O
OHH
O
OHH
 
Laboratory code: F373280 
Molecular formula: C31H49NO5 
Molecular mass: 515.7 
1.2.1.2. Physical and chemical general properties 
Appearance: Clear oily viscous liquid 
Solubilities:  
− Water: Practically insoluble 
− Alcohol: Very soluble  
− Trimethylpentane: Slightly soluble  
1.2.2. Non-clinical Data 
Non-clinical data are exhaustively detailed in the Investigator’s brochure [1]. A brief summary is 
provided below. 
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1.2.2.1. 
Pharmacological profile 
F373280 (mono-ester of panthotenic alcohol and DHA) is a novel pro-drug of DHA which exerts 
antiarrhythmic properties by interacting with the electrical and structural remodelling of the atria.  
Experimental investigations were conducted in HEK293 cell line transfected with human Kv1.5 
channel using the whole cell patch clamp technique to evaluate whether F373280 could block the 
sustained component of IKv1.5. F373280 concentration-dependently reduced Kv1.5 channel activity 
with an IC50 value of 13.7 µM. 
The effects of F373280 on atrial effective refractory period were investigated in anesthetized pig 
using a conventional pacing protocol through epicardial electrodes placed on the left atrium. 
F373280 administered as a bolus and an infusion (10 mg/kg) significantly increased atrial 
effective refractory period (23.8 ± 2.2 ms versus -7.3 ± 11.5 ms in the presence of vehicle, p < 
0.05). In addition, F373280 was devoid of significant effect on the hemodynamic and the 
electrocardiogram (ECG) intervals.  
Proof of the pharmacological concept was performed with a different DHA derivative named: 
Nicotinyl ester of DHA (pro-drug based on DHA delivery). Ventricular tachypacing-induced 
congestive heart failure provides a clinically-relevant animal model of AF associated with 
structural remodelling, as is often seen clinically. It has been shown that sustained oral PUFA 
administration suppresses congestive heart failure-induced AF-promotion and fibrosis in the 
ventricular tachypacing canine model. Nicotinyl ester of DHA was tested in this model, at 1 g/day 
and 5 g/day, during 4 weeks, to prevent congestive heart failure-related atrial structural 
remodelling and AF promotion in dogs. Nicotinyl ester of DHA dose dependently reduced heart 
failure-induced increases in AF duration (989 ± 111 sec, n=5 in the presence of placebo versus 
637 ± 196 sec, n=5 in the presence of 1 g/kg/d Nicotinyl ester of DHA and 79 ± 51 sec, n=5, in 
the presence of 5 g/kg/d Nicotinyl ester of DHA). The protective effect of Nicotinyl ester of DHA 
was associated with a marked increase of plasma level of DHA and important incorporation of 
DHA in the left atrial tissue. Because F373280 similarly to Nicotinyl ester of DHA increases 
plasma level of DHA, it could be estimated that the compound may exert a similar protective 
effect [1]. 
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1.2.2.2. 
Safety pharmacology 
A battery of safety pharmacology studies was performed to evaluate the effects of F373280 on the 
central nervous, cardiovascular and respiratory systems. Data of these studies are exhaustively 
detailed in the Investigator’s brochure [1]. 
No particular alerts were evidenced with F373280. 
1.2.2.3. 
Toxicology profile 
Concerning the toxicological data, 4-week and 26-week repeat-dose studies in rat and dog were 
performed. Compared to the high administered doses of F373280 (500 to 2000 mg/kg/day), low 
circulating concentrations of F373280 were measured.  
During these toxicity studies, no toxicity was observed in rat after 4 and 26 weeks of dosing and 
in dog after 4 weeks of dosing. A NOAEL of 2000 mg/kg/day was established in these repeat 
toxicity studies.  
During the 26-week toxicity study in dogs, the NOAEL was set at 1000 mg/kg/day based on 
changes observed on red blood cell parameters. 
Based on toxicological profiles, F373280 is considered to support the proposed clinical trial. 
1.2.2.4. 
Pharmacokinetic data  
According to animal studies described in the Investigator’s brochure [1], the non-clinical 
pharmacokinetic profile of F373280 is not associated with particular alerts concerning the 
proposed clinical phase IIa study. 
1.2.3. Clinical data 
Part A: Single dose 
Six consecutive single ascending doses were tested (0.5 g, 1 g, 2 g, 4 g, 8 g and 16 g) on 6 
independent cohorts of 8 subjects (6 verum + 2 placebo). 49 subjects were treated and 48 
completed the study. 
No Serious Adverse Events (SAE) occurred in the course of the study. 
Regarding the reported Treatment Emergent Adverse Events (TEAEs) that were judged by the 
Investigator as having a causal relationship with the study drug administration in the absence of 
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an alternative explanation, 3 TEAEs were observed in the placebo group (palpitation, dizziness in 
standing position, symptomatic orthostatic hypotension without loss of consciousness) and 4 in 
the group of F373280 at the dosage of 16 g (meteorism, liquid stool, symptomatic orthostatic 
hypotension and dizziness in standing position). None of these adverse events (AE) were reported 
in the groups of F373280 at the dosages of 0.5 g, 1 g, 2 g, 4 g and 8 g. 
After a single administration of the different tested doses no difference between the tested product 
and placebo has been reported, regarding vital signs (heart rate, systolic blood pressure and 
diastolic blood pressure), biological parameters (related to coagulation: platelets and fibrinogen) 
and coagulation parameters (bleeding time, prothrombin time/INR, activated partial 
thromboplastin time, thrombin clotting time). Variations of these parameters were within the 
physiological ranges. 
After single oral administration of F373280 from 0.5 g to 16 g in 36 young healthy male subjects 
(6 per dose level), the following was observed: 
 
- 
F373280: Whatever the tested dose there is no circulating F373280 in plasma: only few, 
sparse and non consecutive samples with quantifiable level of F373280 close to LOQ were 
observed. This confirms that F373280 is a prodrug. 
- 
Panthenol: Cmax and AUC increased with the administered dose between 0.5 and 16 g. 
Panthenol concentrations were rapidly cleared from plasma with a mean terminal half-life 
around 2 hours. 
- 
DHA: after 0.5 and 1 g, low increased in DHA plasma concentrations compared to the 
baseline levels led to a high inter-individual variability of the corresponding 
Pharmacokinetics parameters. Plasma exposure in DHA increased with the administered 
dose between 2 and 16 g with no departure from proportionality (baseline corrected 
parameters). 
 
Part B: Multiple doses 
Three consecutive repeated ascending doses (1, 2 and 4 g) were tested on 3 independent cohorts of 
12 subjects (9 verum + 3 placebo, double blind). 36 subjects completed the study. Each treatment 
was administered over a period of 28 days. Pharmacokinetic parameters were assessed over a 
period of 14 days.  
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Among the TEAE judged by the investigator as suspected to F373280, 5/9 TEAEs were classified 
according the System Organ Class in vascular system disorder with orthostatic hypotension (2 in 
the 1 g group, 1 in the 2 g group and 2 in the 4 g group) and 4/9 were classified in nervous system 
disorder with 3 dizziness (2 in the 2 g group and 1 in the 4 g group) and 1 migraine (in the 1 g 
group). These TEAEs have already been reported with PUFAs and are commonly observed in 
phase I studies. 
After a repeated administration of the different tested doses, no difference between the tested 
products and placebo was reported regarding vital signs (heart rate, systolic blood pressure and 
diastolic blood pressure), biological parameters. The assessment of coagulation parameters and 
platelet function after administration of repeated dose of F373280 did not report any bleeding 
issue. The reported changes in coagulation parameters and platelet function were within 
physiological ranges. 
After a 14-day repeated oral administration of F373280 from 1 g to 4 g, the following was 
observed: 
 Panthenol: Cmax and AUC increased with the administered dose between 1 and 4 g. No 
accumulation of panthenol in plasma was observed. 
 
 DHA: Plasma exposure increased with dose. A 2-fold accumulation in total plasma exposure 
of DHA was observed after 14 days of administration, whatever the administered dose. 
1.3. 
STUDY RATIONALE 
F373280 is a new therapy based on DHA delivery (pro-drug) developed for the maintenance of 
sinus rhythm after ECV in persistent AF patients with chronic heart failure. 
The results of a pharmacological study performed in animals evidenced that DHA reduces the 
duration of AF induced by burst pacing [1]. 
Moreover, the effectiveness of PUFAs has been proven in the following conditions: 
− Prevention of AF recurrence in patients with persistent AF in co-administration with 
amiodarone (add on therapy) [2], 
− Improvement of ventricular functional parameters, morbi-mortality and duration of 
hospitalisation in patients with heart failure [3, 4, 5]. 
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Taking into account these studies, it seems that DHA might be of therapeutic interest in the 
treatment of patients with both persistent AF and chronic heart failure. 
This phase IIa study is designed to assess the efficacy and the safety of the investigational product 
(F373280) for maintenance of sinus rhythm after ECV in patients with persistent AF and chronic 
heart failure. 
1.4. 
OVERALL RISK AND BENEFIT ASSESSMENT 
F373280 is a new pro-drug of DHA.  
DHA is a well-known long chain PUFAs with a long-term clinical experience in cardiovascular 
diseases. DHA is contained in several medicinal products such as Omacor, (1 g of Omacor 
contains about 320 mg of DHA acid) marketed by Laboratoires Pierre Fabre for 
hypertriglyceridemia and as an adjuvant treatment for secondary prevention after myocardial 
infarction. According to the summary product characteristics of Omacor [9]: 
 
- The frequencies of adverse reactions are ranked according to the following: common 
(>1/100, <1/10); uncommon (>1/1000, <1/100); rare (>1/10000, <1/1000); very rare (<1/10000), 
not known (cannot be estimated from the available data). 
- The reported adverse events are: 
• Infection and infestations: 
Uncommon: gastroenteritis 
• Immune system disorders: 
Uncommon: hypersensitivity 
• Metabolism and nutrition disorders: 
Rare: hyperglycaemia 
• Nervous system disorders: 
Uncommon: dizziness, dysgeusia 
Rare: headache 
• Vascular disorders: 
Very rare: hypotension 
• Respiratory thoracic and mediastinal disorders:  
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Very rare: nasal dryness 
• Gastrointestinal disorders: 
Common: dyspepsia, nausea 
Uncommon: abdominal pain, gastrointestinal disorders, gastritis, abdominal pain upper 
Rare: gastrointestinal pain 
Very rare: lower gastrointestinal haemorrhage 
• Hepatobiliary disorders:  
Rare: hepatic disorders  
• Skin and subcutaneous tissue disorders:  
Rare: acne, rash pruritic 
Very rare: urticaria 
• General disorders and administration site conditions: 
Rare: malaise sensation 
• Investigations: 
Very rare: white blood count increased, blood lactate dehydrogenase increased 
Moderate elevation of transaminases has been reported in patients with hypertriglyceridaemia. 
Panthenol is a well-known substance with a long-term experience in medical, nutraceutic and 
cosmetic uses. According to the summary product characteristics of a product such as 
Bépanthene (tablet indicated in alopecia) which contains panthenol (100 mg), adverse event 
observed are rare cases of urticaria and erythema [10]. Panthenol is metabolised in panthotenic 
acid, i.e. B5 vitamin. 
Concerning toxicological studies performed results can support the administration of F373280 in 
the proposed clinical phase II study without particular alert [1]. 
Any safety warning was reported during a phase I study performed with F373280 administered to 
84 healthy volunteers in single dose in a range between 500 mg and 16 g or in repeated dose 
during 28 days in a range between 1 g and 4 g. Adverse events reported and related to study 
treatment were minor to moderate. The adverse events were palpitations, orthostatic hypotension, 
dizziness, meteorism and liquid stool. Most were reported in both groups (placebo and F373280) 
without a dose relationship. The assessment of coagulation parameters and platelet function after 
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administration of repeated dose of F373280 did not report any bleeding concern: the reported 
changes in coagulation parameters and platelet function were within physiological ranges. 
Moreover, DHA has been associated with anticoagulant products in AF studies [2, 8]. The range 
of PUFAs doses tested was between 2 g to 3 g (640 mg to 960 mg of DHA) and the range of study 
durations between 6 to 12 months. This association did not report a significant side effect of 
bleeding. 
DHA has already been used in HF patients in several studies without safety concern [3, 4, 5]. The 
range of PUFAs doses tested was between 1 g to 5 g (1 g of the tested PUFAs contains about 320 
mg of DHA acid) and the range of study durations was between 3 months to 3.9 years. 
Thus, inclusion of patients with no specific antiarrhythmic treatment is acceptable. They will 
receive an anticoagulant treatment to prevent the thrombo-embolic complications of AF 
(particularly stroke) and the adequate treatments to control the heart rate and heart failure.   
In conclusion, the overall available data allow in safe conditions the treatment of patients with 
persistent AF and chronic heart failure with F373280 in safe conditions. 
2. STUDY OBJECTIVES 
2.1. 
PRIMARY OBJECTIVE 
The primary objective of the study is to assess the efficacy of F373280 on the maintenance of 
sinus rhythm after direct ECV in patients with persistent AF and chronic heart failure. 
2.2. 
SECONDARY OBJECTIVES 
The secondary objectives of the study are to assess: 
• the efficacy of F373280 on the efficiency of direct ECV 
• the effect of F373280 on echocardiographic parameters 
• the safety and tolerability of F373280 
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3. ETHICAL CONSIDERATIONS RELATING TO THE STUDY 
The trial is conducted according to Good Clinical Practices (CPMP/ICH/135/95), the National 
regulations and the Declaration of Helsinki and its subsequent amendments (see Appendix 17.1). 
This protocol and the informed consent form will be submitted for approval to independent local 
or national Institutional Review Boards/Ethics Committees before the study set up, according to 
national regulation. 
All the protocol amendments or critical events liable to increase the risks incurred by the patients 
or to compromise the validity of the study or patients' rights will be submitted to the coordinator 
and to the Ethics Committees. 
After being informed orally and in writing of all potential risks and constraints of the trial, as well 
as their freedom to withdraw their participation at any time, patients will then sign a consent form.  
A time of reflection will be given to the patients, before giving a written consent and starting the 
study procedures. 
The use of a placebo is in accordance with EMA Addendum to the guideline on antiarrhythmics 
on AF and atrial flutter (EMA/CHMP/EWP/213056/2010) [21] and is acceptable because the 
included patients will remain under the standard treatment of AF and chronic heart failure. Except 
antiarrythmics, they will receive anticoagulant (vitamin K antagonist, VKA), rate control 
treatment, chronic heart failure treatment. During the study, in case of AF recurrence or atrial 
flutter emergence that would require cardioversion or the introduction of an anti-arrhythmic 
because of intolerable and/or uncomfortable clinical symptoms for instance, patients will be 
withdrawn and the tested product stopped. These patients will be considered as treatment failure. 
In this study, patients will be carefully screened, particularly for their cardiac condition, with 
ECG, 24-hour holter monitor and echocardiographic data, and their biologic and coagulation 
condition. 
The study will be addressed only to patients requiring an ECV due to their persistent AF, in the 
following conditions: 
- ECV in patients not presenting a contra-indication 
- Anticoagulation with vitamin K antagonist (VKA) for at least 3 weeks before ECV 
- ECV will be performed in patients with AF and without dyskalemia. An INR value 
control must be performed within 24h before ECV. INR values ≥ 2 on the 3 last 
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tests performed before ECV are required. However, if only 2 INR values are ≥ 2 
among those 3 last tests, an ECV can be performed if the presence of atrial 
thrombosis 
can 
be 
excluded 
with 
an 
ECHO–TE 
(transesophageal 
echocardiography) performed on the same day (before ECV) and the patient can 
continue the study. Patients who do not revert to sinus rhythm or present an early 
AF relapse or an early atrial flutter emergence within the observation period after 
ECV will be withdrawn and the tested product stopped. 
During the whole study, patients will remain under medical control: visits in cardiology units will 
be performed throughout the study period. This follow up will include clinical signs, ECG, 
biological and coagulation parameters. Moreover, patient’s cardiac rhythm will be monitored once 
a week between visits using Trans Telephonic ECG Monitoring (TTEM) reviewed by a Central 
Reading Laboratory.  
Patients may withdraw from the study at any time without having to give a reason and can expect 
to receive regular conventional therapy. 
4. STUDY DESIGN 
4.1. 
OVERALL DESCRIPTION 
This phase IIa trial will be conducted as an international, multicentric, 24 weeks, double-blind, 
placebo-controlled, randomised, parallel group design, trial in 152 patients suffering from 
persistent AF and chronic heart failure. 
After a 1 to 4-week of run-in period without study treatment, patients will be randomised into one 
of the following treatment groups: F373280 1g or placebo for 24 weeks.  
Seven visits are planned for the study: 
- 
Visit 1 (V1): W-4 to W-1: Selection visit (7 to 28 days before the Inclusion Visit) 
- 
Visit 2 (V2): D1: Inclusion visit (start of study treatment)  
- 
Visit 3 (V3): W4 (D28-2/+7D): cardioversion visit (outpatient or hospitalization according 
to clinical practice of the centre) (installation of the Holter ECG device) 
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- 
Visit 4 (V4): W5 (D35 -2/+7D): follow-up visit (removing of Holter ECG device and 
installation of the TTEM) 
- 
Visit 6* (V6): W12 (D84 ± 7D): follow-up visit 
 
 
*see amendment PA05 dated 22OCT2014 
- 
Visit 7 (V7): W16 (D112 ± 7D) : follow-up visit 
- 
Visit 9* (V9): W24 (D168 ± 7D): final study visit 
 
 
*see amendment PA05 dated 22OCT2014 
4.2. 
DISCUSSION OF THE STUDY DESIGN 
4.2.1. Choice of the Study Population 
The target indication of F373280 will be the maintenance of sinus rhythm after cardioversion of 
patients with persistent AF and chronic heart failure. In the present proof of concept study, the 
evaluation will focus on patients within this indication. This target population is justified by: 
- 
The proved efficacy of PUFAs in patients with persistent AF with or without heart failure 
in co-administration with amiodarone (add on therapy) [2] 
- 
The proved efficacy of PUFAs on the improvement of ventricular functional parameters, 
morbi-mortality and duration of hospitalisation in patients with heart failure [3, 4, 5] 
The study aim is to investigate the product effect in patients with: 
- 
Previous history of persistent AF with duration of the current episode from 7 days to 6 
months. 
- 
A systolic heart failure defined by a reduced left ventricular ejection fraction (≥ 30% and ≤ 
45%) or for patients with a LVEF > 45%: 
• an increased left ventricular end-diastolic size (diameter ≥ 60 mm and/or > 32 
mm/m² and/or volume > 97 ml/m²),  
• and/or an increased left ventricular end-systolic size (diameter > 45 mm and/or > 
25 mm/m² and/or volume > 43 ml/m²),  
• and/or a reduced left ventricular outflow tract velocity time integral < 15 cm [23, 
24].  
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According to a sub-group analysis performed in patients with persistent AF associated to 
heart failure (Nodari S. personal data), PUFAs would be effective to prevent recurrence of 
AF after cardioversion in patients with moderately abnormal LVEF. 
- 
A Left Atrial Area (LAA) not severely abnormal (no greater than 40 cm2 as defined in the 
report from the American Society of Echocardiography’s Guideline) [23]. According to a 
sub-group analysis performed in patients with persistent AF associated to heart failure 
(Nodari S. personal data), PUFAs would not be effective to prevent recurrence of AF after 
cardioversion of patients with severely abnormal LAA. 
For the successful rate of ECV, patients should have a stable medical treatment of heart failure 
and should not have any myocardial infarction or unstable angina or unstable ischemic 
coronaropathy assessed by coronarography or cardiac stress test (Echo stress, exercise stress test, 
nuclear or MR perfusion evaluation methods) within 6 months before selection.  
4.2.2. Choice of the Study Design 
As the target indication would be the prevention of AF recurrence after ECV, the study design 
meets 
the 
requirements 
of 
EMA 
guideline 
on 
antiarrhythmics 
in 
AF 
(EMA/CHMP/EWP/213056/2010) [21]. 
As F373280 aims to be a safe treatment for the prevention of AF recurrence, it will not be tested 
as an add-on therapy during the study. To avoid any interaction with the tested product, 
antiarrhythmics class I and III will be forbidden during the study. 
The study design is defined in order to avoid methodological bias. A double blind study is 
appropriate to assess the efficacy and safety of the use of F373280 to prevent recurrence of AF 
episodes. Moreover, this study design is similar to the design of almost all trials that have assessed 
intervention for rhythm control [2, 8, 11, 12].  
According to the target indication, only patients with persistent AF and requiring an ECV will be 
included in order to assess the time to first documented recurrence of AF (or emergence of atrial 
flutter) since cardioversion. 
To confirm the persistent nature of AF, a 24-hour holter monitoring will be performed during the 
selection visit.  
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Eligible participants will enter a selection phase in which anticoagulant treatment (VKA) will be 
adjusted to achieve ideally an International Normalized Ratio (INR) of 2 to 3 before ECV. 
According to guidelines for the management of AF [6], VKA should be given at least 3 weeks 
before cardioversion because of risk of thrombo-embolism due to post-cardioversion.  
Experimental data suggest that the maximal incorporation of n-3 PUFAs in the myocardial cell 
membrane takes up to 28 days to occur [22]. In addition, as shown in Nodari’s study [2], the 
duration of pre-treatment with PUFAs before cardioversion appears to be a contributing factor in 
success. Therefore, before starting follow up for the assessment of AF recurrence, treatment with 
F373280 should be started 28 days before ECV.  
Detection of AF recurrence will be performed using systematic (scheduled) ECG recording, thus 
allowing detection of asymptomatic (about 50% of episodes) as well as symptomatic AF episodes. 
According to previous studies, most of AF recurrences occurred during the first days after 
cardioversion [11, 15]. So that, the heart rhythm will be closely monitored during the first week 
after successful cardioversion using an ambulatory continuous 7-day holter ECG recording in 
order to increase sensibility to detect asymptomatic AF episodes. Thereafter, to improve patient 
compliance, this follow up will be continued using an easier device to carry and to use, i.e. a 
TTEM.  
Finally, during the study, patients will be scheduled for a clinical visit every 4 weeks or 8 weeks 
(with an additional visit 7 days after visit 3 (ECV visit)) in order to ensure a close medical 
monitoring and to assess efficacy and safety parameters. 
4.2.3. Choice of the Dose  
According to a previous study in patients with AF [2], the tested PUFA product (Omacor) at the 
dose of 2 g (i.e. 640 mg of DHA acid) was effective in the prevention of AF after cardioversion. 
Moreover, PUFAs at dosage of 1 g and 2 g were also effective on the improvement of ventricular 
functional parameters, morbi-mortality and duration of hospitalisation in patients with heart 
failure [3, 4, 5].  
From the F373280 phase I study, after a 14-day repeated administration of F373280 (1 g/day), 
observed plasma concentrations of DHA measured before treatment (Cmin) were similar to that of 
an effective dose of Omacor at 2 g/day (60 to 95 mg/ml and 60 to 90 mg/ml, respectively) (phase 
I study of F373280 and [16]). With regard to the rhythm of administration, mean peak/trough 
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fluctuation (baseline corrected) was around 0.3. This value supports a once-daily administration 
allowing a 24-hour plasma exposure in DHA. Therefore, a 1 g daily dose of F373280 is 
considered to be appropriate for this proof of concept study. 
4.2.4. Choice of the Sample Size 
See chapter 13. 
5. STUDY POPULATION 
Each patient fulfilling all the inclusion criteria and none of the non inclusion criteria will be 
eligible. 
5.1. 
INCLUSION CRITERIA 
Demographic Characteristics and Other Baseline Characteristics: 
1. Men or women aged more than 18 years (inclusive) 
2. Patient with current episode of persistent AF between 7 days and 6 months duration for whom 
electrical cardioversion is warranted 
3. Previous history of first documented episode of persistent AF  
4. Previous history of ischemic or non ischemic heart failure 
5. NYHA class I or II chronic heart failure at selection and at inclusion 
6. Left ventricular systolic dysfunction defined at selection and at inclusion by a reduced left 
ventricular ejection fraction (LVEF) ≥ 30% and ≤ 45% or for patients with a LVEF > 45%: 
• an increased left ventricular end-diastolic size  
(diameter ≥ 60 mm and/or > 32 mm/m² and/or volume > 97 ml/m²) 
• and/or an increased left ventricular end-systolic size 
(diameter > 45 mm and/or > 25 mm/m² and/or volume > 43 ml/m²) 
• and/or a reduced left ventricular outflow tract velocity time integral < 15 cm 
7. On appropriate, stable medical treatments for heart failure, including a diuretic and/or 
angiotensin-converting enzyme, and/or angiotensin-receptor blocker and/or mineralocorticoid 
receptor (MR) antagonists, and/or betablockers 
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8. Left atrial area ≤ 40 cm² at selection and at inclusion 
9. Patient treated or having to be treated by vitamin K antagonist 
10. For female patient of child-bearing potential:  
• In all the countries except Italy: 
 
- 
Use of an effective method of contraception (hormonal contraception or intra-uterine 
device) assessed by the investigator for at least 2 months before the selection in the 
study and agreement to go on using it during the whole duration of the study and up to 
1 month after the last dose of the study treatment or 
- 
Documented as surgically sterilized 
• In Italy only: 
- 
Absolute abstention from sexual intercourse during the whole duration of the study and 
for a month after the end of the study or 
- 
Use of double barrier contraception method (use of effective medical contraception 
method) from at least 2 months before the start of the study to the entire duration of the 
study and for a month after the end of the study or 
- 
Documented as surgically sterilized  
 
11. For female patient of child-bearing potential: negative urine pregnancy test at inclusion 
12. For male with a child-bearing potential partner (In Italy only): 
- 
Absolute abstention from sexual intercourse during the whole duration of the study and 
for 3 months after the end of the study or 
- 
Use of double barrier contraception method (use of condom for male and effective 
contraception method for the partner) from the entire duration of the study to 3 months 
after the end of the study. 
 
Ethical /legal considerations: 
13. Having signed his/her written informed consent, 
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14. Affiliated to a social security system, or is a beneficiary (if applicable in the national 
regulation) 
5.2. 
NON INCLUSION CRITERIA 
Criteria related to pathologies: 
1. No previous history of first documented episode of persistent Atrial Fibrillation 
2. More than two successful cardioversions (electrical or pharmacological) in the last 6 months, 
3. Secondary Atrial Fibrillation due to alcohol or severe valvular heart disease (grade III to IV), 
4. NYHA class III or IV heart failure at selection or at inclusion 
5. Thyroid disease uncontrolled by treatment: TSH ± T4L ± T3L to be checked in case of 
treatment for thyroid disease  
6. Myocardial infarction or unstable angina or presence of unstable ischemic coronaropathy 
assessed by coronarography or cardiac stress test (Echo stress, exercise stress test, nuclear or 
MR perfusion evaluation methods) within 6 months before selection 
7. Severe chronic kidney disease (creatinine ≥ 25 mg/L or estimated glomerular filtration rate < 
30 ml/min) at selection 
8. Bradycardia (HR ≤ 50 bpm) 
9. Hyperkalemia or hypokalemia (according to the standards of local laboratories) at selection 
10. Cardiac surgery within 3 months before selection or planned during the study duration 
Criteria related to treatments: 
11. Previously ineffective pharmacological or electrical cardioversion 
12. Concomitant treatment with ranolazine or any anti-arrhythmic drug (within 7 days prior to 
selection), except amiodarone, dronedarone and stable dose of digoxin, beta-blockers, 
calcium-blockers. 
13. Concomitant treatment with oral amiodarone or dronedarone from selection  
14. Concomitant treatment with intravenous amiodarone from selection  
15. Patient requiring a cardiac resynchronization therapy (CRT) or having undergone CRT 
implantation within the last 6 months 
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16. Treatment with any Polyunsaturated Fatty Acid within the last 3 months 
17. Dietary supplement with ω3 or ω6 according to investigator’s judgment 
18. Having undergone any form of ablation therapy for AF 
19. Patient treated with oral anticoagulant treatment other than vitamin K antagonist: new oral 
anticoagulants (dabigatran, rivaroxaban, apixaban), or treated with irreversible antiplatelet 
agents P2Y12 inhibitors such as ticlopidine, clopidogrel or prasugrel  
Others criteria:  
20. Patient liable not to comply with protocol instructions and/or with treatment, in the 
investigator’s opinion, 
21. Patient having taken part in a clinical trial in the preceding 2 months or taking part in a trial at 
the time of selection, 
22. Patient linguistically or mentally unable to understand the nature, objectives and possible 
consequences of the trial, or refusing to patient himself / herself to its constraints, 
23. Patient family member or work associate (secretary, nurse, technician…) of the Investigator, 
24. Patient having forfeited his / her freedom by administrative or legal award or being under 
guardianship, 
25. Breastfeeding female patient. 
5.3. 
NUMBER OF PATIENTS 
76 x 2 patients (taking into account 15 % of non evaluable patients). 
5.4. 
RECRUITMENT MODALITIES 
Patients will be recruited within the medical consultation of each centre involved in the study. If 
necessary and when authorized by local and national regulation, some specific supports or tools 
will be used to improve the recruitment (announcement, mailing to general practitioners, leaflet, 
website including ClinicalTrials.gov, CRO…). 
Before implementation, the documents will be submitted to and approved by the Ethics 
Committee. 
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5.5. 
 PATIENT IDENTIFICATION 
Patient's code will contain 7 digits: the 2 first digits corresponding to the country number, the 
following 2 digits corresponding to the centre number and the last 3 digits corresponding to the 
patient's chronological order once having signed the written informed consent. 
5.6. 
WITHDRAWAL CRITERIA 
Reasons for a patient's premature withdrawal from the study may be the following: 
• Patient's decision. A patient who wishes to withdraw from the study for any reason may 
do so at any time but must inform the investigator. In all cases, the Investigator should 
attempt to contact the patient as soon as possible for a final assessment in order to: 
- have the patient's decision written on the consent form 
- obtain the reason(s) for withdrawal and report it/them in the case report form 
- evaluate the patient's clinical condition 
- if necessary, take appropriate therapeutic measures: management of an adverse 
effect or concomitant disease, prescription of another treatment. 
• Investigator's decision in the patient's interest, particularly if a serious adverse event 
occurs and is considered by the Investigator liable to threaten the health of the patient. The 
monitor will be informed by phone or fax and a letter or report explaining the withdrawal 
will be forwarded to the monitor as soon as possible. 
• Erroneous inclusion according to the study protocol. The decision to maintain or not the 
patient in the study will be taken jointly by the investigator and the sponsor. Erroneous 
inclusions will not be paid to the investigator. 
• Patients who could not be treated with VKA for at least 3 weeks before ECV or who will 
experience a VKA intolerance during the study. 
• Patients without dyskalemia who will not have INR values ≥ 2 on the 3 last tests 
performed before ECV should not have an ECV and will be excluded from the study. 
However, if only 2 INR values are ≥ 2 among those 3 last tests, an ECV can be performed 
if the presence of atrial thrombosis can be excluded with an ECHO–TE (transesophageal 
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echocardiography) performed on the same day (before ECV) and the patient can continue 
the study.  
• Patients who will not revert to sinus rhythm (i.e. unsuccessful ECV) or with early AF 
relapse or early atrial flutter emergence within the observation period after ECV will be 
considered to have finished follow-up. 
• Occurrence of AF recurrence or atrial flutter emergence that would require, at the 
investigator’s judgement, a cardioversion or an introduction of an anti-arrhythmic because 
of intolerable and/or uncomfortable clinical symptoms for instance. 
5.7. 
REPLACEMENT OF PATIENTS 
Withdrawn patients will not be replaced. 
5.8. 
POST-STUDY EXCLUSION PERIOD  
Patients will not be allowed to participate in another clinical trial during 3 months following the 
study termination. 
5.9. 
STUDY CARD AND LETTER FOR GENERAL PRACTITIONER(S) 
The patient will receive from the Investigating Centre at Visit 1 - Selection Visit:  
- a personal card to be kept all along the study duration and providing the following information: 
patient's name, sponsor's name, study code, EUDRACT number, start date and expected end date 
of the study, complete address of the Investigating Centre with the name and phone number of the 
Investigator and a sponsor 24H/24 phone contact number in case of emergency (French and 
English languages): 33 (0)5 63 35 25 83. For Italy, this card will be in Italian only, without any 
English mention. 
- in Italy, a letter to be given to his/her general practitioner. This letter intends to inform the 
general practitioner(s) (and any other doctors who take care of the patient) that the patient 
participates to the clinical study. It describes the study treatment and includes some information 
on the forbidden treatment during the study.  
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6. STUDY TREATMENT 
The Clinical Pharmacy Department of the Institut de Recherche Pierre Fabre (IRPF) will supply 
the investigational centres with the treatment necessary for the conduct of the trial.  
6.1. 
SOURCE, PRESENTATION AND COMPOSITION OF 
 
INVESTIGATIONAL PRODUCT 
F373280 and placebo will be prepared in Soft Capsules similar presentation.  
• F373280 
Formulation of F373280, 1 g, Soft Capsules: oral administration, oblong size 20, off-white, Soft 
Capsules containing: Panthenyl ester of DHA, gelatine, glycerol, titanium, dioxide, purified water. 
• Placebo 
Formulation of placebo matching tested product, Soft Capsules: oral administration, oblong size 
20, off-white, Soft Capsules containing: paraffin liquid, fish flavour, gelatine, glycerol, titanium, 
dioxide, purified water. 
 
Placebo and F373280 capsules will be packaged in opaque blisters. 
6.2. 
PACKAGING AND LABELLING 
The treatment units will be packed and labelled by the Clinical Pharmacy Department of the IRPF 
according to European Directive and local requirements. 
6.2.1. Packaging 
Each treatment unit will be composed of 3 cases for a 12-week treatment period. 
Two 12-week treatment units will contain 3 cases, each case of 4-week treatment containing:  
10 blister packs of four 1 g F373280 soft capsules or 1 g placebo soft capsules each. 
6.2.2. Labelling 
Investigational Products will be labelled according to the following rules: 
Labelling should comply with the local requirements for Investigational Medicinal Products. 
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On the treatment units and cases, the labels will bear the following indications:  
a) name and address of the sponsor 
b) protocol number 
c) packaging batch number 
d) treatment number 
e) storage conditions 
f) expiry date 
g) pharmaceutical dose form 
h) route of administration 
i) quantity of dosage units 
j) direction for use 
k) legal statements:  
    -“for clinical trial only”, “keep out of the reach and the sight of children”, “please return to 
your doctor any unused product”, respect the prescribed dose” 
On the treatment unit, another label will be affixed with the mention of the Investigator’s name 
and patient’s code (completed by the Investigator). 
In addition, on each case will be mentioned the case number and a detachable label will bear the 
following indications: 
− Protocol number 
− Packaging batch number 
− Expiry date 
− Case number 
− Treatment number 
On the blister pack, the label will mention the protocol number, the packaging batch number, the 
case number and the treatment number. 
6.3. 
DISTRIBUTION TO CENTRE AND STORAGE 
The Clinical Pharmacy Department of the IRPF will supply the Investigational Centre with the 
treatment units along the study according to the need, upon request triggered by the patient’s 
selection.  
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As soon as the Pharmacist or the Investigator receives the trial medication, he/she will check the 
contents and immediately acknowledges the receipt in the IVRS/IWRS. The copy of the 
acknowledgement will be kept in the Investigator’s or the Pharmacist’s file. The same procedure 
will be applied to all further supplies during the course of the trial. 
At the time of the delivery to the Centre, the following information will be provided: 
• Details of storage conditions that should be respected 
• And, upon request and for the 1st delivery only, a letter of release for the Investigational 
Medicinal Product from the Sponsor's Qualified Person 
The CRA will ensure during the monitoring visits that trial medications have been received in 
good conditions and the acknowledgment of receipt has been performed adequately. 
Treatment units should remain intact until dispensation to the patients. They should be kept at 
temperature below 30°C in an appropriate lockable room only accessible to the person authorised 
to dispense them, under the responsibility of the Pharmacist or the Investigator. 
In the case of undue delay in study execution, the Pharmacist or the Investigator should ensure 
that the expiry date has not been exceeded.  
6.4. 
ALLOCATION OF TREATMENTS AND DISPENSATION TO PATIENT 
A randomisation list will be established by the Clinical Pharmacy Department of the IRPF. This 
list will be computer-generated with internal software. The randomisation methodology is 
validated by the Biometry Department before generation. 
Treatments F373280 or placebo will be balanced in a 1:1 ratio. 
As the treatment units are prepared for 12-week treatment periods, the Investigator will have to 
allocate a treatment number at inclusion visit (V2) and another one at visit 6.  
For each patient, the treatment number given at visit 6 will not be the same that the one given at 
inclusion visit (V2). 
The treatment numbers will be given through the IVRS/IWRS. 
At selection visit (V1), practically, once patient’s eligibility is confirmed:  
• The Investigator: 
− Contacts the IVRS/IWRS 
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− Answers the questions related to the patient  
• The IVRS/IWRS company: 
− Confirms this information by fax/email to the Investigator 
− Fills the “Request for Delivery of Investigational Product” form and sends it by email 
and/or fax to the Clinical Pharmacy Department of the IRPF.  
• The Clinical Pharmacy Department of the IRPF sends the corresponding treatment unit to 
the Investigator within 5 days from reception of the email request form. 
 
At inclusion visit (V2), the treatment number to be allocated for the first 12-week period to the 
patient is given by the IVRS/IWRS.  
At visit 6, the Investigator will contact again the IVRS/IWRS to obtain the treatment number for 
the last 12-week period of treatment. 
The Investigator will dispense to the patient the 4-week treatment cases (one or two according to 
the visit) which label indicates the treatment number and the administration period. 
6.5. 
DRUG ADMINISTRATION 
6.5.1. Duration of Treatment 
For a patient completing the study, the theoretical study treatment exposure to F373280 or 
placebo will be 24 weeks. 
If the ECV is postponed by 1 week to allow INR stabilization, the treatment duration will be 25 
weeks. 
6.5.2. Dose Schedule 
One soft capsule of 1g of F373280 or placebo to be taken each day during 24 weeks. 
6.5.3. Route and Conditions of Administration 
The soft capsules are to be taken orally. One soft capsule is to be taken each evening with the 
dinner during 24 weeks.  
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6.6. 
ACCOUNTABILITY ON SITE AND RETURN/DESTRUCTION OF 
 
INVESTIGATIONAL PRODUCT 
The Investigator should maintain accurate written records of drug received, dispensed, returned 
and any remaining treatment units, on the drug accountability form. These records should be made 
available for Clinical Research Associate (CRA) monitoring. The packaging of the medication 
should remain intact until just before the dispensation. 
At each visit, the Investigator will record the number of soft capsules returned by each patient 
using the appropriate page of the e-CRF. 
At the end of the study, all used and unused treatments including packaging should be noted, and 
return is organised by the CRA to the Clinical Pharmacy Department of the IRPF for destruction. 
A copy of the drug accountability form should be provided by the Investigator to the CRA. 
6.7. 
RECALL OF INVESTIGATIONAL PRODUCTS  
In case of recall of investigational products (decided by the Competent Authorities or the 
Sponsor), the Investigator will immediately be informed by the Sponsor. 
The Investigator in collaboration with the Sponsor’s representatives (Study Manager, CRA) must 
urgently: 
• Stop the delivery of the concerned investigational products to the patients. 
• Inform the concerned patients that they must immediately stop taking these investigational 
products and bring them back. 
The Study Manager/CRA organises the return of the recalled products to the Clinical Pharmacy 
Department of the IRPF according to the Sponsor’s procedures. 
7. CONCOMITANT TREATMENTS 
Any existing concomitant treatment (at selection visit), any new concomitant treatment or change 
in the dosage of an existing concomitant treatment during the course of the study must be noted 
on the electronic Case Report Forms (e-CRF). All treatments should be evaluated by the 
Investigator at patient’s selection, and treatment prolongation or stop during the study should be 
considered. 
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For all concomitant treatments taken during the study, the following information must be noted in 
the relevant section(s) of the e-CRF: 
• The name of the treatment and its form 
• The reason for prescription 
• The route of administration 
• The daily dose 
• The duration of treatment. 
7.1. 
VITAMIN K ANTAGONIST TREATMENT 
VKA should be given for at least 3 weeks before ECV and continued for the whole study 
duration. However, VKA should be stopped in case of occurrence of VKA intolerance during the 
study and the patient should be withdrawn from the study. The VKA used will be left to the 
decision of each Investigator according to his/her local practice. 
7.2. 
PROHIBITED TREATMENTS 
- Class I and class III antiarrhythmic treatments: 
• Class I: 
o Class IA: Disopyramide, Procainamide, Quinidine 
o Class IB: Lidocaine, Mexiletine 
o Class IC: Flecainide, Propafenone 
• Class III: Dofetilide, Ibutilide, Sotalol, Amiodarone, Dronedarone. 
- Ranolazine 
- Any PUFA 
- Any oral anticoagulant treatment other than VKA: new oral anticoagulants (dabigatran, 
rivaroxaban, apixaban), or irreversible antiplatelet agents P2Y12 inhibitors such as ticlopidine, 
clopidogrel or prasugrel 
- Dietary supplement with Omega 3 or Omega 6 
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Prohibited treatments at selection must not be prescribed for the duration of the study except in 
case of occurrence of an adverse event or AF episode that requires a corrective treatment in the 
interest of the patient’s health. 
7.3. 
AUTHORISED TREATMENTS 
Other treatments will be authorised during the study duration. 
However, if medication other than study drugs is administered at any time from the start of the 
study, details must be recorded in the e-CRF. During the study, patients must be asked whether 
they have been on a course of prescribed drug treatment or have taken any OTC or herbal drugs 
since the visit. 
8. EVALUATION CRITERIA 
8.1. 
PRIMARY EFFICACY CRITERION  
8.1.1. Time to the first Atrial Fibrillation Recurrence or Atrial Flutter Emergence 
8.1.1.1. 
Definition 
Time to first AF recurrence or atrial flutter emergence is defined by the time to first episode of AF 
or atrial flutter (symptomatic or not) lasting for at least 10 minutes. 
8.1.1.2. 
Schedule 
The heart rhythm follow up will be performed from the end of ECV visit (visit 3) to the final 
study visit (visit 9).  
For randomised patients with spontaneous cardioversion before ECV, the recurrence of AF or the 
emergence of atrial flutter will be assessed after visit 3 (from week 5). 
8.1.1.3. 
Evaluation Methods 
• 7-day holter monitor: 
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The heart rhythm monitoring will be carried out from visit 3 to visit 4 using a 7-day continuous 
ECG (5-leads/2 or 3 channels) ambulatory recording (holter ECG) fixed after ECV visit.  
Following holter monitoring, the heart rhythm will be documented using Trans Telephonic ECG 
Monitoring (TTEM). 
• Trans Telephonic ECG Monitoring: 
The ECG follow up will be documented using the TTEM: one transmission per week from the day 
of visit 4 (end of week 5) to visit 9 (week 24, end of study). The patient will be requested to 
contact the Central Reading Laboratory for transmission of each stored TTEM.  
Moreover, if patient experiences AF or atrial flutter symptoms during this TTEM period, it should 
be documented using the TTEM. 
In case of AF recurrence or atrial flutter emergence and provided that the patient does not require 
a cardioversion or an introduction of an anti-arrhythmic at Investigator’s judgement, the patient 
could be maintained in the study with the treatment in order to assess a spontaneous 
cardioversion. For that purpose the patient will continue to transmit a TTEM once a week. 
• Process of centralisation of ECG (Holter and TTEM) 
ECG (Holter and TTEM) will be centralized by the Central Reading Laboratory. The ECG will be 
validated by a trained technician, then analysed by a cardiologist. The cardiologist interpretation 
will be emailed to the site (or per fax on request of the site). The investigator will be asked to 
review and sign these documents. 
The Holter and TTEM process will be fully described in separate documents. 
8.2. 
SECONDARY EFFICACY CRITERIA 
8.2.1. Numbers of AF episodes in the first week following visit 3 (ECV visit) 
8.2.1.1. 
Definition 
Number of AF episodes will consist in the assessment of AF episodes with duration at least 10 
minutes (NSup10) and of less than 10 minutes (NInf10), respectively. 
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8.2.1.2. 
Schedule 
The heart rhythm follow up will be performed from the end of successful ECV visit (visit 3) to the 
study visit 4.  
8.2.1.3. 
Evaluation Methods 
• 7-day holter monitor: 
The heart rhythm monitoring will start using a 7-day continuous ECG (5-leads/2 or 3 channels) 
ambulatory recording (holter ECG) after ECV visit from visit 3 to visit 4. 
8.2.2. 
Duration of AF episodes in the first week following visit 3 (ECV visit) 
8.2.2.1. 
Definition 
Duration of AF episodes will consist in the sum of duration of each AF episode. 
8.2.2.2. 
Schedule 
The heart rhythm follow up will be performed from the end of successful ECV visit (visit 3) to the 
follow up study visit (visit 4).  
8.2.2.3. 
Evaluation Methods 
Duration of AF episodes will be assessed using the 7-day continuous ECG (5-leads/2 or 3 
channels) ambulatory recording. 
8.2.3. 
Clinical parameters evaluation 
8.2.3.1. 
EHRA score assessment 
8.2.3.1.1. 
Definition 
AF related symptoms will be evaluated by the EHRA (European Heart Rhythm Association) score 
[20]. The following items “during presumed arrhythmia episodes" are checked to determine the 
score: palpitation, fatigue, dizziness, dyspnea, chest pain and anxiety. 
Classification of AF-related symptoms (EHRA score) are as follows: 
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• EHRA I          - ‘No symptoms’ 
• EHRA II         - ‘Mild symptoms’; normal daily activity not affected 
• EHRA III       - ‘Severe symptoms’; normal daily activity affected 
• EHRA IV       - ‘Disabling symptoms’; normal daily activity discontinued  
This classification relates exclusively to the patient-reported symptoms. 
In addition to this score, the frequency will be classified in three groups, namely occasionally 
(less than once per month), intermediate (1/month to almost daily) and frequent at least daily. 
8.2.3.1.2. 
Schedule 
EHRA evaluation will be performed in case of evocative symptoms of arrhythmia. 
8.2.3.1.3. 
Evaluation Methods 
EHRA evaluation will be collected by Central Reading Laboratory during TTEM period. 
 
8.2.3.2. 
Time to first AF recurrence less than 10 minutes 
Time to first AF recurrence less than 10 minutes will be assessed during TTEM period. 
8.2.3.3. 
Recurrence of symptomatic AF  
Recurrence of symptomatic AF will be assessed during TTEM period. 
The number of recurrences of symptomatic AF consists of the number of AF recurrences 
associated with a symptom (palpitation, fatigue, dizziness, dyspnea, chest pain and anxiety) and 
confirmed by an ECG. 
The time to first symptomatic AF recurrence is defined by the time to first episode of 
symptomatic AF. 
8.2.3.4. 
Number and duration of hospitalizations 
• Number and duration of hospitalizations for cardiovascular events 
− Hospitalization for AF treatment 
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− Hospitalization for worsening of heart failure 
− Hospitalization for myocardial infarction 
− All cause of hospitalization 
• Number and duration of hospitalizations for thromboembolic stroke  
 
8.2.4. 
Cardioversion assessment 
• Assessment of spontaneous cardioversion before visit 3 
• Assessment of successful cardioversion at visit 3 (i.e. return to sinus rhythm) 
• Shocks distribution (1, 2 or 3 shocks) 
• Number of patients needing another cardioversion after initial ECV 
8.2.5. 
Evolution of echocardiographic parameters 
8.2.5.1. 
Definition 
The following echocardiographic parameters will be assessed: Left atrial diameter (mm), LAA 
(cm2), Left atrial volume (ml), Left atrial volume/BSA (ml/m2), LVEF (%), Left ventricular end 
diastolic volume/BSA (ml/m2), Left ventricular end systolic volume/BSA (ml/m2), Left 
ventricular end diastolic diameter (mm), Left ventricular end diastolic volume (ml), Left 
ventricular end systolic diameter (mm) and Left ventricular end systolic volume (ml). 
8.2.5.2. 
 Schedule 
Measurements will be performed at visit 1 and visit 2 to check the eligibility of the patient.  
Measurements performed at visit 4, visit 6 and visit 9 are done to follow the echocardiographic 
evolution of the patients in sinus rhythm. 
8.2.5.3. 
Evaluation method 
The echography evaluations will be carried out according to the recommendations for chamber 
quantification drawn up by the American Society of Echocardiography and the European 
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Association of Echocardiography [23]. So, the recommended method for volume measurements is 
to use the biplane method of discs (modified Simpson’s rule) from 2-D measurement. 
8.3. 
BIOMARKER ASSESSMENT: RED BLOOD CELL 
 
CONCENTRATIONS OF DHA 
8.3.1. Definition 
Because of the limited human tissue accessibility for biopsy, red blood cell DHA contents is a 
marker of tissue DHA concentration [13], [14]. 
8.3.2. Blood samples 
8.3.2.1. 
Collection schedule 
Blood samples will be collected to determine the red blood cells (RBC) concentrations of DHA.  
Blood samples will be performed at visit 2 before treatment, visit 3, visit 6 and visit 9. 
Actual sampling times will be individually reported in the e-CRFs. 
8.3.2.2. 
Technical handling 
Two blood samples (2 x 4 ml) will be collected in EDTA tubes. They will be homogenized slowly 
by inverting the tube without shaking, stored between +2°C/+8°C in a fridge (no freezing will be 
allowed) and sent to Analytical Centre in refrigerated conditions (between +2°C and +8°C). 
Analysis will be performed within 2 weeks following reception at the Analytical Centre. 
8.3.3. DHA concentration measurement 
Analytical determination of RBC concentrations of DHA will be carried out by the Analytical 
Centre. 
Lipids will be extracted from red blood cells samples with a mixture of hexane/isopropanol after 
acidification [17]. Total lipid extracts will be saponified and methylated. The fatty acid methyl 
esters (FAME) will be extracted and analyzed by Gas Chromatography. 
Identification of FAME will be based on retention times obtained for FAME prepared from fatty 
acid standards. The area under peaks will be determined using ChemStation Software (Agilent) 
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and results will be expressed as % of total fatty acids. DHA concentration will be calculated using 
the internal standard and expressed as µg/g for red blood cells samples. Thus, omega-3 index will 
be assessed. The omega-3 index represents the content of EPA plus DHA in red blood cells 
(expressed as a percent of total fatty acids). It is a biomarker considered as a new marker of risk 
for death from coronary disease [18]. 
Results of this analytical determination will be kept confidential by the dosing centre until the end 
of the study, and will be provided only at the end of the study (after database lock) in a separate 
file. 
8.4. 
SAFETY ASSESSMENT 
8.4.1. Adverse Events 
At selection, any concomitant disease will be reported on the e-CRF. At each further visit, the 
occurrence of AEs since the last visit will be based on the patient's spontaneous reporting, the 
Investigator's non-leading questioning and his/her clinical evaluation. All AEs will be reported on 
the e-CRF (see section 10). 
8.4.2. Laboratory Investigations 
8.4.2.1. 
Schedule 
Laboratory investigations will be performed at visit 1 (before treatment) and visit 9 (end of 
treatment) or End of Treatment visit. 
At visit 3 and 6, only a standard haematologic dosage will be performed.  
Furthermore the kalemia will be checked before electrical cardioversion at visit 3. 
The total volume of blood samples taken for haematology and biochemistry analysis should not 
exceed 30 ml. 
8.4.2.2. 
Technical Procedures and Parameters 
The following tests will be performed: 
 
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Haematology: 
haematocrit, haemoglobin, RBC count, white blood cells (WBC) count, WBC 
differential counts (% and/or absolute), reticulocytes, platelets.  
 
Biochemistry: 
sodium, potassium, bicarbonate, chloride, alkaline phosphatase, gamma GT, 
albumin, total bilirubin, conjugated bilirubin, creatinine, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), fasting glucose, 
total cholesterol, cholesterol (HDL, LDL), triglycerides, creatine 
phosphokinase (CPK), fibrinogen. 
Blood samples will be taken in the morning in fasting conditions.  
The estimation of GFR at selection relies on the measurement of serum creatinine and the 
Cockcroft- Gault formula: 
Cockcroft-Gault formula 
- with serum creatinine expressed as mg/L:  
in men: 
GFR (ml/min) = [(140-age) x weight / (7.2 x serum creatinine in mg/L)] 
 
in women: 
GFR (ml/min) = [(140-age) x weight / (7.2 x serum creatinine in mg/L)] x 0.85 
 
- with serum creatinine expressed as μmol/l: 
GFR (ml/min) = [(140-age) x weight / serum creatinine in μmol/l] x k,where k = 1.23 for men, 
1.04 for women. 
 
(weight in kg, age in years) 
Additional tests may be done at the Investigator’s discretion, in the patient’s interest. In case of 
any abnormal and/or clinically significant results, the Investigator should order laboratory control 
tests. 
8.4.3. Global Physical Examination 
A global physical examination including the measurement of body weight will be carried out on 
each body system at visit 1, visit 2, visit 3, visit 6, visit 7, and visit 9. 
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The Body surface area (BSA) will be calculated at the same visits using Mostellers’ formula: 
BSA = [(Weight x Height)/3600]1/2 
(Weight in kg, height in cm) 
The physical examination will be globally evaluated as “normal/abnormal”. Further target 
inspection will be undertaken for any abnormal finding. 
8.4.4. Vital Signs 
Vital signs will consist in blood pressure and heart rate at rest.  
8.4.4.1. 
Schedule 
Vital signs will be measured at each visit. 
8.4.4.2. 
Technical Procedure and Parameters 
Systolic blood pressure (SBP) and diastolic blood pressure (DBP), expressed in mmHg, will be 
measured after at least 5 minutes in supine position and after 2 minutes in standing position.  
The heart rate (HR), expressed in beats per minute (bpm), will be measured by auscultation by 
counting the beats for at least 30 seconds, after at least 5 minutes in supine position and after 2 
minutes in standing position. 
Bodyweight will be measured with patient in underwear and with the same balance at each visit.  
8.4.5. Electrocardiogram (ECG)  
8.4.5.1. 
Schedule 
An ECG will be recorded after at least 10 minutes of rest at visit 1, visit 2, visit 3, visit 6, visit 7, 
and visit 9 using a usual standardised 12-lead cardiograph. 
8.4.5.2. 
Technical Procedure and Parameters 
• Electrocardiogram: 
The global interpretation from manual reading (normality, clinical relevance) and HR (bpm), PR 
(ms), QRS (ms), QT (ms), QTcB (ms), QTcF (ms), repolarisation patterns will be reported in the 
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e-CRF. Each print-out will include the patient’s code, date, time, technician's initials and 
investigator's signature. 
In case of thermic paper ECG print out, a photocopy will be made by the centre to ensure safe 
filing. 
• 24 hour-Holter - ECG 
An ambulatory continuous 24-hour ECG (5-leads/2 or 3 channels) will be recorded at selection 
visit using a holter ECG, in order to confirm persistent AF.  
8.4.6. Coagulation parameters 
Coagulation assessment will be evaluated by the following parameters: 
− Prothrombin Time/INR (PT/INR) 
− Activated Partial Thromboplastin Time (aPTT) 
− Thrombin Clotting Time (TCT) 
The recommendations for the controls of INR are the following [25, 26]: 
1) During the pre-cardioversion period, if the anticoagulation by VKA has to be initiated, the 
treatment must be initiated at least 3 weeks prior to cardioversion then the INR will be monitored 
as follow:  
− The adjustment of the dosage of VKA should be performed stepwise by controlling INR 2 
to 3 times a week until stabilization within the target range (2 - 3) on 2 successive tests. 
− When the INR is within the target range (2 - 3) on 2 successive tests, the dose of VKA 
should be maintained. Then the controls of INR will be progressively spaced within a few 
weeks.  
− When INR is stabilized, at least one test should be performed each week. 
− In all cases, an INR control must be performed within 24 h before ECV. 
2) During the pre-cardioversion period, if the anticoagulation by VKA was already initiated, the 
INR will be monitored as follow: 
− One INR per week up to ECV 
− An INR control must be performed within 24 h before ECV 
3) After cardioversion : one INR every 4 weeks 
4) Throughout the duration of the study if INR > 3 the advocated actions are: 
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− No transesophageal echocardiography before cardioversion 
− For asymptomatic patients:  
- 3 < INR < 4: no omission of VKA (dose adjustment if required), no vitamin K 
- 4 ≤ INR < 6: omit one dose of VKA, no vitamin K 
- 6 ≤ INR < 10: interrupt VKA, vitamin K 2 mg orally 
- INR ≥ 10: interrupt VKA, vitamin K 5 mg orally 
For INR ≥ 6, an adverse event has to be reported (asymptomatic overdose).  
Anti-coagulation by VKA should be given at least 3 weeks before ECV and continued for the 
whole study duration. 
aPTT and TCT will be performed at visit 1, visit 2, visit 3, visit 6, visit 7, and visit 9. 
The quantity of blood samples collected at each time for coagulation parameters will be 2 ml. 
Additional tests may be done at the Investigator’s discretion, in the patient’s interest. In case of 
any abnormal and/or clinically significant results, the Investigator should order laboratory control 
tests. 
8.5. 
CONCOMITANT TREATMENTS 
Concomitant treatments will be evaluated at each study visit. 
Requirements related to patient's concomitant treatments started before selection visit and 
continued throughout the trial, or started during the trial, can be found in section 7.  
8.6. 
COMPLIANCE 
The patient will be reminded at each visit to bring back at the following visit any used or unused 
remaining soft capsule, blister and case. 
At each visit (except at visit 4), the Investigator will record the number of supplied and remaining 
soft capsules in the e-CRF. 
9. STUDY PROCEDURES 
Visit 1 - Selection Visit (Week - 4 to Week -1): 
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The patient considered eligible for selection by the Investigator will be informed of the 
characteristics and the consequences of the trial both verbally and by reviewing the patient's 
information sheet and consent form (see section 14.3). If the patient accepts to participate in the 
study, he/she will sign the informed consent form and will keep a copy. 
The patient will be assessed for the following: 
• Demographic characteristics (gender, age, height, body surface area) 
• Personal and medico-surgical history 
• Habits (Tobacco, alcohol consumption, dietary habits including fish consumption…) 
• Cardiovascular diseases, mainly detailed history of Heart Failure and AF characteristics  
• Echocardiography using a two-dimensional echocardiography 
• 12-lead ECG 
• Concomitant diseases, adverse signs or symptoms (able to be used for treatment emergent 
AE determination) 
• Concomitant treatments (authorised, disallowed) 
• Global physical examination/bodyweight 
• Vital signs 
• Biology: haematology, biochemistry, assessment of coagulation parameters: Prothrombin 
Time/INR (PT/INR), Activated Partial Thromboplastin Time (aPTT), Thrombin Clotting 
Time (TCT) 
• Biology assessment of renal function: creatinine or estimated glomerular filtration rate 
If the results of the above assessments are compatible with the selection criteria: 
• A 24-hour continuous ECG ambulatory recording (Holter ECG) device will be installed 
on the patient to monitor the patient heart rhythm. The patient will be requested to bring 
back the device after the termination of 24 hours recording. The recording will be 
transmitted from the Investigational site to the Central Reading Laboratory. The Central 
Reading Laboratory will send his/her assessment regarding the confirmation of persistent 
AF within 2 working days to the Investigator. 
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• The patient will enter the selection and pre-cardioversion periods in which anticoagulant 
(VKA) will be adjusted to achieve ideally an International Normalized Ratio (INR)  in the 
range of 2 to 3 before ECV.  
At the end of the visit, the Investigator will contact the IVRS/IWRS to confirm the patient 
selection (which will automatically order the treatment delivery) and organise the appointment for 
the next visit.  
The patient will receive from the investigational centre the participant card to be kept for all the 
duration of the study. 
Visit 2 - Inclusion Visit (Day 1):  
If the patient's behaviour during the selection period and/or the result of complementary 
examinations, particularly the confirmation of the presence of persistent AF by the Central 
Reading Laboratory during this period and the laboratory tests, are compatible with the inclusion 
criteria, the patient will be assessed for the following: 
• Adverse events 
• Concomitant treatments (authorised, disallowed) 
• Laboratory examination: red blood cell concentrations of DHA and coagulation 
parameters Prothrombin Time/INR (PT/INR), Activated Partial Thromboplastin Time 
(aPTT), Thrombin Clotting Time (TCT) 
• Global Physical examination/bodyweight 
• Vital signs 
• Echocardiography using a two-dimensional echocardiography 
• 12-lead ECG 
• Urine pregnancy test for women of child bearing potential 
If the results of the above assessments are compatible with the inclusion criteria, the patient will 
be included and the investigator will contact the IVRS/IWRS to obtain the treatment unit number 
to be dispensed at visit 2 for the first 12-week period. 
Between this Inclusion visit and the next visit (V3), the INR will be closely monitored (refer to 
paragraph 8.4.6) in order to fulfil the ECV conditions (refer to paragraph 3).  
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At the end of the visit, the Investigator will organise the appointment for the next visit and will 
give the treatment for the next 4-week period (one case of treatment). 
Visit 3 (Week 4: D28 -2/+7 days) cardioversion: 
Patient will be assessed for the following criteria: 
• Adverse events 
• Concomitant treatments (authorised, disallowed) 
• Laboratory examination: Haematology, RBC concentrations of DHA, Prothrombin 
Time/INR (PT/INR), Activated Partial Thromboplastin Time (aPTT), Thrombin Clotting 
Time (TCT) 
• Global Physical examination /bodyweight 
• Vital signs  
• 12-lead ECG 
• Electrocardioversion (ECV): ECV has to be performed 4 weeks after randomization in 
patients with AF. ECV will be performed in the morning, with the patient in the fasting 
state and without dyskalemia. An INR value control must be performed within 24h before 
ECV. INR values ≥ 2 on the 3 last tests performed before ECV are required. However, if 
only 2 INR values are ≥ 2 among those 3 last tests, an ECV can be performed if the 
presence of atrial thrombosis can be excluded with an ECHO–TE (transesophageal 
echocardiography) performed on the same day (before ECV) and the patient can continue 
the study. Anesthesia will be induced and patients will be cardioverted with administration 
of a synchronized, biphasic current. The initial shock will be set at 100 J if the body 
weight is less than 70 kg and at 150 J for higher body weights. Successful cardioversion 
will be defined as recovery of sinus rhythm lasting at least 1 minute after the shock. If 
unsuccessful, a second 200-J shock, and eventually a third 200-J shock, will be 
administered. Failure of ECV is defined as the persistence of AF after the third attempt at 
cardioversion. After the procedure, patients will be monitored on telemetry for at least 6 
hours before discharge.  
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Patients who will not revert to sinus rhythm or with early AF relapse or early atrial flutter 
emergence within the observation period after ECV will be withdrawn from the study and will 
be considered to have finished their follow-up. 
 
At the end of the visit, a 7-day continuous ECG (5-leads/2 or 3 channels) ambulatory recording 
(holter ECG) will be installed on the patient in order to monitor the patient heart rhythm after 
ECV.  
The Investigator will collect all unused cases, blisters and soft capsules, and will count the unused 
capsules for each 4-week treatment period. 
At the end of the visit, the Investigator will organise the appointment for the next visit and give 
the treatment to be taken during the next 8-week period (two cases of treatment). 
Visit 4 (Week 5: D35 -2/+7 days): 
After removal of the continuous ECG ambulatory device, the patient will be assessed for the 
following criteria: 
• Assessment of AE 
• Concomitant treatments (authorised, disallowed) 
• Bodyweight (bodyweight measured at V3 to be used) 
• Vitals Signs 
• Echocardiography using a two-dimensional echocardiography 
At the end of the visit, the patient will be given the TTEM device for cardiac monitoring. The 
patient will be clearly instructed on the frequency and modalities of transmission. The patient will 
be requested to perform one transmission per week from this visit (initial call to perform with the 
patient) to the visit 9 (week 24 – end of study). Moreover, in case of AF or atrial flutter 
symptoms, additional transmissions may be performed.  
Visit 6* (Week 12: D84 ± 7 days) - Visit 7 (Week 16: D112 ± 7 days) : 
*see amendment PA05 dated 22OCT2014 
Patient will be assessed for the following criteria: 
• Adverse events 
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• Concomitant treatments (authorised, disallowed) 
• Laboratory 
examination: 
Prothrombin 
Time/INR 
(PT/INR), 
Activated 
Partial 
Thromboplastin Time (aPTT), Thrombin Clotting Time (TCT). However, in case of 
discontinuation of anticoagulation after ECV due to occurrence of VKA intolerance, the 
monitoring of INR, aPTT and TCT should be stopped. 
• Global Physical examination/bodyweight  
• Vital signs  
• 12-lead ECG 
• The cardiac monitoring will be continued using the TTEM device through one 
transmission per week from the day of visit 4 (end of week 5) to visit 9 (week 24, end of 
study). Moreover, in case of AF or atrial flutter symptoms, additional transmissions may 
be performed. 
The Investigator will collect all unused cases, blisters and soft capsules, and will count the unused 
capsules for each 4-week treatment period. 
In addition, at visit 6: 
• the investigator will contact the IVRS/IWRS to obtain the treatment unit number to be 
dispensed at visit 6 for the last 12-week period. 
• an echocardiography will be performed, an haematology examination will be done and the 
RBC concentration of DHA will be measured.  
At the end of each visit, the Investigator will organise the appointment for the next visit and give 
the treatment to be taken during the next treatment period: one case at visit 6 and two cases at visit 
7. 
Visit 9* - End-of-Study Visit (Week 24: D168 ± 7 days):  
*see amendment PA05 dated 22OCT2014 
Patient will be assessed for the following: 
• Adverse events 
• Concomitant treatments (authorised, disallowed) 
• Global Physical examination/bodyweight 
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• Vital signs 
• 12-lead ECG 
• Laboratory examination: haematology, biochemistry, assessment of coagulation 
parameters: Prothrombin Time/INR (PT/INR), Activated Partial Thromboplastin Time 
(aPTT), Thrombin Clotting Time (TCT), Red blood cell concentration of DHA. 
• Urine pregnancy test for women of childbearing potential 
• Echocardiography using a two-dimensional echocardiography 
The Investigator will collect all unused cases, blisters and soft capsules, and will count the unused 
soft capsules. 
 
The total volume of blood collected should be about 90 ml for the study duration (30 ml for the 
total volume of haematology and biochemistry, 2 ml for each blood samples for coagulations 
parameters and 4 ml for each blood samples of DHA). 
10. ADVERSE EVENTS: DEFINITION AND REPORTING 
10.1. ADVERSE EVENTS 
10.1.1. Definition of Adverse Events 
An AE is any adverse change from the patient's baseline condition, i.e. any subjective signs and 
symptoms or change in a concomitant disease present at the Selection Visit considered or not 
related to the treatment. 
AE includes intercurrent signs, symptoms, illnesses and significant deviations from baseline for 
vital signs and laboratory values which may occur during the course of the clinical study. 
All laboratory tests for which abnormal results are collected after study treatment initiation should 
be repeated until the values return to normal or to a stable status. Abnormal results are defined as 
those falling out of the laboratory normal ranges and that are clinically significant. The frequency 
of such checks should be defined by the Investigator according to the degree of abnormality. 
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In all cases, the aetiology should, as much as possible, be identified and Pierre Fabre Médicament 
notified. 
10.1.2. Grading of Adverse Events 
Adverse or intercurrent events are graded as follows: 
• Mild: awareness of signs or symptoms, but easily tolerated 
• Moderate: uncomfortable enough to cause interference with usual activity 
• Severe: incapacity with inability to work or do usual activity 
10.1.3. Reporting of Adverse Events 
The records of AE in the e-CRF describe the nature (diagnosis, signs and symptoms), severity, 
onset date, stop date, outcome and actions taken, and relationship to study treatment (in the 
Investigator's opinion). It must be specified whether the event is serious or not. 
10.2. SERIOUS ADVERSE EVENTS (SAE) 
10.2.1. Definition 
A SAE includes, but is not necessarily restricted to, any event which: 
• Results in death (whatever may be the cause) 
• Is life-threatening 
• Results in persistent or significant disability/incapacity 
• Requires the patient's hospitalisation or prolongation of current hospitalisation * 
• Is a congenital anomaly or birth defect 
Other events such as cancer and any additional adverse experience or abnormal laboratory values 
occurring during the study period, defined by the protocol as serious or which the Investigator 
considers significant enough or that suggest a significant hazard, contra-indications, side effect or 
precaution, must be handled as serious adverse events. 
Any overdosage meeting a seriousness criteria should be reported as a SAE (see section 10.3). 
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Any pregnancy occurring during/after exposure to the study drug(s) should be reported on the 
SAE notification form (see section 10.4). 
* any hospitalisation, or prolongation of hospitalisation due to the circumstances listed below: 
− planned (as per protocol) medical/surgical procedure 
− preparation for routine health assessment/procedure (e.g. routine colonoscopy) 
− planned medical/surgical admission (planned prior to entry into study trial, appropriate 
documentation required) 
− administrative or social reasons (e.g. lack of housing, economic inadequacy, care-giver 
respite, family circumstances) 
will not be reported as a SAE. 
10.2.2. Reporting of SAE 
All Serious Adverse Events, according to the above-mentioned definitions and regardless of 
treatment or relationship to study drug, and occurring once the informed consent form has been 
signed, must be reported by the Investigator as soon as he/she is informed of the event. 
The Investigator must notify the Sponsor of this event by sending, within 24 hours, the 
"Notification of serious adverse event" form ("first notification") with all the available 
information about the event (see appendix 17.2), to the Sponsor's Corporate Vigilances e-mail 
dedicated box: 
HQ.pharmacovigilance@pierre-fabre.com 
 
 In case it is not possible to send the report by e-mail it can be sent by FAX at the 
following number: 
+ 33 1 49 10 80 90 
In case of non-inclusion, the reporting period ends when the non-inclusion is documented. 
10.2.3. Follow-up of SAE 
The Investigator must draw-up a specific clinical report and use the "Notification of serious 
adverse event" form ("follow-up") (see appendix 17.2) and collect the results of the carried out 
examinations and the reports of hospitalisation. 
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The serious adverse events must be followed up until resolution or stabilisation. 
10.2.4. SAE Occurring After the Study 
Any SAE occurring during 30 days following the end of the study for the patient should be 
notified to the Sponsor. 
Must also be notified to the Sponsor any event occurring at any time after the end of the study for 
the patient which may be related to the study treatment in the Investigator's opinion. 
10.3. REPORTING OF OVERDOSAGE TO THE SPONSOR 
For the purpose of this trial, an overdosage will be defined as any dose exceeding the planned 
prescribed dose of the study drug or the administration of any dose of an associated product that is 
considered both excessive and medically important. 
In the absence of seriousness criteria, the overdosage and associated adverse event if any, are 
reported only on the Adverse Event page of the e-CRF. If the definition of seriousness criteria is 
met, the SAE notification form must also be transmitted to the Sponsor. 
10.4. REPORTING OF PREGNANCY TO THE SPONSOR 
Pregnancies discovered in the period in between the informed consent form signed but before any 
study drug exposure are not to be reported to the Sponsor unless associated to a seriousness 
criteria (e.g. serious adverse event study-protocol related procedure). If pregnancy is confirmed, 
the women must not be administered the study drug and must be withdrawn immediately from the 
study.  
If pregnancy is suspected while the patient is receiving study treatment, the study drug should be 
discontinued immediately until the result of the pregnancy testing is known. If pregnancy is 
confirmed, then the study treatment is permanently discontinued in an appropriate manner and the 
patient is withdrawn from the study.  
The Investigator must report to the Sponsor any pregnancy which occurs during or after the 
patient has been exposed to the study drug and until 30 days after the last study drug 
administration. The Investigator must immediately notify the Sponsor using the SAE notification 
form and also report the pregnancy on the AE page of the e-CRF. 
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Women who become pregnant after exposure to the study drug must be followed by the 
Investigator until the completion/termination of the pregnancy. If the pregnancy goes to term, the 
outcome will have to be reported to the Sponsor (baby's healthy status). 
10.5. SPONSOR'S RESPONSIBILITIES FOR SAFETY REPORTING 
 
PURPOSES 
Sponsor will submit expedited and periodic reports to both Competent Authorities and Ethics 
Committees per corporate standard operating procedures as regards to the EU directive 
2001/20/EC taking into account local specific requirements. 
11. DATA COLLECTION AND STUDY MONITORING 
11.1. DATA COLLECTION 
11.1.1. Case Report Form 
An e-CRF will be used to record all patient data required by the protocol except the central ECG 
(Holter ECG, TTEM) and DHA data which will be transferred from vendors to the subcontractor 
as electronic data files that will be loaded into the study database.  
The e-CRF should be fully validated, compliant with ICH-GCP requirements and European 
regulations and should include a traceability system for data corrections and deletions (audit trail). 
Prior to the start of the study, the Investigator will complete a "Delegation of significant study-
related duties" form. The signature and initials of all personal in charge of e-CRF completion 
should be recorded on this form. Each person involved in e-CRF completion, review, correction 
and / or validation will be trained and will have an individual login and access code to the e-CRF. 
Training sessions will be held by the subcontractor for all participants using this tool. An e-CRF 
user manual will be available for investigators and CRAs.  
All the information included into the e-CRF will be recorded from source documents onto the e-
CRF by an authorised person. 
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The Investigator is responsible for the management and accuracy of the information on the e-
CRF. At each monitoring visit, the e-CRF(s) should be at the CRA's disposition for review and 
validation.  
At the end of the study, a CD-ROM containing the pdf version of all e-CRFs (including audit-
trail) will be sent by the subcontractor to the Sponsor and to the investigational sites for archiving. 
The subcontractor must store all study data for at least 15 years after the end of the study and 
ensure their legibility and accessibility during all the storage period. 
11.1.2. Source Documents 
A source document is an original record or certified copy of an original record of clinical findings, 
observations or any other medical or paramedical activities performed during the clinical trial, 
necessary for the transcription and the verification of the collected data. 
Source documents along with all other trial-related documents (copies of all "informed consent" 
forms, e-CRFs CD-ROM, drug inventories and any correspondence related to the study) must be 
kept in the investigator's file throughout the study, and then, must be stored in the study centre's 
archives for a period of at least 15 years or as per local legal requirements, whatever is the 
longest.  
For further details see section 15.2. 
11.2. STUDY MONITORING 
11.2.1. Monitoring visits 
On-site visits will be carried out by a representative of the Sponsor's staff (Study Manager or 
CRA) prior to study initiation and at regular intervals (every 4 to 6 weeks) throughout the study. 
Additional visits and communication by telephone fax or meeting may be performed if necessary. 
Any site visit performed by the Sponsor's representatives will be recorded in the Investigator's 
study file. 
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11.2.1.1. Site Preselection Visit 
Before selecting a centre for the study, a visit will be carried out by the CRA and/or the Study 
Manager to ensure that the Investigator has the necessary capacities (availability, patient's 
recruitment, environment), technical means and staff to carry out the study. 
11.2.1.2. Initiation Visit 
Before the start of the study at all investigational sites, an initiation visit will be carried out by the 
CRA to check at the latest that: 
• The Investigator: 
− has received the technical protocol, administrative and financial agreement signed by all 
parties 
− has received the written statement of the Ethics Committee approval and the list of its 
members and their functions 
• The original dated and signed curriculum vitae of the investigator(s) has been collected 
• Laboratory normal ranges have been collected  
• All study materials are available on the study site 
• All participants agree with the monitoring procedures and know the study procedures 
• All participants are aware of a possible audit or inspection 
The CRA has also to provide training on the study protocol requirements and study specific 
procedures. 
11.2.1.3. Follow-up Visits 
Throughout the study, regular follow-up visits will be carried out by the CRA to check 
compliance with GCP, patient’s informed consents, strict application of the protocol, conformity 
of the data entered on the e-CRF with the source documents and ensure its correct completion, 
adverse events reporting, proper retention, storage and management of the study medication, as 
well as the source and other trial-related documents. 
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11.2.1.4. Closing Visit 
At the end of the study, a final visit will be carried out by the CRA to: 
• Verify that the e-CRFs CD-ROM with pdf files are correctly stored 
• Control the accountability of intact and used treatment units and return them to the 
Clinical Pharmacy Department of the IRPF for destruction 
• Obtain the last data clarifications and/or solutions if any 
• Collect the patient's consent forms in sealed envelopes (except in case of specific country 
requirements),  
• Make an on-site review of all study documentation and complete it if necessary 
• And finally, remind the Investigator of his regulatory obligations, study document 
archiving process and duration. 
11.2.2. Direct Access to Source Documents 
In accordance to the requirements of the GCP, all Sponsor representatives (Study Manager, CRA 
and Auditors) have to be given a direct access to all source and study data to perform quality 
monitoring/audit, thus ensuring accuracy and completeness of data).  
Investigators are reminded that all Sponsor representatives keep professional confidentiality with 
regards to the patient data. 
11.3. INDEPENDENT DATA MONITORING COMMITTEE 
An Independent Data Monitoring Committee (IDMC) will be established to assess at intervals the 
progress of the clinical trial, the compliance with the inclusion criteria, the quality of follow up, 
the quality of primary end point measures, the safety data. The IDMC will thereafter recommend 
to the Sponsor whether to continue, modify, or stop the study.  
The IDMC operating procedures will be described in an independent document.  
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12. DATA MANAGEMENT  
All clinical data related to the study will be collected and saved in a computerised database by the 
Data Management Department of the subcontractor and under the supervision of the Data 
Manager of Pierre Fabre Biometry (PFB) according to the following procedures.  
12.1. DATA ENTRY 
All required data will be collected by the Investigator or authorised designee (duly identified into 
the delegation task list) on the e-CRFs.  
The e-CRFs used for this study will be developed and maintained by the Data Management 
Department of the subcontractor and approved by the Sponsor.  
Electronic data (Holter ECG, TTEM and DHA) will be transferred by the 3rd party vendor 
according to the specifications given by the Data Manager of the subcontractor. These data will be 
captured and handled in accordance with the European GCP ICH E6 guideline. 
12.2. DATA CLEANING 
The subcontractor will define in the Data Validation Plan for reviewing and querying data, 
descriptions of both manual and electronic edit checks. Upon Sponsor approval, the subcontractor 
will program the checks.  
The subcontractor will review the data over the course of the study, working with the Sponsor to 
identify data inconsistencies. The Investigator will be asked to resolve queries by making changes 
directly into the e-CRF.  
12.3. DATA CODING 
Adverse events, concomitant diseases, medical/surgical histories will be coded by the 
subcontractor using the MedDRA dictionary (latest version in use). 
Concomitant medication will be coded by the subcontractor using the WHO-DRUG dictionary 
(latest version in use).  
The Sponsor Clinical Development Physician will validate the coding. 
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12.4. DATA STORAGE 
Computer data files as well as their modifications will be archived by the subcontractor and kept 
available upon request of the Sponsor. 
12.5. DATABASE LOCK 
The validated database will be locked by the subcontractor upon request of the Data Manager of 
PFB following the completion of all steps required, i.e. data entry and check of all data, resolution 
of all queries, validation of the coding, Clinical and Products Safety databases reconciliation and 
validation committee.  
Then, the subcontractor will transfer the locked database in SAS format to the Data Manager of 
PFB who assume storage on the PFB secured server. 
13. STATISTICAL ANALYSIS 
After the database lock and the randomisation code release, the statistical analysis will be 
performed by PFB or under the supervision of the statistician of PFB using SAS® software, 
according to the Statistical Analysis Plan approved by the Validation Committee. 
13.1. GENERAL CONSIDERATIONS 
The main objective of the study is to assess the efficacy of F373280 versus placebo on the 
maintenance of sinus rhythm after direct ECV in patients with persistent AF and chronic heart 
failure. 
Only the primary analysis of the primary efficacy criterion, on which is based the sample size 
justification, may lead to a causal interpretation. All other statistical results are to be regarded 
within a descriptive perspective. 
The statistical significance level of the various two sided tests of all analyses will be 5 %. 
13.2. SAMPLE SIZE 
Assuming an AF recurrence or atrial flutter emergence rate of 85% under placebo and 65% under 
active group, i.e. a clinically relevant difference ∆ of 20%, a sample size of 64 assessable patients 
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per group is required, using a log-rank test of survival curves with a 80 % power and a 5 % two-
sided significance level. 
According to the previous assumptions and assuming a rate of not assessable patients of 15%, a 
minimum of 76 patients will have to be randomised per group. 
13.3. PROTOCOL DEVIATIONS 
Prior to the database lock and the randomisation code release, the Validation Committee members 
will review the protocol deviations and will classify them as either minor or major. A protocol 
deviation will be considered major when it is likely to bias significantly the treatment effect 
estimate based on the primary efficacy criterion. 
Patients with major deviation(s) will be excluded from the Per Protocol data set (see section 13.4). 
A listing of all protocol deviations will be provided for all randomised patients, including the type 
(major/minor) of protocol deviations according to the decisions made by the members of the 
Validation Committee. 
The number and percentage of patients with major protocol deviations will be tabulated by 
treatment group and type of major protocol deviations on the Full Analysis Set defined in section 
13.4. 
13.4. DATA SETS ANALYSED 
The following 3 data sets will be analysed (as defined by the Validation Committee):  
 
• The Safety Set composed of all randomised patients having received at least one dose of 
the study treatment. This data set will be used to perform analyses of Safety. 
• The Full Analysis Set (FAS) composed of all randomised patients having received at least 
one dose of the study treatment and with a successful cardioversion observed at visit 3. 
This data set will be used to perform analyses of Efficacy.  
• The Per Protocol Set (PP) which is the subset of the Full Analysis Set composed of all 
patients with a primary efficacy criteria available and without any major protocol 
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deviation or other source of bias for primary criteria analyses. This data set will be used to 
perform the supportive analysis of the primary efficacy criterion. 
13.5. HANDLING OF DROPOUTS AND MISSING DATA 
13.5.1. Dropouts 
The number of patients who withdraw from the study after their randomisation will be provided 
by treatment group for all treated patients (Safety Set). All withdrawn patients will be further 
described regarding their time to dropout and reasons for withdrawal. 
13.5.2. Repositioning of Visits 
No repositioning of visits will be done. 
13.5.3. Missing Data 
Missing values will not be substituted by estimated values, but considered as missing in statistical 
analysis. 
13.6. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Before the first trial drug intake, patient’s background, medical and surgical history, demographic 
data and disease characteristics will be described by treatment group on the Safety Set. 
- Quantitative parameters will be described by treatment group and overall using the 
following: number of patients, number of missing data, mean, standard deviation, 
minimum, median and maximum values. 
- Qualitative parameters will be described by treatment group and overall using 
frequencies. 
Concomitant diseases, as well as medical and surgical histories will be tabulated descriptively by 
treatment group and overall using the MedDRA codes of System Organ Classes and preferred 
terms. 
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If more than 10% of patients are excluded from the FAS and PP set, the description of patients by 
treatment group at selection and inclusion will be repeated on the FAS and PP set for all 
parameters. 
No statistical test of comparability of treatment groups at baseline will be performed.  
13.7. EFFICACY ANALYSIS  
13.7.1. Primary Criterion  
13.7.1.1. Primary Analysis 
The primary criteria, time to first recurrence of AF or atrial flutter emergence, will be analysed 
using the Kaplan Meier method and compared with the Log rank test. Hazard ratios and 95% 
confidence intervals will be estimated with the Cox regression model. 
The primary analysis will be performed on the FAS. 
13.7.1.2. Supportive Analysis 
The primary analysis will be repeated on the PP set. 
13.7.2. Secondary Criteria 
All secondary analyses will be performed on the FAS. If more than 10% of patients are excluded 
from the PP set, the secondary analyses will be repeated on the PP set.  
13.7.2.1. Numbers of Atrial Fibrillation Episodes in the first week following V3 
Both the numbers of AF episodes (symptomatic or not) lasting for at least 10 minutes and with 
duration less than 10 minutes (NSup10 and NInf10) will be described by treatment group and 
compared by the chi-square test (or CMH test adjusted for centre) or Fisher’s exact Test. 
13.7.2.2. Duration of Atrial Fibrillation Episodes in the first week following V3 
The duration of all AF Episodes will be described by treatment group and compared using the 
Student t (or using an ANOVA with treatment and centres effects) or Wilcoxon test. 
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13.7.2.3. Time to first AF recurrence less than 10 minutes or symtomatic 
The time to the first AF recurrence less than 10 minutes and the time to the first symptomatic AF 
recurrence will be analysed as the primary analysis.  
13.7.2.4. Clinical parameters evaluation 
The EHRA score will be described by treatment group and analysed using a chi-squared test (or 
CMH test adjusted for centre) or Fisher’s exact Test.  
The frequency of presumed arrhythmia will be described by treatment group. 
The number of recurrence of symptomatic AF, of hospitalizations (for cardiovascular events, for 
thromboembolic stroke and for all causes), of spontaneous cardioversion, of successful 
cardioversion (including number of shocks distribution) and the number of patients needing 
cardioversion after initial ECV will be described by treatment group and compared using a chi-
square test or a Fisher Test (if the numbers are relevant).  
The duration of hospitalizations for cardiovascular events, for thromboembolic stroke and for any 
cause will be described by treatment group and compared using the Student t (or using an 
ANOVA with treatment and centre effects) or Wilcoxon test. 
The echocardiographic parameters values will be described at each time (V1, V2, V4, V6 and V9) 
and changes described from V4 to V9 and from V2 to V9. 
13.7.2.5. Biomarker analysis: red blood cell concentrations of DHA 
Values and changes from baseline for red blood cell concentration of DHA will be performed by 
treatment group and assessment time. 
13.8. SAFETY ANALYSIS 
The Safety Set will be used to perform all analyses of the safety criteria. 
13.8.1. Adverse Events 
Any adverse event having been reported during the study for a given patient will be classified by 
preferred term and corresponding system organ class using the MedDRA terminology. 
Adverse events will be classified as: 
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• Treatment emergent adverse events, i.e., any adverse event which occurs or worsens on 
study treatment during the randomised period. 
• Or non treatment emergent adverse events, i.e., any adverse event which occurs during the 
run-in period (before V2) or is reported as concomitant disease with the same intensity. 
For each study period, any patient with at least one reported adverse event will be classified as a 
patient: 
• With at least one adverse event 
• With at least one treatment emergent adverse event 
• With one TEAE 
• With two TEAEs 
• With at least three TEAEs 
• With at least one related TEAE 
• With an adverse event leading to the study treatment discontinuation (definitive or 
temporary) 
• With an adverse event leading to withdrawal 
• With at least one serious adverse event. 
Numbers and percentages of patient with at least one reported treatment emergent adverse event 
will be tabulated by treatment group: 
• By system organ class 
• By system organ class and preferred term 
• By system organ class and preferred term, taking into consideration its most severe 
intensity 
• And by system organ class and preferred term, taking into consideration the most severe 
relationship to the study treatment. 
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Recurring adverse events (i.e., adverse events classified with the same preferred term) for a given 
patient will only be counted once and only their most severe intensity or most severe relationship 
to the study treatment will be tabulated. 
The number and percentage of patient with at least one most common (reported in 1% patients in 
any group) drug related TEAE ("not excluded or unassessable") will be tabulated by Preferred 
Term and Treatment group in decreasing order for the treatment group (for all patients). 
The number and percentage of patients with at least one reported most common treatment 
emergent adverse event will also be plotted by treatment group. This graphical representation will 
highlight the frequencies of the most severe intensities reported by system organ class and 
preferred term. 
SAE will also be described on an individual basis: treatment group, patient's code, sex and age, 
Investigator's reported term, preferred term, time of onset according to the time of the first study 
treatment administration, duration, action taken regarding the study treatment administration, use 
of a corrective treatment, outcome and relationship to the study treatment in the Investigator’s 
opinion. 
13.8.2. Clinical Laboratory Evaluation  
For each laboratory parameter, data will be tabulated by treatment group and assessment time. 
The absolute changes post-trial drug administration - baseline (the baseline value being the value 
measured on the last blood sample collected before the first trial drug administration) will be 
calculated and tabulated by parameter, treatment group and post-trial drug administration 
assessment time. Results of retests performed post-trial drug administration will not be analysed 
and tabulated. They will only be displayed in individual data listings. 
For all biochemistry parameters, scatter plots highlighting individual results will display the 
baseline and week 24 of the laboratory measurements for each patient by locating the point 
defined by the baseline value on the abscissa and respectively week 24 value in the ordinate.  
For all haematology parameters, scatter plots highlighting individual results will display the 
baseline and week 4, week 12 and week 24 of the laboratory measurements for each patient by 
locating the point defined by the baseline value on the abscissa and respectively week 4, week 12 
and week 24 value in the ordinate.  
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Each treatment group will be differently identified. The first bisecting line (45° line), the lines of 
lower and upper normal range, the lines of Potentially Clinically Significant Change (PSC) range 
and Clinically noteworthy abnormal laboratory value (CNALV) range added on the plots (see 
Appendix 17.3). 
For all blood laboratory parameters, shift tables will be provided to depict the numbers of  patients 
with post-trial drug administration variations at each assessment time as compared to the baseline 
values (measured on the last blood sample collected before the first trial drug administration) by 
treatment group. A 3-point scale (low, normal, high) will be used as defined by the normal ranges 
in use in the laboratory in charge of the assays. 
CNALV (see in Appendix 17.3) will be identified and described on an individual basis. If 
relevant, five separate individual data listings by treatment group will be provided: 
• CNALV for haemoglobin (including corresponding individual results of erythrocytes and 
haematocrit) 
• CNALV for neutrophils or leucocytes (including corresponding individual results of 
basophils, eosinophils, lymphocytes and monocytes) 
• CNALV for platelets (including corresponding individual results of erythrocytes and 
leucocytes) 
• CNALV for liver function parameters (including corresponding individual results of 
gamma-GT) 
• CNALV for serum creatinine  
13.8.3. Global Physical Examination 
Recorded data of the global physical examination performed will not be tabulated as any 
abnormal findings post-randomisation should be reported as AEs (if clinically significant). 
Physical examination assessments will be provided in the listings of individual data. 
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13.8.4. Vital Signs, Physical Findings and Other Observations Related to Safety 
13.8.4.1. Vital Sign Measurements Over Time 
For each parameter (systolic blood pressure, diastolic blood pressure and HR in supine and 
standing positions), descriptive statistics over time of values and changes from baseline will be 
tabulated by treatment group and assessment time. 
13.8.4.2. Body weight 
Descriptive statistics over time of values and changes from baseline will be tabulated by treatment 
group and assessment time. 
13.8.4.3. Individual Patient Changes 
The number and percentage of patient with at least one Predefined Potentially Clinically 
Significant Change (PSC) and with at least one PSC Leading to Clinically Significant Value 
(PSCV) will be tabulated by treatment group (see Table 1 in Appendix 17.3).  
According to the pharmacological drug profile mentioned previously in this Protocol, the changes 
from baseline to the maximum and/or minimum post-baseline value could be categorized and 
tabulated by treatment group with frequencies and decreasing cumulative percentages. 
If there is a signal of a drug effect toward one direction rather than the other, additionally shift 
tables of variations from baseline to the maximum or minimum post-baseline value could be also 
provided (see Table 2 to 4 in Appendix 17.3). 
An individual data listing of patients with symptomatic or asymptomatic orthostatic hypotension 
will be provided by treatment group (see Table 5 in Appendix 17.3). 
13.8.5. ECG 
Frequencies on the clinical interpretation (normal, abnormal CS or NCS) will be presented by 
treatment group and assessment time. Individual tabulated data for ECG abnormalities will be also 
displayed. 
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13.8.6. Coagulation parameters 
Scatter plots highlighting individual results for coagulation parameters (prothrombin time/INR, 
activated partial thromboplastin time and thrombin clotting time) before and after study treatment 
administration will be produced. 
13.9. CONCOMITANT TREATMENTS 
Concomitant treatments will be tabulated by treatment group within a descriptive perspective. 
They will be classified by therapeutic area according to the WHO-DRUG dictionary using the 
"anatomical therapeutic chemical" classification on the safety set. 
13.10. COMPLIANCE 
 
The percentage of compliance will be described by treatment group using the quantity 
 
100
_
_
_
(%)
×
=
n
consumptio
l
Theoretica
n
consumptio
actual
Estimated
Compliance
 
 
 
with: Estimated actual consumption = number of tablets provided at the start of study (Visit 2) 
minus number of tablets returned at the end of study (Visit 9) 
Theoretical consumption = number of days of treatment intake planned between the start and the 
end of study (168 days ± 7days) 
 
13.11. INTERIM ANALYSIS AND DATA MONITORING 
No analyses of efficacy data are planned for IDMC that ensures that the overall probability of type 
I error is controlled. No Type I error and sample size adjustments are necessary. Any 
recommendations of the IDMC to alter study conduct will be based on safety, so IDMC 
monitoring of the study will not affect the statistical operating characteristics of the final analysis. 
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The IDMC will review, two times during the study period (after the first 30 subjects will have 
been randomized and when the first 80 subjects will have terminated their study participation), 
safety data results across treatment groups and judges whether the overall safety and feasibility 
(not futility) of the trial remain acceptable. 
14. GENERAL ETHICAL CONSIDERATIONS  
14.1. ETHICAL CONDITIONS 
This study is performed in accordance with the principles stated in the Declaration of Helsinki 
(1964) and subsequent amendments and in accordance with the Good Clinical Practice Guideline 
(CPMP/ICH/135/95). 
14.2. ETHICS COMMITTEE AND LEGAL REQUIREMENTS 
All the documents required by National Regulations and any other informative documents that 
may be requested are submitted for review to an Ethics Committee whose procedures and 
operations meet the GCP and National Legal Requirements. 
Depending on National Regulations, the application is submitted to the Ethics Committee by the 
Sponsor (or representative) or by the Investigator. 
A copy of the formal written approval from the Ethics Committee is provided to the Sponsor 
(directly by the Ethics Committee or via the Investigator) with a list of names and qualifications 
of its members. 
The request for authorisation by the Competent Authority or its notification if required (depending 
on National Regulations) is carried out by the Sponsor. 
The screening of patients does not start before the approval of the Ethics Committee has been 
obtained and the study authorised by the Competent Authority or notified to the Competent 
Authority (depending on National Regulations). 
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14.3. PATIENT'S INFORMATION LEAFLET AND INFORMED CONSENT 
 
FORM 
An information must be given to the patients before their decision to participate or abstain from 
participation. 
This information is based on the elements set out in the Declaration of Helsinki and the ICH GCP 
Guidelines. It must also describe the measures taken to safeguard patient’s privacy and protection 
of personal data, according to European Directive 95/46 EC or other local regulation. 
Restraints and risks must be explained, as well as the right to discontinue participation in the 
study at any stage, without affecting their further relationship with the Investigator and/or their 
future care. 
The written information and consent form must be submitted to the patient with an oral 
explanation. It must be agreed and signed by the patient before any study-related procedure starts. 
This information and consent procedure is under the Investigator’s responsibility. 
The information and consent document are made in triplicate: the original copy is kept by the 
Investigator, one copy is given to the patient and the last copy is kept by the Clinical Quality 
Assurance Unit of the Sponsor in a sealed envelope at the end of study (except in case of specific 
country requirement). 
Specific areas of the Sponsor’s copy are not triplicated to avoid the reading of the patient’s 
surname (except the first 3 letters), first name, address and signature.  
If any information becomes available during the trial that may be relevant to the patient’s 
willingness to keep on participating in the trial, an updated written informed consent must be 
submitted to the patient to confirm  agreement to continue participating. 
14.4. PERSONAL DATA PROTECTION 
All information from this study (excluding data from the informed consent) is entered into a 
computer under the Sponsor’s responsibility in accordance with the French law, "Loi 
Informatique et Libertés" (January 6, 1978, and subsequent amendments) and with the European 
Directive 95/46/CE. 
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14.5. INSURANCE POLICY 
In accordance with the provisions of the law and the GCP, the Sponsor Pierre Fabre Médicament, 
has an insurance policy intended to guarantee against possible damage resulting from the research. 
The studies and/or experiments performed on behalf of the Sponsor Pierre Fabre Médicament are 
specifically and expressly guaranteed. 
It is advisable to underline that non compliance with the Research Legal Conditions is a cause for 
guarantee exclusion. 
15. ADMINISTRATIVE PROCEDURES 
15.1. PROTOCOL AMENDMENT 
Neither the Investigator nor the Sponsor may alter the protocol without the authorisation of the 
other party.  
All changes to the protocol are subject to an amendment which must be dated and signed by both 
parties and must appear as an amendment to the protocol. 
Substantial amendments are submitted for approval / authorisation to the Ethics Committees and 
Competent Authorities. 
Urgent amendments are submitted for approval / authorisation to the Ethics Committees and 
Competent Authorities, but could be implemented immediately under specific conditions defined 
with the Sponsor. 
15.2. SOURCE DOCUMENTS, INVESTIGATOR'S FILE STORAGE 
The Investigator: 
• Keeps all trial-related documents in appropriate file folders. Records of patient, original 
informed consent forms, source documents, a CD Rom containing a pdf copy of e-CRF, 
drug inventory, Ethics Committees and Sponsor correspondence pertaining to the study 
must be kept on file. 
• Retains all documents relating to the screening (consent and investigation results) of all 
patients included in the trial or not. 
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• Retains a list of the patient’s names, addresses (and/or number of medical file), code 
numbers to allow checking of data reported on e-CRFs with those from source documents. 
• Authorises direct access to source documents for monitoring, audits and inspections. 
• The trial-related documents must be retained as strictly confidential at the Investigator’s 
site for at least 15 years or according to local requirements, whatever is the longest after 
the completion or discontinuation of the trial (European Directive 2003/63/EC). 
15.3. END OF THE STUDY 
15.3.1. Definition of the End of Study 
The end of study is the last visit of the last patient undergoing the trial. 
Any change to this definition during the study, for whatever reason, must be notified as a 
substantial amendment. 
15.3.2. Early Study Termination 
15.3.2.1. Early Study Termination Decided by the Sponsor 
The Sponsor may discontinue the study at any time for any of the following reasons: 
• Lack of recruitment 
• Deviations from good clinical practice and/or regulations 
• Poor product safety 
• New information that could jeopardise the patient’s safety 
• Stopping of the development … 
15.3.2.2. Early Study Termination Decided by the Competent Authorities 
The Competent Authorities may suspend or prohibit a study if they consider that either the 
conditions of authorisation are not being met or has doubt about the safety or scientific validity of 
the study. 
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15.4. AUDIT 
The Sponsor is responsible for making sure that both its representatives (Study Manager, CRA...) 
and the Investigator fulfil the requirements as specified by the GCP Guideline.  
An audit can be organised internally at Pierre Fabre Médicament and at the investigational site 
where the e-CRFs are matched against source documents. 
All study documentation must be directly accessible to auditors. 
The practical conditions for the audit are discussed between the Investigator and the Clinical 
Quality Assurance Department. 
Oral information about the audit results are given to the Investigator. 
15.5. INSPECTION 
The Health Authorities may inspect any investigation site or the Sponsor in the course of the study 
or after its completion, to verify the conduct of the study and quality of the data. The Investigator 
must provide to the inspectors direct access to study documents. 
15.6. CONFIDENTIALITY 
The present materials (protocol and related documentation, e-CRF, Investigator's Brochure) 
contain confidential information.  
Except if agreed in writing with the Study Manager, the Investigators must hold such information 
confidential, and must not disclose it to others (except where required by Applicable Law). 
15.7. CLINICAL STUDY REPORT 
Data analysis and clinical study report writing are under the Sponsor’s responsibility.  
Upon data analysis completion, a final report including a review of the objectives and methods, a 
presentation and a discussion of the results is drawn up according to ICH Guidelines (Structure 
and Content of Clinical Study Reports, ICH-E3, CPMP/ICH/137/95). 
The report is a clinical and statistical integrated report. It must be signed by the Sponsor's 
representative(s) and the Coordinating Investigator. 
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15.8. STUDY RESULTS COMMUNICATION 
Upon completion of the study, the global results of the Research are communicated to the 
Investigator. According to the Local Regulation, the patient can ask the Investigator for the 
results. 
15.9. STUDY RESULTS PUBLICATION 
The information and data collected during the conduct of this clinical study are considered 
confidential and are used by the Sponsor in connection with the development of the study drug. 
This information may be disclosed if deemed necessary by the Sponsor. 
To allow the use of the information derived from this clinical study and to insure compliance with 
Current Regulations, the Investigator must provide the Sponsor with complete test results and all 
data collected during the study.  
Only the Sponsor may make study information available to physicians and to Regulatory 
Agencies, except as required by Current Regulations. 
All the results of this study including data, reports, discoveries and inventions resulting from the 
study, are the property of the Sponsor. 
In the event the Sponsor chooses to publish study data, the manuscript must be provided to the 
author(s) at least 30 days prior to the expected date of submission to the intended publisher. 
The Investigator(s) can reserve the right to publish or present study data; if so, the manuscript or 
abstract must be provided to the Sponsor for review at least 30 days prior to the expected date of 
submission to the intended publisher or of planned presentation. 
In addition, if necessary, (the) Investigator(s) shall withhold publication for an additional 60 days, 
to allow the filing of a patent application, or to allow the Sponsor to take any measures he deems 
appropriate to establish and preserve his proprietary rights. 
It is agreed that publication of study results by each site shall be made only as part of a 
publication of the study results obtained by all sites performing the protocol, once the study is 
completed and finalised.  
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The authors list is agreed by all Investigators prior to publication. The names of the authors are 
provided according to their participation in the design of the protocol as well as their recruitment 
of eligible and analysable patients. 
 
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16. REFERENCES 
 
[1]. 
F373280 INVESTIGATOR'S BROCHURE, version October 2013 
 
[2]. 
NODARI S., TRIGGIONAI M., CAMPIA U., MANERBA A., MILESI G., CESANA 
M.B., GHEORGHIADE M., DEI CAS L. 
n-3 Polyunsaturated Fatty Acids in the prevention of atrial Fibrillation Recurrences after 
electrical cardioversion. A prospective, Randomised study 
Circulation, 2011; 124:1100-1106 
 
[3]. 
NODARI S., TRIGGIANI M., CAMPIA U., MANERBA A., MILESI G., CESANA 
M B., GHEORGHIADE M., DEI CAS L. 
Effects of n-3 polyunsaturated fatty acids on left ventricular function and functional 
capacity in patients with dilated cardiomyopathy 
J. Am. Coll. Cardiol. 2011;57;870-879 
 
[4]. 
MOERTL D., HAMMER A., STEINER S., HUTULEAC R., VONBANK K., 
BERGER R. 
Dose-dependant effects of omega-3-polyunsaturated fatty acids on systolic left ventricular 
function, endothelial function, and markers of inflammation in chronic heart failure of non 
ischemic origin: A double-blind, placebo-controlled, 3-arm study  
American Heart Journal 2011; 161:915.e1-915.e9 - volume 161, number 5 
 
[5]. 
GISSI-HF INVESTIGATORS 
Effects of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GSSI-
HF Trial): a randomised, double-blind, placebo-controlled trial 
The lancet on line - August 2008 
 
[6]. 
CAMM A.J., KIRCHHOF P., LIP G.Y., SCHOTTEN U., SAVELIEVA I., ERNST 
S., VAN GELDER I.C., AL-ATTAR N., HINDRICKS G., PRENDERGAST B., 
HEIDBUCHEL H., ALFIERI O., ANGELINI A., ATAR D., COLONNA P., DE 
CATERINA R., DE SUTTER J., GOETTE A., GORENEK B., HELDAL M., 
HOHLOSER S.H., KOLH P., LE HEUZEY J.Y., PONIKOWSKI P., RUTTEN F.H. 
Guidelines for the management of atrial fibrillation: the Task Force for the Management of 
Atrial Fibrillation of the European Society of Cardiology (ESC). 
European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery, 
Eur Heart J. 2010 Oct;31(19):2369-429 
 
 
[7]. 
KOWEY PR, REIFFEL JA, ELLENBOGEN KA, NACCARELLI GV, PRATT CM. 
Efficacy and safety of prescription omega-3 fatty acids for the prevention of recurrent 
symptomatic atrial fibrillation: a randomised controlled trial. 
JAMA. 2010;304:2363–2372. 
 
 
 
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[8]. 
BIANCONI L., CALO L., MENNUNI M., SANTINI L., MOROSETTI P., 
AZZOLINI P., BARBATO G., BISCIONE F., ROMANO P., SANTINI M.  
N-3 polyunsaturated fatty acids for the prevention of arrhythmia recurrence after electrical 
cardioversion of chronic persistent atrial fibrillation: a randomised, double-blind, 
multicentre study  
Europace (2011) 13, 174-181 
 
[9]. 
OMACOR® SUMMARY PRODUCT CARACTERISTICS (SPC) dated 17/02/2012 
 
[10]. 
BEPANTHENE ® SUMMARY PRODUCT CARACTERISTICS (SPC) 
 
[11]. 
TOUBOUL P, BRUGADA J, CAPUCCI A, CRIJNS HJ, EDVARDSSON N, 
HOHNLOSER SH.  
Dronedarone for prevention of atrial fibrillation: a dose-ranging study.  
Eur Heart J 2003;24(16):1481-7. 
 
[12]. 
LE HEUZEY JY AND ALL.  
A Short-Term, Randomised, Double-Blind, Parallel-Group Study to Evaluate the Efficacy 
and Safety of Dronedarone versus Amiodarone in Patients with Persistent Atrial 
Fibrillation: The DIONYSOS Study. 
J Cardiovasc Electrophysiol. 
 
[13]. 
METCALF G.R., JAMES J.M., GIBSON A.R., EDWARDS J., STUBBERFIELD J., 
STUKLIS R., YOUNG D.G., ROBERTS-THOMSON K. & CLELAND G.L.M.L. & 
OKEN H. 
Effects of fish-oil supplementation on myocardial fatty acids in humans.  
Am J Clin Nutr (2007); 85 : 1225. 
 
[14]. 
ARTERBURN M.L. & OKEN H. 
Distribution, interconversion and dose response of n-3 fatty acids in humans.  
Am J Clin Nutr (2006);83 : 1469-1473S. 
 
[15]. 
TIELEMAN RG, VAN GELDER IC, CRIJNS HJ, DE KAM PJ, VAN DEN BERG 
MP, HAAKSMA J, VAN DER WOUDE HJ, AND ALLESSIE MA. 
Early recurrences of atrial fibrillation after electrical cardioversion: a result of 
fibrillation-induced electrical remodelling of the atria? 
J. Am. Coll. Cardiol. 1998;31;167-173 
 
[16]. 
SALM P, TAYLOR PJ, KOSTNER K 
Simultaneous quantification of total eicosapentaenoic acid, docosahexaenoic acid and 
arachidonic acid in plasma by high-performance liquid chromatography-tandem mass 
spectrometry.  
Biomed Chromatogr 2011 Jun;25(6):652-9. 
 
[17]. 
LEGRAND P., SCHMITT B., MOUROT J., CATHELINE D., CHESNEAU G., 
MIREAUX M., KERHOAS N., WEILL P. 
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The consumption of food products from linseed-fed animals maintains erythrocyte omega-
3 fatty acids in obese human.  
Lipids, 2010, 45, 11-19. 
 
[18]. 
HARRIS WS, VON SCHACKY C. 
The Omega-3 Index: a new risk factor for death from coronary heart disease? 
 Prev Med. 2004 Jul; 39(1):212-20 
 
[19]. 
ABSTRACT: P5161.  
NODARI S, MANERBA A., MADURERI A., BERLINGHIERI N., PULCINI E., 
FRATTINI S., METRA M, DEI CAS L. 
Effects of Polyunsaturated Fatty Acids n-3 (PUFA n-3) in the prophylaxis of atrial 
fibrillation relapses after external electric cardioversion 
World Congress of Cardiology 2006, 2-6 September, Barcelona – Spain 
[20]. 
KIRCHHOF P., AURICCHIO A., BAX J., CRIJNS H., CAMM J., DIENER HC., 
GOETTE A., HINDRICKS G., HOHNLOSER S., KAPPENBERGER L., KUCK 
KH., LIP HYG., OLSSON B., MEINERTZ T., PRIORI S., RAVENS U., 
STEINBECK G., SVERHAGE E., TIJSSEN J., VINCENT A., BREITHARDT G. 
Outcome parameters from a consensus conference organized by the German Atrial Fibrillation 
Competence NETwork and the European Heart Rhythm Association. 
Europace 2007, 9, 1006-1023 
[21]. 
EUROPEAN MEDICINES AGENCY 
Addendum to the guideline on antiarrhythmics on atrial fibrillation and atrial flutter. 
EMA/CHMA/EWP/213056/2010 
[22]. 
OWEN AJ, PETER-PRZYBOROWSKA BA, HOY AJ, MCLENNAN PL. 
Dietary fish oil dose- and time-response effects on cardiac phospholipid fatty acid composition. 
Lipids. 2004;39:955–961 
[23]. 
ROBERTO M. LANG, MICHELLE BIERIG, RICHARD B. DEVEREUX, FRANK 
A. FLACHSKAMPF*, ELYSE FOSTER, PATRICIA A. PELLIKKA, MICHAEL H. 
PICARD, MARY J. ROMAN, JAMES SEWARD, JACK SHANEWISE, SCOTT 
SOLOMON, KIRK T. SPENCER, MARTIN ST. JOHN SUTTON, WILLIAM 
STEWART. 
 
Recommendations for chamber quantification 
 
Eur J Echocardiography (2006) 7, 79-108 
[24]. 
JOHN J.V. MCMURRAY, STAMATIS ADAMOPOULOS, STEFAN D. ANKER, 
ANGELO 
AURICCHIO, 
MICHAEL 
BÖHM, 
KENNETH 
DICKSTEIN, 
VOLKMAR FALK, GERASIMOS FILIPPATOS, CÂNDIDA FONSECA, MIGUEL 
ANGEL GOMEZ-SANCHEZ, TINY JAARSMA, LARS KØBER, GREGORY Y.H. 
LIP, ALDO PIETRO MAGGIONI, ALEXANDER PARKHOMENKO, BURKERT 
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M. PIESKE, BOGDAN A. POPESCU, PER K. RØNNEVIK, FRANS H. RUTTEN, 
JUERG SCHWITTER, PETAR SEFEROVIC, JANINA STEPINSKA, PEDRO T. 
TRINDADE, ADRIAAN A. VOORS, FAIEZ ZANNAD, ANDREAS ZEIHER 
ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012 
European Heart Journal (2012) 33, 1787–1847 
[25]. 
AGENCE NATIONALE DE SECURITE DU MEDICAMENT ET DES PRODUITS 
DE SANTE (ANSM). 
 
Bon usage des médicaments antivitamine K (AVK) 
 
Actualisation – Juillet 2012 
[26]. 
GILLES PERNOD, ANNE GODIER, CLAIRE GOZALO, BENJAMIN TREMEY, 
PIERRE SIE 
French clinical practice guidelines on the management of patients on vitamin K 
antagonists in at-risk situations (overdose, risk of bleeding, and active bleeding) 
Thrombosis Research 126 (2010) e167–e174 
 
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17. APPENDICES 
 
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17.1. DECLARATION OF HELSINKI 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
ETHICAL PRINCIPLES FOR MEDICAL RESEARCH INVOLVING 
HUMAN SUBJECTS 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 29th WMA 
General Assembly, Tokyo, Japan, October 1975 35th WMA General Assembly, Venice, Italy, October 1983 41st 
WMA General Assembly, Hong Kong, September 1989 48th WMA General Assembly, Somerset West, Republic of 
South Africa, October 1996 52nd WMA General Assembly, Edinburgh, Scotland, October 2000 53th WMA General 
Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 55th WMA General Assembly, Tokyo 
2004 (Note of Clarification on Paragraph 30 added) 59th WMA General Assembly, Seoul, October 2008 
 
A. INTRODUCTION  
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of 
ethical principles for medical research involving human subjects, including research on identifiable 
human material and data. The Declaration is intended to be read as a whole and each of its constituent 
paragraphs should not be applied without consideration of all other relevant paragraphs.  
2. Although the Declaration is addressed primarily to physicians, the WMA encourages other participants 
in medical research involving human subjects to adopt these principles.  
3. It is the duty of the physician to promote and safeguard the health of patients, including those who are 
involved in medical research. The physician's knowledge and conscience are dedicated to the fulfilment 
of this duty.   
4. The Declaration of Geneva of the WMA binds the physician with the words, “The health of my patient 
will be my first consideration,” and the International Code of Medical Ethics declares that, “A physician 
shall act in the patient's best interest when providing medical care.”  
5. Medical progress is based on research that ultimately must include studies involving human subjects. 
Populations that are underrepresented in medical research should be provided appropriate access to 
participation in research.  
6. In medical research involving human subjects, the well-being of the individual research subject must 
take precedence over all other interests.  
7. The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic interventions 
(methods, procedures and treatments). Even the best current interventions must be evaluated continually 
through research for their safety, effectiveness, efficiency, accessibility and quality.  
8. In medical practice and in medical research, most interventions involve risks and burdens.  
9. Medical research is subject to ethical standards that promote respect for all human subjects and protect 
their health and rights. Some research populations are particularly vulnerable and need special 
protection. These include those who cannot give or refuse consent for themselves and those who may be 
vulnerable to coercion or undue influence.  
10. Physicians should consider the ethical, legal and regulatory norms and standards for research involving 
human subjects in their own countries as well as applicable international norms and standards. No 
national or international ethical, legal or regulatory requirement should reduce or eliminate any of the 
protections for research subjects set forth in this Declaration.  
 
B. PRINCIPLES FOR ALL MEDICAL RESEARCH  
11. It is the duty of physicians who participate in medical research to protect the life, health, dignity, 
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integrity, right to self-determination, privacy, and confidentiality of personal information of research 
subjects.  
12. Medical research involving human subjects must conform to generally accepted scientific principles, be 
based on a thorough knowledge of the scientific literature, other relevant sources of information, and 
adequate laboratory and, as appropriate, animal experimentation. The welfare of animals used for 
research must be respected.   
13. Appropriate caution must be exercised in the conduct of medical research that may harm the 
environment.  
14. The design and performance of each research study involving human subjects must be clearly described 
in a research protocol. The protocol should contain a statement of the ethical considerations involved 
and should indicate how the principles in this Declaration have been addressed. The protocol should 
include information regarding funding, sponsors, institutional affiliations, other potential conflicts of 
interest, incentives for subjects and provisions for treating and/or compensating subjects who are 
harmed as a consequence of participation in the research study. The protocol should describe 
arrangements for post-study access by study subjects to interventions identified as beneficial in the 
study or access to other appropriate care or benefits.   
15. The research protocol must be submitted for consideration, comment, guidance and approval to a 
research ethics committee before the study begins. This committee must be independent of the 
researcher, the sponsor and any other undue influence. It must take into consideration the laws and 
regulations of the country or countries in which the research is to be performed as well as applicable 
international norms and standards but these must not be allowed to reduce or eliminate any of the 
protections for research subjects set forth in this Declaration. The committee must have the right to 
monitor ongoing studies. The researcher must provide monitoring information to the committee, 
especially information about any serious adverse events. No change to the protocol may be made 
without consideration and approval by the committee.  
16. Medical research involving human subjects must be conducted only by individuals with the appropriate 
scientific training and qualifications. Research on patients or healthy volunteers requires the 
supervision of a competent and appropriately qualified physician or other health care professional. The 
responsibility for the protection of research subjects must always rest with the physician or other health 
care professional and never the research subjects, even though they have given consent.  
17. Medical research involving a disadvantaged or vulnerable population or community is only justified if 
the research is responsive to the health needs and priorities of this population or community and if 
there is a reasonable likelihood that this population or community stands to benefit from the results of 
the research.   
18. Every medical research study involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and communities involved in the research in 
comparison with foreseeable benefits to them and to other individuals or communities affected by the 
condition under investigation.  
19. Every clinical trial must be registered in a publicly accessible database before recruitment of the first 
subject.  
20. Physicians may not participate in a research study involving human subjects unless they are confident 
that the risks involved have been adequately assessed and can be satisfactorily managed. Physicians 
must immediately stop a study when the risks are found to outweigh the potential benefits or when 
there is conclusive proof of positive and beneficial results.  
21. Medical research involving human subjects may only be conducted if the importance of the objective 
outweighs the inherent risks and burdens to the research subjects.  
22. Participation by competent individuals as subjects in medical research must be voluntary. Although it 
may be appropriate to consult family members or community leaders, no competent individual may be 
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enrolled in a research study unless he or she freely agrees.  
23. Every precaution must be taken to protect the privacy of research subjects and the confidentiality of 
their personal information and to minimize the impact of the study on their physical, mental and social 
integrity.   
24. In medical research involving competent human subjects, each potential subject must be adequately 
informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional 
affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort 
it may entail, and any other relevant aspects of the study. The potential subject must be informed of the 
right to refuse to participate in the study or to withdraw consent to participate at any time without 
reprisal. Special attention should be given to the specific information needs of individual potential 
subjects as well as to the methods used to deliver the information. After ensuring that the potential 
subject has understood the information, the physician or another appropriately qualified individual 
must then seek the potential subject’s freely-given informed consent, preferably in writing. If the 
consent cannot be expressed in writing, the non-written consent must be formally documented and 
witnessed.  
25. For medical research using identifiable human material or data, physicians must normally seek consent 
for the collection, analysis, storage and/or reuse. There may be situations where consent would be 
impossible or impractical to obtain for such research or would pose a threat to the validity of the 
research. In such situations the research may be done only after consideration and approval of a 
research ethics committee.   
26. When seeking informed consent for participation in a research study the physician should be 
particularly cautious if the potential subject is in a dependent relationship with the physician or may 
consent under duress. In such situations the informed consent should be sought by an appropriately 
qualified individual who is completely independent of this relationship.  
27. For a potential research subject who is incompetent, the physician must seek informed consent from the 
legally authorized representative. These individuals must not be included in a research study that has 
no likelihood of benefit for them unless it is intended to promote the health of the population 
represented by the potential subject, the research cannot instead be performed with competent persons, 
and the research entails only minimal risk and minimal burden.   
28. When a potential research subject who is deemed incompetent is able to give assent to decisions about 
participation in research, the physician must seek that assent in addition to the consent of the legally 
authorized representative. The potential subject’s dissent should be respected.  
29. Research involving subjects who are physically or mentally incapable of giving consent, for example, 
unconscious patients, may be done only if the physical or mental condition that prevents giving 
informed consent is a necessary characteristic of the research population. In such circumstances the 
physician should seek informed consent from the legally authorized representative. If no such 
representative is available and if the research cannot be delayed, the study may proceed without 
informed consent provided that the specific reasons for involving subjects with a condition that renders 
them unable to give informed consent have been stated in the research protocol and the study has been 
approved by a research ethics committee. Consent to remain in the research should be obtained as soon 
as possible from the subject or a legally authorized representative.  
30. Authors, editors and publishers all have ethical obligations with regard to the publication of the results 
of research. Authors have a duty to make publicly available the results of their research on human 
subjects and are accountable for the completeness and accuracy of their reports. They should adhere to 
accepted guidelines for ethical reporting. Negative and inconclusive as well as positive results should 
be published or otherwise made publicly available. Sources of funding, institutional affiliations and 
conflicts of interest should be declared in the publication. Reports of research not in accordance with 
the principles of this Declaration should not be accepted for publication.  
 
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C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE  
31. The physician may combine medical research with medical care only to the extent that the research is 
justified by its potential preventive, diagnostic or therapeutic value and if the physician has good 
reason to believe that participation in the research study will not adversely affect the health of the 
patients who serve as research subjects.   
32. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the 
best current proven intervention, except in the following circumstances:  
• 
The use of placebo, or no treatment, is acceptable in studies where no current proven intervention 
exists; or  
• 
Where for compelling and scientifically sound methodological reasons the use of placebo is 
necessary to determine the efficacy or safety of an intervention and the patients who receive 
placebo or no treatment will not be subject to any risk of serious or irreversible harm.  Extreme 
care must be taken to avoid abuse of this option.  
33. At the conclusion of the study, patients entered into the study are entitled to be informed about the 
outcome of the study and to share any benefits that result from it, for example, access to interventions 
identified as beneficial in the study or to other appropriate care or benefits.  
34. The physician must fully inform the patient which aspects of the care are related to the research. The 
refusal of a patient to participate in a study or the patient’s decision to withdraw from the study must 
never interfere with the patient-physician relationship.  
35. In the treatment of a patient, where proven interventions do not exist or have been ineffective, the 
physician, after seeking expert advice, with informed consent from the patient or a legally authorized 
representative, may use an unproven intervention if in the physician's judgement it offers hope of 
saving life, re-establishing health or alleviating suffering. Where possible, this intervention should be 
made the object of research, designed to evaluate its safety and efficacy. In all cases, new information 
should be recorded and, where appropriate, made publicly available.  
 
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17.2. SAE REPORT FORM 
 
 
 
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N O T I F I C A T I O N  O F  S E R I O U S  A D V E R S E  E V E N T  ( S A E )  O R  P R E G N A N C Y   
T O  P I E R R E  F A B R E  C O R P O R A T E  V I G I L A N C E S  D I V I S I O N   
 
TO 
BE 
TRANSMITTED 
TO 
THE 
CORPORATE 
VIGILANCES 
DIVISION 
BY 
E-MAIL 
WITHIN 
24H 
TO 
HQ.pharmacovigilance@pierre-fabre.com OR BY FAX WITHIN 24H – Fax N°: 33 (0) 1.49.10.80.90 
Transmission date  
 
 
  
 
  
 
 
 
(ddmmyyyy) 
Country :  
........................................
 
 
 
   SAE N° 
 
 
 
                      FIRST NOTIFICATION           FOLLOW-UP   N° 
 
 SUBJECT CHARACTERISTICS  
 
 
 
 
 
 
 
 
Birth date  
 
 
 
 
 
 
 
 
  
 
 
Gender 
 
1=M,    2=F 
   Height 
 
 
 
cm 
 Weight 
 
 
 
 
 
kg 
 
 
 DESCRIPTION OF THE EVENT 
The serious adverse event resulted in : 
 Death (whatever may be the cause) 
 Hospitalisation (*) or extension thereof 
 Life threatening 
 Invalidity or disability 
 
 Congenital abnormality or abnormal pregnancy outcome 
 Cancer 
 Other  (any other serious clinical or laboratory event 
     according to the investigator or the protocol, overdosage 
      meeting seriousness criteria, suicide attempts) 
Other fact to be notified : 
 Pregnancy exposure 
Nature of the event (if clinical nature, indicate the diagnosis or the major symptom) : 
........................................................................................................................................................................................................... 
........................................................................................................................................................................................................... 
........................................................................................................................................................................................................... 
AE onset date  |__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
 
Seriousness onset date  |__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
 
Summary description (if clinical cause, significant history, progression of event, available laboratory results, etc...) : 
 
 
 
 
 
 
(*) Except hospitalisations with durations and goals planned in the protocol 
 
 THE SAE IN RELATION TO THE TRIAL 
                                                      TREATMENT NUMBER         |___|___|___|___|___|___| 
• Time of occurrence of SAE 
 
 During the selection or run-in period 
 
 During the administration phase of the study treatment 
 
 After the administration phase of the study treatment 
• Date of first study treatment administration 
• Date of last study treatment administration 
   before the occurence of SAE 
|__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
 
|__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
• Was the blind broken ?       Yes         No          Not applicable 
   If yes, or if this is an open study, drug(s) administered : 
 
 
 
 
 
  Conditions of administration (cycles(s), daily dose(s), route(s) of administration, etc..) :  
 
 
 
 
 
 
 
 
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Transmission date 
 
 
 
 
 
 
 
 
 
 
  (ddmmyyyy) 
Country : ............................................ 
 
 
 
  SAE N° 
 
 
 
                     FIRST NOTIFICATION           FOLLOW-UP   N° 
 
 CONCOMITANT MEDICATION SINCE TRIAL INITIATION and UP UNTIL THE OCCURRENCE OF THE SAE 
     (EXCEPT THE TREATMENTS GIVEN FOR THE SAE)  
 
Trade name  
(or INN) 
 
Daily dose 
 
Start date 
(dd/mm/yy) 
Ongoing at 
occurence of the 
event 
 
Stop date 
(dd/mm/yy) 
Route of 
admin. 
 
Indication 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 MEASURES TAKEN FOLLOWING THE SAE 
• Study treatment 
 
 No change 
 
 Dosage modification, specify :……………………………..….      Modification Date : 
 
 Temporarily discontinued                                                       Readministration date : 
 
 Withdrawn                                                                                                  End date : 
 
 Not applicable 
 
____/____/_____ 
 ____/____/_____ 
 ____/____/_____ 
• The event led to : 
 
 Prescription of corrective or symptomatic treatments: 
 
 
Trade name  
(or INN) 
 
Daily dose 
 
Start date 
(dd/mm/yy) 
Ongoing at 
occurence of the 
event 
 
Stop date 
(dd/mm/yy) 
Route of 
admin. 
 
Indication 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 Discontinuation of concomitant treatments: 
 
 
Trade name  
(or INN) 
 
Daily dose 
 
Start date 
(dd/mm/yy) 
Ongoing at 
occurence of the 
event 
 
Stop date 
(dd/mm/yy) 
Route of 
admin. 
 
Indication 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
 Others, specify : 
 
 
 OUTCOME 
         Not recovered/Not resolved                  Recovering/Resolving               Recovered/Resolved 
         Recovered/Resolved with sequelae     Fatal                                          Unknown 
 
                In case of death, has an autopsy been conducted ?       Yes         No 
 
 INVESTIGATOR CAUSALITY ASSESSMENT (investigator’s assessment to be done as soon as possible) 
Study drug:                                                                         Related to study protocol: 
 Not Suspected                 Suspected                             Not Suspected                          Suspected                   
Comments: ............................................................................................................................................................. 
 
Enclose in the notification the results of carried out examinations, reports of hospitalisation, etc... 
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17.3. PREDEFINED LIMITS OF LABORATORY AND VITAL SIGN 
POTENTIALLY CLINICALLY SIGNIFICANT CHANGES AND VALUES  
List of Predefined Potentially Clinically Significant Change For Laboratory Values(¤) 
 
 
PARAMETERS 
UNIT 
PSC 
 
 
 
Decrease 
Increase 
MUSCLE 
Creatine  Phosphokinase 
U / l 
- 
236 
KIDNEY 
Creatinine 
Urea 
Uric acid 
Phosphate 
Calcium 
µmol/l 
mmol/l 
µmol/l 
mmol/l 
mmol/l 
- 
- 
- 
0.39 
0.30 
35 
3.2 
119 
0.39 
0.30 
ELECTROLYTES 
Sodium 
Potassium 
Chloride 
Bicarbonate 
mmol/l 
mmol/l 
mmol/l 
mmol/l 
8 
1.1 
8 
7 
8 
1.1 
7 
8 
METABOLISM/ 
NUTRITIONAL 
Glucose (random) 
Albumin 
Protein 
Cholesterol 
HDL cholesterol 
LDL cholesterol 
Triglycerides 
mmol/l 
g/l 
g/l 
mmol/l 
mmol/l 
mmol/l 
mmol/l 
3 
6 
11 
- 
0.91 
2.17 
- 
3.7 
6 
10 
1.97 
0.85 
2.04 
2.91 
ERYTHROCYTES 
Erythrocyte count 
Haemoglobin 
Haematocrit 
MCV  
MCH (Fe) 
MCHC (Fe) 
T/l 
g/l 
1 
fl 
fmol 
mmol/l 
0.7 
20 
0.06 
7 
0.19 
2 
0.7 
- 
0.06 
7 
0.19 
2 
LEUKOCYTES 
Leukocyte count 
G/l 
4.2 
3.8 
DIFFERENTIAL 
COUNT 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
G/l 
G/l 
G/l 
G/l 
G/l 
3.47 
1.76 
- 
- 
- 
3.19 
1.63 
0.49 
0.41 
0.14 
URINE 
Specific gravity 
pH 
- 
- 
0.017 
2 
0.015 
2 
LIVER 
Total bilirubin 
ASAT (SGOT) 
ALAT (SGPT) 
Gamma GT 
Alkaline phosphatase 
µmol/l 
U/l 
U/l 
U/l 
U/l 
- 
- 
- 
- 
-- 
10 
N x (23/36) 
N x (28/45) 
N x (25/38) 
N x (30/95) 
 
N = upper limit of normal range 
 
(¤) Delta-limits from « Routine Laboratory Tests in Clinical Trials » W. Leigh Thompson, Rocco 
L. Brunelle, Gregory G. Enas, Patrick J. Simpson and Randy L. Walker Lilly Research 
Laboratories, Lilly Corporate Centre, Indianapolis, Indiana in « Clinical Trials and Tribulations » 
1988. 
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Definition of Clinically Noteworthy Abnormal Laboratory Values (CNALV) 
 
 
PARAMETERS 
CNALV 
HAEMOGLOBIN 
 
• Decrease of at least 2g/dl and value < 10 g/dl whatever the baseline 
value 
• If missing baseline : value <10g/dl 
NEUTROPHILS 
• < 1 500/mm3 whatever the baseline value 
WBC 
(if missing value for neutrophils) 
• < 3 000/mm3 whatever the baseline value 
PLATELETS 
• < 100 000/mm3 whatever the baseline value 
SERUM CREATININE 
• Increase of at least 30 % as compared to baseline value and 
value > 150 µmol/l whatever the baseline value 
• If missing baseline : value > 150 µmol/l 
LIVER FUNCTION TESTS 
 
 
ALAT 
 
 If normal baseline :  
 
 
•ALAT > 2 N 
 If abnormal baseline : 
→if baseline value ≤ 2.5 N : 
  
• increase of at least 100 % as compared to baseline value 
→ if baseline value > 2.5 N :  
 
 
• value > 5 N 
and/or 
ASAT 
 
  If normal baseline :  
 
 
• ASAT > 2 N 
  If abnormal baseline : 
→ if baseline value ≤ 2.5 N : 
  
• increase of at least 100 % as compared to baseline value 
→ if baseline value > 2.5 N :  
 
 
• value > 5 N 
and/or 
Alkaline phosphatase (AP) 
 
  If normal baseline :  
 
 
• AP > 1.25 N 
  If abnormal baseline :  
 
 
• AP > 2 N 
and/or 
Total bilirubin (TB) 
  If normal baseline :  
 
 
• TB > 1.5 N 
  If abnormal baseline :  
 
 
• TB > 2 N 
N=upper limit of normal range 
International consensus Meeting. International Journal of Clinical Pharmacology, Therapy and Toxicology, 1990;28:317-322 
Standardisation of definitions and criteria of causality assessment of adverse drug reactions: drugs-induced liver disorders: report 
of an Standardisation of definitions and criteria of causality assessment of adverse drug reactions: drugs-induced cytopenia. 
International Journal of Clinical Pharmacology, Therapy and Toxicology, 1991;29:75-81 
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Cardiovascular Safety 
 
Table 1: Predefined Limits for Potentially Clinically Significant Changes (PSC) and PSC 
Leading to Clinically Significant Values (PSCV) 
 
Parameter 
PSC 
PSCV 
SBP 
Increase ≥ 20 mmHg 
Decrease ≥ 20 mmHg 
SBP ≥ 160 mmHg and increase ≥ 20 mmHg 
SBP ≤ 90 mmHg and decrease ≥ 20 mmHg 
DBP 
Increase ≥ 10 mmHg 
Decrease ≥ 10 mmHg 
DBP ≥ 100 mmHg and increase ≥ 10 mmHg 
DBP ≤ 50 mmHg and decrease ≥ 10 mmHg 
HR 
Increase ≥ 10 bpm 
Decrease ≥ 10 bpm 
HR ≥ 110 bpm and increase ≥ 10 bpm 
HR ≤ 50 bpm and decrease ≥ 10 bpm 
 
Table 2: Predefined Classes for changes from Baseline to the Maximum (and/ or Minimum) 
Post-baseline Value 
Classes of Change from Baseline to the Maximum 
Post-baseline Value 
Classes of Change from Baseline to the 
Minimum Post-baseline Value 
SBP  mmHg 
DBP  mmHg 
HR bpm 
SBP  mmHg 
DBP  mmHg 
HR bpm 
All 
All 
All 
All 
All 
All 
≥  0 
≥  0 
≥  0 
≤  0 
≤  0 
≤  0 
>  0 
>  0 
>  0 
<  0 
<  0 
<  0 
≥ 10 
≥  5 
≥ 10 
≤ -10 
≤ - 5 
≤ -10 
≥ 20 
≥ 10 
≥ 20 
≤ -20 
≤ -10 
≤ -20 
≥ 30 
≥ 15 
≥ 30 
≤ -30 
≤ -15 
≤ -30 
≥ 40 
≥ 20 
 
≤ -40 
≤ -20 
 
 
≥ 25 
 
 
≤ -25 
 
 
≥ 30 
 
 
≤ -30 
 
 
Table 3: Classes for Vital Signs Maximum or Minimum Values 
Classes  for  the Maximum Post-baseline Value 
for each parameter 
Classes  for  the Minimum Post-baseline Value 
for each parameter 
SBP  mmHg 
DBP  mmHg 
HR bpm 
SBP  mmHg 
DBP  mmHg 
HR bpm 
< 120 
< 80 
≤ 50 
≤ 90 
≤ 50 
≤ 50 
[120 ;140[ 
[80;90[ 
]50 ;75[ 
[90 ;120[ 
[50;80[ 
]50 ;75[ 
[140;160[ 
 [90;100[ 
[75;100[ 
[120;140[ 
 [80;90[ 
[75;100[ 
≥ 160 
≥ 100 
≥ 100 
≥ 140 
≥ 90 
≥ 100 
 
Table 4: Classes for Maximum or Minimum of BP in its entirety 
Classification of Maximum Values for Blood 
Pressure (mmHg) 
Classification of Minimum Values Blood 
Pressure (mmHg) 
SBP < 140 and DBP < 90 
SBP > 90 and DBP > 50 
SBP [140;160[ and DBP < 100 
or DBP [90;100[ and SBP < 160 
SBP ≤  90 or DBP ≤  50 
SBP ≥ 160 or DBP ≥ 100 
 
 
Table 5: Definition of orthostatic hypotension 
Orthostatic Hypotension * 
SBP Decrease ≥ 20 mmHg or DBP Decrease ≥ 10 mmHg between supine and standing positions 
* Consensus Committee of the American Autonomic Society and the American Academy of Neurolog :Consensus statement on the definition of 
orthostatic hypotension, pure autonomic failure and multiple system atrophy. Neurology 1996;46:1470-3. 
 
 
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Title of the study: 
Efficacy and safety study of F373280 for maintenance of sinus rhythm after electrical cardioversion 
in patients with persistent Atrial Fibrillation and Chronic Heart Failure. 
An international, multicentric, randomised, double-blind, placebo controlled study. 
 
 
 
Dear patient,  
 
You are currently or you have been taking part of the above-named research study evaluating the 
effect of F373280 on the maintenance of normal cardiac rhythm after direct electrical cardioversion 
in patients with persistent Atrial Fibrillation and cardiac failure.  
 
The purpose of this letter it is to provide you with new information about the study.  
 
In fact, as it was explained to you at the beginning of your participation in the trial, it was planned to 
involve in the study 152 male or female patients suffering from persistent Atrial Fibrillation, aged 
more than 18 years, in several countries.  
 
However, since May 2013, only 88% of needed patients have been involved in the study. Therefore, 
due to very slow recruitment over more than 3 years, the Sponsor, Pierre Fabre Médicament, has 
decided to stop prematurely the recruitment of patients. There will be a maximum of 135 patients 
involved in this trial.  
This decision is not related to any new safety information linked to the product. Ongoing patients 
may therefore, continue being involved in the study, receiving treatment; and, analyses of all 
collected data are maintained. 
 
All the other information that were given to you previously remain unchanged 
 
 
CONTACT FOR FURTHER INFORMATION 
If you feel that you would need more information or should there be anything that is not clear, don't 
hesitate to ask your investigator (doctor in charge of the study):  
 
Dr. _  _  _  _  _  _  _  _  _  _  _  _  _  _ 
Telephone number : _  _  _  _  _  _  _  _  _  _  _  _  _ 
 
 
 
We thank you for your participation in this study. 
 
 
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16.1.1.11. 
Protocol amendment n° PA07  
Local (Italy) and substantial dated on 06 December 
2016 linked to Protocol and appendices 
(version 9: 06 December 2016) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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F 373280 CA 2 01 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Pierre Fabre Médicament 
Represented by: Institut de Recherche Pierre Fabre 
45, Place Abel Gance 
F-92100 Boulogne 
CLINICAL STUDY PROTOCOL 
 
Efficacy and safety study of F373280 for maintenance of sinus rhythm after 
electrical cardioversion in patients with persistent Atrial Fibrillation and 
Chronic Heart Failure. 
International, multicentric, randomised, double-blind, placebo controlled study 
F373280 / Soft Capsules / 1g  
Pierre Fabre Study Code: 
EudraCT Number: 
 
Sponsor's Representative: 
 
 
 
 
 
 
 
 
Study Coordinating Investigator 
F 373280 CA 2 01  
2012 – 003487 - 48 
 
Marine FAGARD  
INSTITUT DE RECHERCHE PIERRE FABRE - 
Centre de R&D Pierre Fabre - BP 13562  
3 avenue Hubert Curien  
31035 TOULOUSE Cédex 1, FRANCE 
Phone: +33 5 34 50 63 54  
Fax:+33 5 34 50 65 92  
E-mail:marine.fagard@pierre-fabre.com  
 
Pr Savina NODARI 
Associate Professor of Cardiology 
Department of Clinical and Surgical Specialities, 
Radiological Science and Public Health 
Section of Cardiovascular Diseases 
University Medical School and Spedali Civili Hospital of 
Brescia 
c/o Spedali Civili di Brescia 
Piazzale Spedali Civili, 1 
25123 - BRESCIA, ITALY 
Phone: +39 030 3996 587 – +39 030 393849 
Fax: +39 030 3700 359 
E-mail: savinanodari@gmail.com; nodari@med.unibs.it 
 
Version 9 – 06DEC2016 
The information contained in this document is confidential and is the property of the Sponsor, Pierre Fabre 
Medicament. This information is given for the needs of the study and must not be disclosed without prior written 
consent of the Sponsor Pierre Fabre Medicament. Persons to whom this information is given for the needs of the 
study must be informed that it is confidential and must not be disclosed. 
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SPONSOR PERSONNEL 
PIERRE FABRE MEDICAMENT 
represented by 
Institut de Recherche Pierre Fabre 
 
Clinical Study Manager (Monitor) 
Marine FAGARD  
 
Phone: +33 5 34 50 63 54  
Fax: + 33 5 34 50 65 92 
E-mail: marine.fagard@pierre-
fabre.com 
Institut de Recherche Pierre Fabre 
Centre de R&D Pierre Fabre 
BP 13 562 
3, Avenue Hubert Curien 
31035 TOULOUSE Cedex 1, FRANCE 
 
 
Head of Medical Unit 
Karim KEDDAD, MD, PhD 
 
Phone: +33 5 34 50 61 69 
Fax: +33 5 34 50 65 29 
E-mail: karim.keddad@pierre-
fabre.com 
Institut de Recherche Pierre Fabre 
Centre de R&D Pierre Fabre 
BP 13 562 
3, Avenue Hubert Curien 
31035 TOULOUSE Cedex 1, FRANCE 
 
 
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CONTRACT RESEARCH ORGANISATIONS 
 
For Feasibility, Monitoring and Regulatory issues (in Hungary, Czech Republic and Italy): 
Pharmaceutical Service Network (PSN) 
Rufino Gonzalez 
28 037 Madrid - SPAIN 
Phone: +34 91 375 6930 - Fax: +34 91 375 6931 
E-mail:  rzurita@psnglobal.org 
 
For Feasibility, Monitoring and Regulatory issues (in Spain): 
Alpha Bioresearch 
Paseo de la Castellana, 163 - 2º Izquierda 
28 046 Madrid - SPAIN 
Phone: +34 91 745 2520 - Fax: +34 91 745 0653 
E-mail: teresa.bricio@alphabioresearch.com 
 
For Centralised Randomisation and Electronic Case Report Form 
S-Clinica 
6, Chaussée de Boondael 
B-1050 Brussels - BELGIUM 
Phone: +32 2 645 0567 - Fax: +32 2 645 0569 
E-mail: irena.seredina@s-clinica.com 
 
For Centralised Reading of Holter ECG and TTEM and equipment supply: 
Biomedical System 
1945 Chaussée de Wavre 
B-1160 Brussels - BELGIUM 
Phone: +32 2 661 20 70 - Fax: +32 2 661 20 71 
E-mail: sjacobs@biomedsys.com 
 
For intra erythrocyte DHA dosage: 
Agrocampus Ouest 
Laboratoire de Biochimie 
65 rue de Saint Brieuc – CS 84215 
35042 RENNES Cedex - FRANCE 
Phone: +33 2 23 48 55 49 - Fax: +33 2 23 48 55 50 
E-mail: daniel.catheline@agrocampus-ouest.fr 
 
For transportation of blood sample to the Analytical centre (Agrocampus) and material 
supply: 
Theradis Pharma 
41, chemin des Presses 
06800 CAGNES-SUR-MER – FRANCE 
Phone: +33 (0)4 97 02 07 07 - Fax: +33 (0)4 97 10 08 78 
E-mail: chantal.raffy@theradis.pharma.com 
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TABLE OF CONTENTS OF CLINICAL STUDY PROTOCOL 
 
1. 
INTRODUCTION AND STUDY RATIONALE ................................................................ 22 
1.1. 
TARGET PATHOLOGY AND THERAPY ........................................................................ 22 
1.2. 
INFORMATION ON THE TEST PRODUCT .................................................................... 24 
1.2.1. 
Chemical and pharmaceutical characteristics .................................................................... 25 
1.2.1.1. 
Nomenclature and structure ............................................................................................ 25 
1.2.1.2. 
Physical and chemical general properties ...................................................................... 25 
1.2.2. 
Non-clinical Data .............................................................................................................. 25 
1.2.2.1. 
Pharmacological profile ................................................................................................. 26 
1.2.2.2. 
Safety pharmacology ...................................................................................................... 27 
1.2.2.3. 
Toxicology profile .......................................................................................................... 27 
1.2.2.4. 
Pharmacokinetic data ..................................................................................................... 27 
1.2.3. 
Clinical data ....................................................................................................................... 27 
1.3. 
STUDY RATIONALE ......................................................................................................... 29 
1.4. 
OVERALL RISK AND BENEFIT ASSESSMENT ............................................................ 30 
2. 
STUDY OBJECTIVES ......................................................................................................... 32 
2.1. 
PRIMARY OBJECTIVE ..................................................................................................... 32 
2.2. 
SECONDARY OBJECTIVES ............................................................................................. 32 
3. 
ETHICAL CONSIDERATIONS RELATING TO THE STUDY .................................... 33 
4. 
STUDY DESIGN ................................................................................................................... 34 
4.1. 
OVERALL DESCRIPTION ................................................................................................ 34 
4.2. 
DISCUSSION OF THE STUDY DESIGN .......................................................................... 35 
4.2.1. 
Choice of the Study Population ......................................................................................... 35 
4.2.2. 
Choice of the Study Design ............................................................................................... 36 
4.2.3. 
Choice of the Dose ............................................................................................................ 37 
4.2.4. 
Choice of the Sample Size ................................................................................................. 38 
5. 
STUDY POPULATION ........................................................................................................ 38 
5.1. 
INCLUSION CRITERIA ..................................................................................................... 38 
5.2. 
NON INCLUSION CRITERIA ........................................................................................... 40 
5.3. 
NUMBER OF PATIENTS ................................................................................................... 41 
5.4. 
RECRUITMENT MODALITIES ........................................................................................ 41 
5.5. 
PATIENT IDENTIFICATION ............................................................................................ 42 
5.6. 
WITHDRAWAL CRITERIA ............................................................................................... 42 
5.7. 
REPLACEMENT OF PATIENTS ....................................................................................... 43 
5.8. 
POST-STUDY EXCLUSION PERIOD .............................................................................. 43 
5.9. 
STUDY CARD AND LETTER FOR GENERAL PRACTITIONER(S) ............................ 43 
6. 
STUDY TREATMENT ......................................................................................................... 44 
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6.1. 
SOURCE, PRESENTATION AND COMPOSITION OF  INVESTIGATIONAL 
PRODUCT ........................................................................................................................... 44 
6.2. 
PACKAGING AND LABELLING ..................................................................................... 44 
6.2.1. 
Packaging .......................................................................................................................... 44 
6.2.2. 
Labelling ............................................................................................................................ 44 
6.3. 
DISTRIBUTION TO CENTRE AND STORAGE .............................................................. 45 
6.4. 
ALLOCATION OF TREATMENTS AND DISPENSATION TO PATIENT ................... 46 
6.5. 
DRUG ADMINISTRATION ............................................................................................... 47 
6.5.1. 
Duration of Treatment ....................................................................................................... 47 
6.5.2. 
Dose Schedule ................................................................................................................... 47 
6.5.3. 
Route and Conditions of Administration ........................................................................... 47 
6.6. 
ACCOUNTABILITY ON SITE AND RETURN/DESTRUCTION OF  
INVESTIGATIONAL PRODUCT ...................................................................................... 48 
6.7. 
RECALL OF INVESTIGATIONAL PRODUCTS ............................................................. 48 
7. 
CONCOMITANT TREATMENTS ..................................................................................... 48 
7.1. 
VITAMIN K ANTAGONIST TREATMENT ..................................................................... 49 
7.2. 
PROHIBITED TREATMENTS ........................................................................................... 49 
7.3. 
AUTHORISED TREATMENTS ......................................................................................... 50 
8. 
EVALUATION CRITERIA ................................................................................................. 50 
8.1. 
PRIMARY EFFICACY CRITERION ................................................................................. 50 
8.1.1. 
Time to the first Atrial Fibrillation Recurrence or Atrial Flutter Emergence ................... 50 
8.1.1.1. 
Definition ........................................................................................................................ 50 
8.1.1.2. 
Schedule ......................................................................................................................... 50 
8.1.1.3. 
Evaluation Methods ........................................................................................................ 50 
8.2. 
SECONDARY EFFICACY CRITERIA .............................................................................. 51 
8.2.1. 
Numbers of AF episodes in the first week following visit 3 (ECV visit) ......................... 51 
8.2.1.1. 
Definition ........................................................................................................................ 51 
8.2.1.2. 
Schedule ......................................................................................................................... 52 
8.2.1.3. 
Evaluation Methods ........................................................................................................ 52 
8.2.2. 
Duration of AF episodes in the first week following visit 3 (ECV visit) .......................... 52 
8.2.2.1. 
Definition ........................................................................................................................ 52 
8.2.2.2. 
Schedule ......................................................................................................................... 52 
8.2.2.3. 
Evaluation Methods ........................................................................................................ 52 
8.2.3. 
Clinical parameters evaluation .......................................................................................... 52 
8.2.3.1. 
EHRA score assessment ................................................................................................. 52 
8.2.3.2. 
Time to first AF recurrence less than 10 minutes .......................................................... 53 
8.2.3.3. 
Recurrence of symptomatic AF ...................................................................................... 53 
8.2.3.4. 
Number and duration of hospitalizations ....................................................................... 53 
8.2.4. 
Cardioversion assessment .................................................................................................. 54 
8.2.5. 
Evolution of echocardiographic parameters ...................................................................... 54 
8.2.5.1. 
Definition ........................................................................................................................ 54 
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8.2.5.2. 
Schedule ......................................................................................................................... 54 
8.2.5.3. 
Evaluation method .......................................................................................................... 54 
8.3. 
BIOMARKER ASSESSMENT: RED BLOOD CELL  CONCENTRATIONS OF 
DHA ..................................................................................................................................... 55 
8.3.1. 
Definition ........................................................................................................................... 55 
8.3.2. 
Blood samples ................................................................................................................... 55 
8.3.2.1. 
Collection schedule ........................................................................................................ 55 
8.3.2.2. 
Technical handling ......................................................................................................... 55 
8.3.3. 
DHA concentration measurement ..................................................................................... 55 
8.4. 
SAFETY ASSESSMENT .................................................................................................... 56 
8.4.1. 
Adverse Events .................................................................................................................. 56 
8.4.2. 
Laboratory Investigations .................................................................................................. 56 
8.4.2.1. 
Schedule ......................................................................................................................... 56 
8.4.2.2. 
Technical Procedures and Parameters ............................................................................ 56 
8.4.3. 
Global Physical Examination ............................................................................................ 57 
8.4.4. 
Vital Signs ......................................................................................................................... 58 
8.4.4.1. 
Schedule ......................................................................................................................... 58 
8.4.4.2. 
Technical Procedure and Parameters.............................................................................. 58 
8.4.5. 
Electrocardiogram (ECG) .................................................................................................. 58 
8.4.5.1. 
Schedule ......................................................................................................................... 58 
8.4.5.2. 
Technical Procedure and Parameters.............................................................................. 58 
8.4.6. 
Coagulation parameters ..................................................................................................... 59 
8.5. 
CONCOMITANT TREATMENTS ..................................................................................... 60 
8.6. 
COMPLIANCE .................................................................................................................... 60 
9. 
STUDY PROCEDURES ....................................................................................................... 60 
10. ADVERSE EVENTS: DEFINITION AND REPORTING ............................................... 66 
10.1. ADVERSE EVENTS ........................................................................................................... 66 
10.1.1. Definition of Adverse Events ............................................................................................ 66 
10.1.2. Grading of Adverse Events ............................................................................................... 67 
10.1.3. Reporting of Adverse Events ............................................................................................ 67 
10.2. SERIOUS ADVERSE EVENTS (SAE) .............................................................................. 67 
10.2.1. Definition ........................................................................................................................... 67 
10.2.2. Reporting of SAE .............................................................................................................. 68 
10.2.3. Follow-up of SAE ............................................................................................................. 68 
10.2.4. SAE Occurring After the Study ......................................................................................... 69 
10.3. REPORTING OF OVERDOSAGE TO THE SPONSOR ................................................... 69 
10.4. REPORTING OF PREGNANCY TO THE SPONSOR ...................................................... 69 
10.5. SPONSOR'S RESPONSIBILITIES FOR SAFETY REPORTING  PURPOSES ............... 70 
11. DATA COLLECTION AND STUDY MONITORING ..................................................... 70 
11.1. DATA COLLECTION ......................................................................................................... 70 
11.1.1. Case Report Form .............................................................................................................. 70 
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11.1.2. Source Documents ............................................................................................................. 71 
11.2. STUDY MONITORING ...................................................................................................... 71 
11.2.1. Monitoring visits ............................................................................................................... 71 
11.2.1.1. Site Preselection Visit .................................................................................................... 72 
11.2.1.2. Initiation Visit ................................................................................................................. 72 
11.2.1.3. Follow-up Visits ............................................................................................................. 72 
11.2.1.4. Closing Visit ................................................................................................................... 73 
11.2.2. Direct Access to Source Documents ................................................................................. 73 
11.3. INDEPENDENT DATA MONITORING COMMITTEE ................................................... 73 
12. DATA MANAGEMENT ...................................................................................................... 74 
12.1. DATA ENTRY ..................................................................................................................... 74 
12.2. DATA CLEANING ............................................................................................................. 74 
12.3. DATA CODING .................................................................................................................. 74 
12.4. DATA STORAGE ............................................................................................................... 75 
12.5. DATABASE LOCK ............................................................................................................. 75 
13. STATISTICAL ANALYSIS ................................................................................................. 75 
13.1. GENERAL CONSIDERATIONS ........................................................................................ 75 
13.2. SAMPLE SIZE ..................................................................................................................... 75 
13.3. PROTOCOL DEVIATIONS ................................................................................................ 76 
13.4. DATA SETS ANALYSED .................................................................................................. 76 
13.5. HANDLING OF DROPOUTS AND MISSING DATA ..................................................... 77 
13.5.1. Dropouts ............................................................................................................................ 77 
13.5.2. Repositioning of Visits ...................................................................................................... 77 
13.5.3. Missing Data ...................................................................................................................... 77 
13.6. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ............................... 77 
13.7. EFFICACY ANALYSIS ...................................................................................................... 78 
13.7.1. Primary Criterion ............................................................................................................... 78 
13.7.1.1. Primary Analysis ............................................................................................................ 78 
13.7.1.2. Supportive Analysis ....................................................................................................... 78 
13.7.1.3. Additional Analysis ........................................................................................................ 78 
13.7.2. Secondary Criteria ............................................................................................................. 78 
13.7.2.1. Numbers of Atrial Fibrillation Episodes in the first week following V3 ....................... 78 
13.7.2.2. Duration of Atrial Fibrillation Episodes in the first week following V3 ....................... 79 
13.7.2.3. Time to first AF recurrence less than 10 minutes or symtomatic .................................. 79 
13.7.2.4. Clinical parameters evaluation ....................................................................................... 79 
13.7.2.5. Biomarker analysis: red blood cell concentrations of DHA ........................................... 79 
13.8. SAFETY ANALYSIS .......................................................................................................... 79 
13.8.1. Adverse Events .................................................................................................................. 80 
13.8.2. Clinical Laboratory Evaluation ......................................................................................... 81 
13.8.3. Global Physical Examination ............................................................................................ 82 
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13.8.4. Vital Signs, Physical Findings and Other Observations Related to Safety ....................... 83 
13.8.4.1. Vital Sign Measurements Over Time ............................................................................. 83 
13.8.4.2. Body weight ................................................................................................................... 83 
13.8.4.3. Individual Patient Changes ............................................................................................. 83 
13.8.5. ECG ................................................................................................................................... 83 
13.8.6. Coagulation parameters ..................................................................................................... 84 
13.9. CONCOMITANT TREATMENTS ..................................................................................... 84 
13.10. COMPLIANCE .................................................................................................................... 84 
13.11. INTERIM ANALYSIS AND DATA MONITORING ........................................................ 84 
14. GENERAL ETHICAL CONSIDERATIONS .................................................................... 85 
14.1. ETHICAL CONDITIONS ................................................................................................... 85 
14.2. ETHICS COMMITTEE AND LEGAL REQUIREMENTS ................................................ 85 
14.3. PATIENT'S INFORMATION LEAFLET AND INFORMED CONSENT  FORM ........... 86 
14.4. PERSONAL DATA PROTECTION ................................................................................... 86 
14.5. INSURANCE POLICY ........................................................................................................ 87 
15. ADMINISTRATIVE PROCEDURES ................................................................................ 87 
15.1. PROTOCOL AMENDMENT .............................................................................................. 87 
15.2. SOURCE DOCUMENTS, INVESTIGATOR'S FILE STORAGE ..................................... 87 
15.3. END OF THE STUDY ......................................................................................................... 88 
15.3.1. Definition of the End of Study .......................................................................................... 88 
15.3.2. Early Study Termination ................................................................................................... 88 
15.3.2.1. Early Study Termination Decided by the Sponsor ......................................................... 88 
15.3.2.2. Early Study Termination Decided by the Competent Authorities.................................. 88 
15.4. AUDIT .................................................................................................................................. 89 
15.5. INSPECTION ....................................................................................................................... 89 
15.6. CONFIDENTIALITY .......................................................................................................... 89 
15.7. CLINICAL STUDY REPORT ............................................................................................. 89 
15.8. STUDY RESULTS COMMUNICATION .......................................................................... 90 
15.9. STUDY RESULTS PUBLICATION ................................................................................... 90 
16. REFERENCES ...................................................................................................................... 92 
17. APPENDICES ....................................................................................................................... 96 
17.1. DECLARATION OF HELSINKI ........................................................................................ 97 
17.2. SAE REPORT FORM ........................................................................................................ 101 
17.3. PREDEFINED LIMITS OF LABORATORY AND VITAL SIGN POTENTIALLY 
CLINICALLY SIGNIFICANT CHANGES AND VALUES ............................................ 104 
 
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SYNOPSIS 
 
Name of Sponsor: 
Pierre Fabre Médicament represented by the Institut de Recherche Pierre Fabre (IRPF) 
Name of Finished Product: 
Not applicable 
Name of Active Substance:  
F373280 (Panthenyl-Ester of DHA) 
Title of the Study: 
Efficacy and safety study of F373280 for maintenance of sinus rhythm after electrical 
cardioversion in patients with persistent Atrial Fibrillation and Chronic Heart Failure. 
International, multicentric, randomised, double-blind, placebo controlled study 
Abbreviated Title: 
Not applicable 
Study Coordinating Investigator: 
Pr Savina NODARI 
Study Centres: 
International, multicentric 
Publication / Rationale: 
F373280 is a new therapy based on DHA delivery (pro-drug) developed for the maintenance 
of sinus rhythm after electrical cardioversion in persistent atrial fibrillation (AF) patients with 
chronic heart failure. 
The results of a pharmacological study performed in animals evidenced that DHA reduces the 
duration of AF induced by burst pacing.[1] 
Moreover, the effectiveness of PolyUnsaturated Fatty Acid (PUFA) has been proven in the 
following conditions: 
− 
prevention of AF recurrence in patients with persistent AF, in co-administration 
with amiodarone (add on therapy) [2]  
− 
Improvement of ventricular functional parameters, morbi-mortality and duration of 
hospitalisation in patients with heart failure [3, 4, 5] 
Taking into account these studies, it seems that DHA might be of therapeutic interest in the 
treatment of patients with both persistent atrial fibrillation and chronic heart failure. 
This phase IIa study is designed to assess the efficacy and the safety of the investigational 
product (F373280) for maintenance of sinus rhythm after electrical cardioversion (ECV) in 
patients with persistent atrial fibrillation and chronic heart failure. 
Planned Study Period: 
January 2013 –  April 2017 
Clinical Phase: IIa 
Objectives: 
Primary: 
- Efficacy of F373280 on the maintenance of sinus rhythm after direct electrical 
cardioversion in patients with persistent atrial fibrillation and chronic heart failure 
Secondary: 
- Efficacy of F373280 on the efficiency of direct electrical cardioversion 
- Effect of F373280 on echocardiographic parameters 
- Safety and tolerability of F373280 
Methodology: 
- International, multicentre, randomised, double-blind, placebo-controlled 
- Selection period 
- Start of treatment 4 weeks before ECV 
• 
Condition to ECV:  
− 
Ideally INR 2-3 (vitamin K antagonist should be given at least 3 weeks before 
ECV) 
− 
No spontaneous cardioversion before ECV 
- Follow-up 20 weeks after visit 3 (ECV visit) 
• 
Condition: successful ECV or spontaneous CV 
- Cardiac monitoring: 
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• 
7-days continuous ECG ambulatory recording (Holter ECG) between visit 3 (ECV 
visit) and visit 4 (week 5) in patients with sinusal rhythm 
• 
TTEM: one transmission per week from the day of visit 4 (end of week 5) to visit 9 
(week 24) and at any time in case of AF or atrial flutter symptoms. 
- Treatment duration: 24 weeks 
Study Schedule: 
 7 visits will be scheduled: 
- V1/ W-4 to W-1: selection visit (7 to 28 days before the inclusion visit)  
- V2/ D1: Inclusion visit (start of study treatment) 
- V3/ W4 (D28 -2/+7 days): cardioversion visit (outpatient or hospitalization according to 
clinical practice of the centre) (installation of the Holter device) 
- V4/ W5 (D35 -2/+7 days): follow-up visit (removing of the Holter device and 
installation of the TTEM) 
- V6/ W12* (D84 ± 7 days): follow-up visit    
 *see amendment PA05 dated 22OCT2014 
- V7/ W16 (D112 ± 7 days): follow-up visit     
- V9/ W24* (D168 ± 7 days): final study visit    
 *see amendment PA05 dated 22OCT2014 
Number of  Patients: 
Maximum 135  patients  
Diagnosis and Criteria for Inclusion: 
Inclusion Criteria: 
 
Demographic Characteristics and Other Baseline Characteristics: 
1. 
Men or women aged more than 18 years (inclusive) 
2. 
Patients with current episode of persistent AF between 7 days and 6 months duration for 
whom electrical cardioversion is warranted 
3. 
Previous history of first documented episode of persistent AF. 
4. 
Previous history of ischemic or non ischemic heart failure  
5. 
NYHA class I or II chronic heart failure at selection and at inclusion 
6. 
Left ventricular systolic dysfunction defined at selection and at inclusion by a reduced 
left ventricular ejection fraction (LVEF) ≥ 30% and ≤ 45% or for patients with a LVEF 
> 45%: 
• an increased left ventricular end-diastolic size  
(diameter ≥ 60 mm and/or > 32 mm/m² and/or volume > 97 ml/m²) 
• and/or an increased left ventricular end-systolic size 
(diameter > 45 mm and/or > 25 mm/m² and/or volume > 43 ml/m²) 
• and/or a reduced left ventricular outflow tract velocity time integral < 15 cm 
7. 
On appropriate, stable medical treatments for heart failure, including a diuretic and/or 
angiotensin-converting enzyme, and/or angiotensin-receptor blocker and/or 
mineralocorticoid receptor (MR) antagonists, and/or betablockers 
8. 
Left atrial area ≤ 40 cm² at selection and at inclusion 
9. 
Patients treated or having to be treated by vitamin K antagonist 
10. For female patient of child-bearing potential:  
• 
In all the countries except Italy:  
- Use of an effective method of contraception (hormonal contraception or intra-
uterine device) assessed by the investigator, for at least 2 months before the 
selection in the study, and agreement to go on using it during the whole duration of 
the study and up to 1 month after the last dose of the study treatment 
- Documented as surgically sterilized 
• 
In Italy only:  
- Absolute abstention from sexual intercourse during the whole duration of the study 
and for a month after the end of the study or 
- Use of double barrier contraception method (use of effective medical contraception 
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method) from at least 2 months before the start of the study to the entire duration of 
the study and for a month after the end of the study or 
- Documented as surgically sterilized 
11. For female patient of child-bearing potential: negative urine pregnancy test at inclusion 
12. For male with a child-bearing potential partner (In Italy only): 
- Absolute abstention from sexual intercourse during the whole duration of the study 
and for 3 months after the end of the study or 
- Use of double barrier contraception method (use of condom for male and effective 
contraception method for the partner) from the entire duration of the study to 3 
months after the end of the study. 
Ethical / legal considerations: 
13. Having signed his/her written informed consent, 
14. Affiliated to a social security system, or is beneficiary (if applicable in the national 
regulation) 
 
Non-Inclusion Criteria: 
Criteria related to pathologies: 
1. 
No previous history of first documented episode of persistent AF  
2. 
More than two successful cardioversions (electrical or pharmacological) in the last 6 
months 
3. 
Secondary Atrial Fibrillation due to alcohol or severe valvular heart disease (grade III to 
IV) 
4. 
NYHA class III or IV heart failure at selection or at inclusion 
5. 
Thyroid disease uncontrolled by treatment: TSH ± T4L ± T3L to be checked in case of 
treatment for thyroid disease 
6. 
Myocardial infarction or unstable angina or presence of unstable ischemic 
coronaropathy assessed by coronarography or cardiac stress test (Echo stress, exercise 
stress test, nuclear or MR perfusion evaluation methods) within 6 months before 
selection 
7. 
Severe chronic kidney disease (creatinine ≥ 25 mg/L or estimated glomerular filtration 
rate < 30 ml/min) at selection 
8. 
Bradycardia (HR ≤ 50 bpm) 
9. 
Hyperkalemia or hypokalemia (according to the standards of local laboratories) at 
selection  
10. Cardiac surgery within 3 months before selection or planned during the study duration 
Criteria related to treatments: 
11. Previously ineffective pharmacological or electrical cardioversion 
12. Concomitant treatment with ranolazine or any antiarrhythmic drug (within 7 days prior 
to selection), except amiodarone, dronedarone and stable dose of digoxin, betablockers, 
calcium-blockers 
13. Concomitant treatment with oral amiodarone or dronedarone from selection  
14. Concomitant treatment with intravenous amiodarone from selection  
15. Patient requiring a cardiac resynchronization therapy (CRT) or having undergone CRT 
implantation within the last 6 months  
16. Treatment with any Polyunsaturated Fatty Acid (PUFA) within the last 3 months 
17. Dietary supplement with ω 3 or ω 6 according to investigator’s judgement 
18. Having undergone any form of ablation therapy for AF 
19. Patient treated with oral anticoagulant treatment other than vitamin K antagonist: new 
oral anticoagulants (dabigatran, rivaroxaban, apixaban), or treated with irreversible 
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antiplatelet agents P2Y12 inhibitors such as ticlopidine, clopidogrel or prasugrel 
 
Other criteria: 
20. Patient liable not to comply with protocol instructions and/or with treatment, in the 
investigator’s opinion 
21. Patient having taken part in a clinical trial in the preceding 2 months or taking part in a 
trial at the time of selection 
22. Patient linguistically or mentally unable to understand the nature, objectives and 
possible consequences of the trial, or refusing to patient himself/herself to its constraints 
23. Patient family member or work associate (secretary, nurse, technician,..) of the 
Investigator 
24. Patient having forfeited his / her freedom by administrative or legal award or being 
under guardianship 
25. Breastfeeding female patient 
 
Exclusion criteria before V3: 
Patients without dyskalemia who will not have INR values ≥ 2 on the 3 last tests performed 
before ECV should not have an ECV and will be excluded from the study. 
However, if only 2 INR values are ≥ 2 among those 3 last tests, an ECV can be performed if 
the presence of atrial thrombosis can be excluded with an ECHO–TE (transesophageal 
echocardiography) performed on the same day (before ECV) and the patient can continue the 
study. 
If necessary, for meeting these INR conditions, the ECV (and following visits) could be 
postponed by 7 days. 
Test Product:  
F373280  
Soft Capsules  
Dose: 
Arm with 1g of F373280 
Mode of Administration: 
Oral, one capsule each evening with dinner. 
Duration of Treatment: 
24 weeks of treatment exposure with F373280 (25 weeks if ECV postponed by 1 week) 
Reference Therapy 
Placebo soft capsules 
Placebo will be administered in the same conditions as the tested product. 
Mode of Administration: 
Oral, one capsule each evening with dinner 
Evaluation Criteria: 
Efficacy evaluation variables: 
Primary evaluation variable: 
- Time to first Atrial Fibrillation recurrence or atrial flutter emergence defined by the time to 
first episode of AF or atrial flutter lasting for at least 10 minutes (Follow up of 20 weeks 
after visit 3 – ECV visit). 
Handling of AF recurrences or atrial flutter emergences: 7-day continuous ECG (5-leads/2 
or 3 channels) ambulatory recording (holter ECG) between visit 3 (ECV visit) and visit 4 
(week 5). Then, the follow up will be documented using the TTEM: one transmission per 
week from the day of visit 4 (end of week 5) to visit 9 (week 24). 
For randomised patients with spontaneous cardioversion before ECV, the recurrence of AF 
or the emergence of atrial flutter will be assessed after visit 3 (from week 5).  
Moreover, during this TTEM period, if patient experiences any AF or atrial flutter 
symptoms, it should be recorded and documented using the TTEM.  
All ECG (Holter and TTEM) will be evaluated by a Central Reading Laboratory. 
Secondary evaluation variables: 
During the 7-day continuous ECG monitoring, 
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• 
Numbers of AF episodes 
• 
Duration of AF episodes 
Clinical parameters: 
During the whole study: 
• 
Number of recurrence of symptomatic AF episodes 
• 
EHRA score 
• 
Hospitalization for cardiovascular events 
• 
Hospitalization for thromboembolic stroke 
• 
All causes of hospitalization 
Cardioversion: 
• 
Assessment of spontaneous cardioversion 
• 
Assessment of successful cardioversion 
• 
Shocks distribution (1, 2 or 3 shocks) 
• 
Number of patients needing an other cardioversion after the initial ECV 
 
Other: 
• 
Evolution of echocardiographic parameters (at V4,  V6 and V9) (Left atrial 
diameter (mm), Left atrial area (cm²), Left atrial volume (ml), Left atrial 
volume/BSA (ml/m2), Left ventricular ejection fraction (%), Left ventricular end 
diastolic volume/BSA (ml/m2), Left ventricular end systolic volume/BSA(ml/m2), 
Left ventricular end diastolic diameter (mm), Left ventricular end diastolic volume 
(ml) Left ventricular end systolic diameter (mm), Left ventricular end systolic 
volume (ml)) 
• 
Evolution of omega 3 index and intra erythrocyte DHA (For this assessment 
samples will be centralized). 
 
Safety criteria: 
• 
Adverse events (observed and / or spontaneously reported) 
• 
Vital signs (Blood pressure (supine and standing), heart rate) 
• 
Physical examination (body weight, body surface area)  
• 
Standard 12-lead ECG: heart rate (bpm), PR (ms), QRS (ms), QT (ms), QTcB 
(ms), QTcF (ms), repolarisation patterns (ECG not centralized) 
• 
Haematology: haematocrit, haemoglobin, red blood cell (RBC) count, white blood 
cell (WBC) count, WBC differential count, reticulocytes, platelets 
• 
Biochemistry: sodium, potassium, bicarbonate, chloride, alkaline phosphatase, 
gamma GT, albumin, total bilirubin, conjugated bilirubin, creatinine, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), fasting glucose, total 
cholesterol, cholesterol (HDL, LDL), triglycerides, creatin phosphokinase (CPK) 
fibrinogen (local laboratory) 
• 
Coagulation parameters: Activated partial thromboplastin time (aPTT), thrombin 
clotting time (TCT), INR (local laboratory), Prothrombine Time (PT). 
 
Concomitant treatments 
 
Compliance 
 
Statistical Methods: 
Sample Size: 
Assuming an AF recurrence or atrial flutter emergence rate under placebo of 85%, a power of 
80%, an alpha risk of 5% and a rate of not assessable patients of 15%, 76 randomised patients 
per group will be necessary, using a log-rank test of survival curves, a difference between 
groups of 20%.  
Primary Efficacy Analysis 
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The primary analysis, performed on the Full Analysis Set (FAS: all randomised patients with 
at least one dose of treatment and with a successful cardioversion observed at visit 3), will be 
a survival analysis using the Kaplan Meier method and Cox regression model. 
Secondary Analyses  
All secondary efficacy criteria will be described and compared using appropriate tests on the 
FAS. 
Safety Analyses 
Descriptive statistics will be performed on the Safety Set (all randomised patients with at 
least one dose of treatment).  
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STUDY FLOW-CHART 
F373280 CA 201 
V1 
V2 
V3 
V4 
 
V6 
V7 
 
V9 
Weeks 
W-4 to W-1 
D1 
W4 
(28 -2D/+7 D) 
W5 
(35 -2D/+7 D) 
 
W12 
(84+/-7D) 
W16 
(112+/-7D) 
 
W24 
(168+/-7D) 
  
  
  
  
  
  
  
  
  
  
Outpatient or Hospitalization (1) 
  
  
X 
  
 
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
  
  
  
  
  
  
  
  
Demographic characteristics 
X 
  
  
  
  
  
  
  
  
Medico-surgical history 
X 
  
  
  
  
  
  
  
  
Concomitant disease 
X 
  
  
  
  
  
  
  
  
Concomitant treatment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Habits 
X 
  
  
  
  
  
  
  
  
Global physical examination (body weight) 
X 
X 
X 
 
X 
X 
X 
X 
X 
Echocardiography 
X 
X 
  
X 
  
X 
  
  
X 
Eligibility criteria check 
X 
X 
  
  
  
  
  
  
  
Blood pressure, heart rate  
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead  ECG Recording 
X 
X 
X 
  
X 
X 
X 
X 
X 
INR  
 
 
                   
  
X 
 
 
X 
                     (2) 
aPTT, TCT  
X 
X 
X 
  
X 
X 
X 
X 
X 
Biochemistry 
X 
  
  
  
  
  
  
  
X 
Haematology  
X 
  
X 
  
  
X 
  
  
X 
Urinary pregnancy test 
  
X 
  
  
  
  
  
  
X 
Red Blood Cell concentrations of DHA  
  
X 
X 
  
  
X 
  
  
X 
Treatment number allocation 
  
X 
  
  
  
X 
  
  
  
IVRS/IWRS 
X 
X 
  
  
 
X 
  
  
  
ECV (3) 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Drug administration  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Adverse events recording 
  
X 
X 
X 
X 
X 
X 
X 
X 
Holter ECG 
                (4) 
  
 
                (5) 
 
 
 
 
 
TTEM (6) 
  
  
 
 
 
  
  
  
  
(1) Outpatient or hospitalization according to clinical practice of the centre (less or more than 24 hours) 
(2) In case of VKA introduction: INR 2 to 3 times a week until stabilization, then weekly until the ECV, then every 4 weeks after ECV 
(3) In patients with AF 
(4) 24-hour Holter ECG 
(5) 7-day Holter ECG 
(6) TTEM: one transmission per week from the day of visit 4 (end of week 5) to visit 9 (week 24) and at any time in case of AF or atrial flutter symptoms. 
TTEM once a week even in case of AF recurrence or atrial flutter emergence for at least 10 minutes. 
 
 
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LIST OF ABBREVIATIONS 
 
aPTT 
: 
Activated partial thromboplastin time 
AE 
: 
Adverse event 
AF 
: 
Atrial fibrillation 
ALA 
: 
Alpha-linoleic acid 
ALT 
: 
Alanine aminotransferase 
AST 
: 
Aspartate aminotransferase 
AUC 
: 
Area under the plasma concentration versus time curve 
AUCinf 
: 
Total area under the curve extrapolated to infinity 
βHCG 
: 
beta human chorionic gonadotrophin 
BLQ 
: 
Below the limit of quantification 
BMI 
: 
Body mass index 
BP 
: 
Blood pressure 
BSA 
: 
Body Surface Area 
CEP 
: 
Protocol evaluation committee 
CHMP 
: 
Committee for medicinal products for human use 
Cmax 
: 
Maximum concentration 
Cmin 
: 
Minimum concentration 
CNALV 
: 
Clinically noteworthy abnormal laboratory value 
CPK 
: 
Creatin phosphokinase 
CPP 
: 
Comité de protection des personnes  
CRA 
: 
Clinical research associate 
CRT 
: 
Cardiac resynchronization therapy 
CSC 
: 
“Clinically Significant Change”, i.e., Predefined potentially clinically significant 
change leading to a potentially clinically significant value (vital signs) 
CV 
: 
Coefficient of variation 
DBP 
: 
Diastolic blood pressure 
DHA 
: 
Docosahexaenoic acid 
EC 
: 
Ethics committee 
ECG 
: 
Electrocardiogram 
ECHO –TE : 
Transesophageal echocardiograph 
ECV 
: 
Electrical cardioversion 
EHRA 
: 
European heart rhythm association 
EPA 
: 
Eicosapentaenoic acid 
e-CRF 
: 
Electronic case report form 
FAS 
: 
Full analysis set 
Fe 
: 
Fraction of the administered drug excreted in urine 
GCP 
: 
Good clinical practice 
GFR 
:  Glomerular Filtration Rate 
HBs 
: 
Hepatitis B antigen 
HCV 
: 
Hepatitis C virus 
HDL 
: 
High density lipoprotein 
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HF 
: 
Heart failure 
HIV 
: 
Human immunodeficiency virus 
HR 
: 
Heart rate 
ICH 
: 
International conference on harmonisation of technical requirements for 
registration of pharmaceuticals for human use 
IDMC 
: 
Independent data monitoring committee 
INR 
: 
International normalized ratio 
IRPF 
: 
Institut de Recherche Pierre Fabre 
IVRS 
: 
Interactive voice response system 
LAA 
: 
Left atrial area 
LC/MS-MS : 
Liquid chromatography with tandem mass spectrometry 
LDL 
: 
Low density lipoprotein 
LOQ 
: 
Limit of quantification 
LVEF 
: 
Left ventricular ejection fraction 
MedDRA 
: 
Medical dictionary for regulatory activities 
MR 
: 
Mineralocorticoid receptor 
MR perfusion : 
Magnetic Resonance perfusion 
MTD 
: 
Maximum tolerated dose 
N 
: 
Number of determinations or replicates 
NOAEL 
: 
No observed adverse effect level 
NYHA 
: 
New York heart association 
od 
: 
Once a day 
PC 
: 
“Predefined Change”, i.e., Predefined potentially clinically significant change (lab 
or vital signs) 
PCA 
: 
PC leading to an out-of-range value (lab values) 
PFB 
: 
Pierre Fabre Biométrie 
PSC 
: 
Potentially Clinically Significant Change 
PSCV 
: 
Potentially Clinically Significant Value 
PUFA 
: 
PolyUnsaturated fatty acid 
p.o. 
: 
Per os 
PP 
: 
Per protocol data set 
QTcB 
: 
QT interval using Bazett’s correction formula 
QTcF 
: 
QT interval using Fridericia’s correction formula 
RBC 
: 
Red blood cells 
SAE 
: 
Serious adverse event 
SBP 
: 
Systolic blood pressure 
SD 
: 
Standard deviation 
T1/2 
: 
Terminal half-life 
T0 
: 
Time of drug administration 
Tmax 
: 
Time to reach the maximal concentration 
TCT 
: 
Thrombin clotting time 
TEAEs 
: 
Treatment emergent adverse events 
TTEM 
: 
TransTelephonic ECG monitoring 
VKA 
: 
Vitamin K Antagonist 
WBC 
: 
White blood cells 
WHO-DRUG : 
World health organization drug reference list 
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1. INTRODUCTION AND STUDY RATIONALE 
1.1. 
TARGET PATHOLOGY AND THERAPY 
 
Atrial Fibrillation (AF) is a supraventricular arrhythmia characterized by uncoordinated atrial 
electric activity with consequent deterioration of atrial mechanical function. It is the most 
common sustained cardiac rhythm disorder, increasing in prevalence with age. Haemodynamic 
impairment and thromboembolic events related to AF result in significant morbidity and mortality 
[7]. 
In 2009, Decision Resources estimated that there were 7.8 million diagnosed prevalent cases of 
AF in US, Europe and Japan. This age-related pathology should increase to 9.4 million cases in 
2019.  
Except for the conventional class I and class III anti-arrhythmic agents, the Polyunsaturated Fatty 
Acids (PUFAs) constitute one emerging antiarrhythmic therapy. These compounds potently 
address the AF substrate by directly targeting both the electrical and the structural remodelling of 
the deficient atria. The n-3 PUFAs, essential for human, are alpha-linoleic acid (ALA), 
eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). First, PUFAs specifically 
modulate ionic channels by fastening their inactivating mode which renders these compounds 
selective for pathological situations (such as AF) without any major effect in normal conditions. 
PUFAs are “open Kv1.5 channel blockers” leading to a lengthening of atrial action potential 
duration and are “persistent Nav1.5 channel blockers” leading to hyperpolarization of diastolic 
resting potential. Second, PUFAs influence structural remodelling through their anti-inflammatory 
effects as they directly compete with arachidonic acid in the production of inflammatory 
eicosanoids. In summary, PUFAs share unique, well-tolerated antiarrhythmic potential by 
interacting with the electrical and structural remodelling during sustained AF. In animal studies, it 
was recently demonstrated that DHA is particularly effective in pathologic conditions such as 
ischemia and/or AF. 
The potential anti-arrythmic effects of a PUFA were previously developed in AF: nicotinyl ester 
of DHA (pro-drug based on DHA delivery) was assessed in a two-week ventricular tachypaced 
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canine model. Dogs were subjected to 4 weeks of medication prior to undergoing an 
electrophysiology study, and received either placebo or nicotinyl ester of DHA. Dogs were 
tachypaced at 240 beats per min for the final two weeks of the treatment plan. The results showed 
that the tested PUFA reduced the duration of AF induced by burst pacing, and the incidence of 
sustained AF, compared to dogs treated with the placebo [1]. 
In clinical practice, Nodari and coll [2] assessed n-3 PUFAs in the prevention of AF recurrences 
after electrical cardioversion (ECV). All included patients were treated with amiodarone and a 
renin-angiotensin-aldosterone system inhibitor. The 199 patients were assigned either to placebo 
or n-3 PUFAs 2 g/d and then underwent direct ECV 4 weeks later. The primary end point was the 
maintenance of sinus rhythm at 1 year after cardioversion. At the 1-year follow up, the 
maintenance of sinus rhythm was significantly higher in the n-3 PUFAs treated patients compared 
with the placebo group (hazard ratio, 0.62 [95% confidence interval, 0.52 to 0.72] and 0.36 [95% 
confidence interval, 0.26 to 0.46], respectively; p = 0.0001). The study concludes that in patients 
with persistent AF on amiodarone and a renin-angiotensin-aldosterone system inhibitor, the 
addition of n-3 PUFAs 2 g/d improves the probability of the maintenance of sinus rhythm after 
direct current cardioversion. Previously, during the World Congress of Cardiology in 2006, an 
abstract reported the effectiveness of PUFAs on top of traditional treatment (amiodarone, beta 
blockers, renin-angiotensin-aldosterone system inhibitor) in the prevention of AF relapses in 
patients having undergone ECV. In the PUFA group, AF relapses were significantly lower than in 
the placebo group at 1 month (3.3% vs 10%; p = 0.043), at 3 months (10% vs 25%; p = 0.004) and 
at 6 months (13.3% vs 40%; p < 0.0001) [19]. 
In contrast, in the general AF population (paroxystic atrial fibrillation and persistent atrial 
fibrillation), PUFAs failed to prove their efficacy [7] because of the absence of cardiac 
remodelling or because of a short pre-treatment duration before ECV (1 week) [8]. The effects of 
PUFAs were only observed in patients with persistent AF on add on therapy and after a sufficient 
pre-treatment before ECV. Persistent AF is commonly associated to heart failure. Previous studies 
performed in heart failure population demonstrated the benefit of PUFAs on the improvement of 
functional ventricular parameters and morbi-mortality, and on the reduction of hospitalisation [3, 
4, 5]. 
Nodari and coll [3] performed a trial in patients with chronic heart failure (NYHA I to III and 
LVEF< 45%). After a treatment of 133 patients with PUFAs (n=67) or placebo (n=66) at a dosage 
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of 5 g/day for 1 month, then 2 g/day for 11 months, the n-3 PUFAs group and the placebo group 
differed significantly (p <0.001) in regard to:  
− LVEF (increased by 10.4% and decreased by 5.0%, respectively) 
− peak VO2 (increased by 6.2% and decreased by 4.5%, respectively) 
− exercise duration (increased by 7.5% and decreased by 4.8%, respectively) 
− mean New York Heart Association functional class (decreased from 1.88+/- 0.33 to 1.61 
+/- 0.49 and increased from 1.83+/- 0.38 to 2.14 +/- 0.65, respectively).  
The hospitalization rates for patients with HF were 6% in the n-3 PUFAs and 30% in the placebo 
group (p <0.0002). 
Moertl and coll [4] performed a dose-ranging study in patients with a more severe chronic heart 
failure (NYHA III and IV and LVEF < 35%). It was a double-blind, randomised, controlled pilot 
trial in 43 patients treated with PUFAs or placebo for 3 months (1 g/d n3-PUFA (n = 14), 4 g/d 
n3-PUFA (n = 13), or placebo (n = 16)). After treatment, left ventricular ejection fraction 
increased in a dose-dependent manner (p = 0.01 for linear trend) in the 4 g/d (baseline vs 3 
months [mean ± SD]: 24% ± 7% vs 29% ± 8%, p = 0.005) and 1 g/d treatment groups (24% ± 8% 
vs 27% ± 8%, p = 0.02). 
No changes in any investigated parameters were noted with placebo. 
Taking into account these studies performed with PUFAs, it seems that the best target for DHA is 
persistent AF in patients with heart failure. The aim of this proof of concept study is to assess in 
stand alone therapy (without association of other anti-arrhythmic treatments), the effect of 
F373280 in patients with persistent AF and heart failure in the maintenance of sinus rhythm after 
ECV. 
1.2. 
INFORMATION ON THE TEST PRODUCT 
F373280 or panthenyl ester of DHA is the mono-ester of panthotenic alcohol and DHA, selected 
to be developed for the management of AF.  
F373280 is a prodrug of DHA. 
A brief summary of F373280 known characteristics is presented in this section. For further details, 
please refer to the F373280 Investigator’s Brochure. [1] 
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1.2.1. Chemical and pharmaceutical characteristics 
1.2.1.1. 
Nomenclature and structure 
Chemical name (IUPAC):  
(4Z,7Z,10Z,13Z,16Z,19Z)-3-((R)-2,4-dihydroxy-3,3-diméthylbutanamido) 
propyl 
docosa-
4,7,10,13,16,19-hexaenoate 
Structural formula: 
O
O
O
O
NNHH
O
O
OHH
O
OHH
 
Laboratory code: F373280 
Molecular formula: C31H49NO5 
Molecular mass: 515.7 
1.2.1.2. Physical and chemical general properties 
Appearance: Clear oily viscous liquid 
Solubilities:  
− Water: Practically insoluble 
− Alcohol: Very soluble  
− Trimethylpentane: Slightly soluble  
1.2.2. Non-clinical Data 
Non-clinical data are exhaustively detailed in the Investigator’s brochure [1]. A brief summary is 
provided below. 
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1.2.2.1. 
Pharmacological profile 
F373280 (mono-ester of panthotenic alcohol and DHA) is a novel pro-drug of DHA which exerts 
antiarrhythmic properties by interacting with the electrical and structural remodelling of the atria.  
Experimental investigations were conducted in HEK293 cell line transfected with human Kv1.5 
channel using the whole cell patch clamp technique to evaluate whether F373280 could block the 
sustained component of IKv1.5. F373280 concentration-dependently reduced Kv1.5 channel activity 
with an IC50 value of 13.7 µM. 
The effects of F373280 on atrial effective refractory period were investigated in anesthetized pig 
using a conventional pacing protocol through epicardial electrodes placed on the left atrium. 
F373280 administered as a bolus and an infusion (10 mg/kg) significantly increased atrial 
effective refractory period (23.8 ± 2.2 ms versus -7.3 ± 11.5 ms in the presence of vehicle, p < 
0.05). In addition, F373280 was devoid of significant effect on the hemodynamic and the 
electrocardiogram (ECG) intervals.  
Proof of the pharmacological concept was performed with a different DHA derivative named: 
Nicotinyl ester of DHA (pro-drug based on DHA delivery). Ventricular tachypacing-induced 
congestive heart failure provides a clinically-relevant animal model of AF associated with 
structural remodelling, as is often seen clinically. It has been shown that sustained oral PUFA 
administration suppresses congestive heart failure-induced AF-promotion and fibrosis in the 
ventricular tachypacing canine model. Nicotinyl ester of DHA was tested in this model, at 1 g/day 
and 5 g/day, during 4 weeks, to prevent congestive heart failure-related atrial structural 
remodelling and AF promotion in dogs. Nicotinyl ester of DHA dose dependently reduced heart 
failure-induced increases in AF duration (989 ± 111 sec, n=5 in the presence of placebo versus 
637 ± 196 sec, n=5 in the presence of 1 g/kg/d Nicotinyl ester of DHA and 79 ± 51 sec, n=5, in 
the presence of 5 g/kg/d Nicotinyl ester of DHA). The protective effect of Nicotinyl ester of DHA 
was associated with a marked increase of plasma level of DHA and important incorporation of 
DHA in the left atrial tissue. Because F373280 similarly to Nicotinyl ester of DHA increases 
plasma level of DHA, it could be estimated that the compound may exert a similar protective 
effect [1]. 
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1.2.2.2. 
Safety pharmacology 
A battery of safety pharmacology studies was performed to evaluate the effects of F373280 on the 
central nervous, cardiovascular and respiratory systems. Data of these studies are exhaustively 
detailed in the Investigator’s brochure [1]. 
No particular alerts were evidenced with F373280. 
1.2.2.3. 
Toxicology profile 
Concerning the toxicological data, 4-week and 26-week repeat-dose studies in rat and dog were 
performed. Compared to the high administered doses of F373280 (500 to 2000 mg/kg/day), low 
circulating concentrations of F373280 were measured.  
During these toxicity studies, no toxicity was observed in rat after 4 and 26 weeks of dosing and 
in dog after 4 weeks of dosing. A NOAEL of 2000 mg/kg/day was established in these repeat 
toxicity studies.  
During the 26-week toxicity study in dogs, the NOAEL was set at 1000 mg/kg/day based on 
changes observed on red blood cell parameters. 
Based on toxicological profiles, F373280 is considered to support the proposed clinical trial. 
1.2.2.4. 
Pharmacokinetic data  
According to animal studies described in the Investigator’s brochure [1], the non-clinical 
pharmacokinetic profile of F373280 is not associated with particular alerts concerning the 
proposed clinical phase IIa study. 
1.2.3. Clinical data 
Part A: Single dose 
Six consecutive single ascending doses were tested (0.5 g, 1 g, 2 g, 4 g, 8 g and 16 g) on 6 
independent cohorts of 8 subjects (6 verum + 2 placebo). 49 subjects were treated and 48 
completed the study. 
No Serious Adverse Events (SAE) occurred in the course of the study. 
Regarding the reported Treatment Emergent Adverse Events (TEAEs) that were judged by the 
Investigator as having a causal relationship with the study drug administration in the absence of 
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an alternative explanation, 3 TEAEs were observed in the placebo group (palpitation, dizziness in 
standing position, symptomatic orthostatic hypotension without loss of consciousness) and 4 in 
the group of F373280 at the dosage of 16 g (meteorism, liquid stool, symptomatic orthostatic 
hypotension and dizziness in standing position). None of these adverse events (AE) were reported 
in the groups of F373280 at the dosages of 0.5 g, 1 g, 2 g, 4 g and 8 g. 
After a single administration of the different tested doses no difference between the tested product 
and placebo has been reported, regarding vital signs (heart rate, systolic blood pressure and 
diastolic blood pressure), biological parameters (related to coagulation: platelets and fibrinogen) 
and coagulation parameters (bleeding time, prothrombin time/INR, activated partial 
thromboplastin time, thrombin clotting time). Variations of these parameters were within the 
physiological ranges. 
After single oral administration of F373280 from 0.5 g to 16 g in 36 young healthy male subjects 
(6 per dose level), the following was observed: 
 
- 
F373280: Whatever the tested dose there is no circulating F373280 in plasma: only few, 
sparse and non consecutive samples with quantifiable level of F373280 close to LOQ were 
observed. This confirms that F373280 is a prodrug. 
- 
Panthenol: Cmax and AUC increased with the administered dose between 0.5 and 16 g. 
Panthenol concentrations were rapidly cleared from plasma with a mean terminal half-life 
around 2 hours. 
- 
DHA: after 0.5 and 1 g, low increased in DHA plasma concentrations compared to the 
baseline levels led to a high inter-individual variability of the corresponding 
Pharmacokinetics parameters. Plasma exposure in DHA increased with the administered 
dose between 2 and 16 g with no departure from proportionality (baseline corrected 
parameters). 
 
Part B: Multiple doses 
Three consecutive repeated ascending doses (1, 2 and 4 g) were tested on 3 independent cohorts of 
12 subjects (9 verum + 3 placebo, double blind). 36 subjects completed the study. Each treatment 
was administered over a period of 28 days. Pharmacokinetic parameters were assessed over a 
period of 14 days.  
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Among the TEAE judged by the investigator as suspected to F373280, 5/9 TEAEs were classified 
according the System Organ Class in vascular system disorder with orthostatic hypotension (2 in 
the 1 g group, 1 in the 2 g group and 2 in the 4 g group) and 4/9 were classified in nervous system 
disorder with 3 dizziness (2 in the 2 g group and 1 in the 4 g group) and 1 migraine (in the 1 g 
group). These TEAEs have already been reported with PUFAs and are commonly observed in 
phase I studies. 
After a repeated administration of the different tested doses, no difference between the tested 
products and placebo was reported regarding vital signs (heart rate, systolic blood pressure and 
diastolic blood pressure), biological parameters. The assessment of coagulation parameters and 
platelet function after administration of repeated dose of F373280 did not report any bleeding 
issue. The reported changes in coagulation parameters and platelet function were within 
physiological ranges. 
After a 14-day repeated oral administration of F373280 from 1 g to 4 g, the following was 
observed: 
 Panthenol: Cmax and AUC increased with the administered dose between 1 and 4 g. No 
accumulation of panthenol in plasma was observed. 
 
 DHA: Plasma exposure increased with dose. A 2-fold accumulation in total plasma exposure 
of DHA was observed after 14 days of administration, whatever the administered dose. 
1.3. 
STUDY RATIONALE 
F373280 is a new therapy based on DHA delivery (pro-drug) developed for the maintenance of 
sinus rhythm after ECV in persistent AF patients with chronic heart failure. 
The results of a pharmacological study performed in animals evidenced that DHA reduces the 
duration of AF induced by burst pacing [1]. 
Moreover, the effectiveness of PUFAs has been proven in the following conditions: 
− Prevention of AF recurrence in patients with persistent AF in co-administration with 
amiodarone (add on therapy) [2], 
− Improvement of ventricular functional parameters, morbi-mortality and duration of 
hospitalisation in patients with heart failure [3, 4, 5]. 
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Taking into account these studies, it seems that DHA might be of therapeutic interest in the 
treatment of patients with both persistent AF and chronic heart failure. 
This phase IIa study is designed to assess the efficacy and the safety of the investigational product 
(F373280) for maintenance of sinus rhythm after ECV in patients with persistent AF and chronic 
heart failure. 
1.4. 
OVERALL RISK AND BENEFIT ASSESSMENT 
F373280 is a new pro-drug of DHA.  
DHA is a well-known long chain PUFAs with a long-term clinical experience in cardiovascular 
diseases. DHA is contained in several medicinal products such as Omacor, (1 g of Omacor 
contains about 320 mg of DHA acid) marketed by Laboratoires Pierre Fabre for 
hypertriglyceridemia and as an adjuvant treatment for secondary prevention after myocardial 
infarction. According to the summary product characteristics of Omacor [9]: 
 
- The frequencies of adverse reactions are ranked according to the following: common 
(>1/100, <1/10); uncommon (>1/1000, <1/100); rare (>1/10000, <1/1000); very rare (<1/10000), 
not known (cannot be estimated from the available data). 
- The reported adverse events are: 
• Infection and infestations: 
Uncommon: gastroenteritis 
• Immune system disorders: 
Uncommon: hypersensitivity 
• Metabolism and nutrition disorders: 
Rare: hyperglycaemia 
• Nervous system disorders: 
Uncommon: dizziness, dysgeusia 
Rare: headache 
• Vascular disorders: 
Very rare: hypotension 
• Respiratory thoracic and mediastinal disorders:  
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Very rare: nasal dryness 
• Gastrointestinal disorders: 
Common: dyspepsia, nausea 
Uncommon: abdominal pain, gastrointestinal disorders, gastritis, abdominal pain upper 
Rare: gastrointestinal pain 
Very rare: lower gastrointestinal haemorrhage 
• Hepatobiliary disorders:  
Rare: hepatic disorders  
• Skin and subcutaneous tissue disorders:  
Rare: acne, rash pruritic 
Very rare: urticaria 
• General disorders and administration site conditions: 
Rare: malaise sensation 
• Investigations: 
Very rare: white blood count increased, blood lactate dehydrogenase increased 
Moderate elevation of transaminases has been reported in patients with hypertriglyceridaemia. 
Panthenol is a well-known substance with a long-term experience in medical, nutraceutic and 
cosmetic uses. According to the summary product characteristics of a product such as 
Bépanthene (tablet indicated in alopecia) which contains panthenol (100 mg), adverse event 
observed are rare cases of urticaria and erythema [10]. Panthenol is metabolised in panthotenic 
acid, i.e. B5 vitamin. 
Concerning toxicological studies performed results can support the administration of F373280 in 
the proposed clinical phase II study without particular alert [1]. 
Any safety warning was reported during a phase I study performed with F373280 administered to 
84 healthy volunteers in single dose in a range between 500 mg and 16 g or in repeated dose 
during 28 days in a range between 1 g and 4 g. Adverse events reported and related to study 
treatment were minor to moderate. The adverse events were palpitations, orthostatic hypotension, 
dizziness, meteorism and liquid stool. Most were reported in both groups (placebo and F373280) 
without a dose relationship. The assessment of coagulation parameters and platelet function after 
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administration of repeated dose of F373280 did not report any bleeding concern: the reported 
changes in coagulation parameters and platelet function were within physiological ranges. 
Moreover, DHA has been associated with anticoagulant products in AF studies [2, 8]. The range 
of PUFAs doses tested was between 2 g to 3 g (640 mg to 960 mg of DHA) and the range of study 
durations between 6 to 12 months. This association did not report a significant side effect of 
bleeding. 
DHA has already been used in HF patients in several studies without safety concern [3, 4, 5]. The 
range of PUFAs doses tested was between 1 g to 5 g (1 g of the tested PUFAs contains about 320 
mg of DHA acid) and the range of study durations was between 3 months to 3.9 years. 
Thus, inclusion of patients with no specific antiarrhythmic treatment is acceptable. They will 
receive an anticoagulant treatment to prevent the thrombo-embolic complications of AF 
(particularly stroke) and the adequate treatments to control the heart rate and heart failure.   
In conclusion, the overall available data allow in safe conditions the treatment of patients with 
persistent AF and chronic heart failure with F373280 in safe conditions. 
2. STUDY OBJECTIVES 
2.1. 
PRIMARY OBJECTIVE 
The primary objective of the study is to assess the efficacy of F373280 on the maintenance of 
sinus rhythm after direct ECV in patients with persistent AF and chronic heart failure. 
2.2. 
SECONDARY OBJECTIVES 
The secondary objectives of the study are to assess: 
• the efficacy of F373280 on the efficiency of direct ECV 
• the effect of F373280 on echocardiographic parameters 
• the safety and tolerability of F373280 
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3. ETHICAL CONSIDERATIONS RELATING TO THE STUDY 
The trial is conducted according to Good Clinical Practices (CPMP/ICH/135/95), the National 
regulations and the Declaration of Helsinki and its subsequent amendments (see Appendix 17.1). 
This protocol and the informed consent form will be submitted for approval to independent local 
or national Institutional Review Boards/Ethics Committees before the study set up, according to 
national regulation. 
All the protocol amendments or critical events liable to increase the risks incurred by the patients 
or to compromise the validity of the study or patients' rights will be submitted to the coordinator 
and to the Ethics Committees. 
After being informed orally and in writing of all potential risks and constraints of the trial, as well 
as their freedom to withdraw their participation at any time, patients will then sign a consent form.  
A time of reflection will be given to the patients, before giving a written consent and starting the 
study procedures. 
The use of a placebo is in accordance with EMA Addendum to the guideline on antiarrhythmics 
on AF and atrial flutter (EMA/CHMP/EWP/213056/2010) [21] and is acceptable because the 
included patients will remain under the standard treatment of AF and chronic heart failure. Except 
antiarrythmics, they will receive anticoagulant (vitamin K antagonist, VKA), rate control 
treatment, chronic heart failure treatment. During the study, in case of AF recurrence or atrial 
flutter emergence that would require cardioversion or the introduction of an anti-arrhythmic 
because of intolerable and/or uncomfortable clinical symptoms for instance, patients will be 
withdrawn and the tested product stopped. These patients will be considered as treatment failure. 
In this study, patients will be carefully screened, particularly for their cardiac condition, with 
ECG, 24-hour holter monitor and echocardiographic data, and their biologic and coagulation 
condition. 
The study will be addressed only to patients requiring an ECV due to their persistent AF, in the 
following conditions: 
- ECV in patients not presenting a contra-indication 
- Anticoagulation with vitamin K antagonist (VKA) for at least 3 weeks before ECV 
- ECV will be performed in patients with AF and without dyskalemia. An INR value 
control must be performed within 24h before ECV. INR values ≥ 2 on the 3 last 
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tests performed before ECV are required. However, if only 2 INR values are ≥ 2 
among those 3 last tests, an ECV can be performed if the presence of atrial 
thrombosis 
can 
be 
excluded 
with 
an 
ECHO–TE 
(transesophageal 
echocardiography) performed on the same day (before ECV) and the patient can 
continue the study. Patients who do not revert to sinus rhythm or present an early 
AF relapse or an early atrial flutter emergence within the observation period after 
ECV will be withdrawn and the tested product stopped. 
During the whole study, patients will remain under medical control: visits in cardiology units will 
be performed throughout the study period. This follow up will include clinical signs, ECG, 
biological and coagulation parameters. Moreover, patient’s cardiac rhythm will be monitored once 
a week between visits using Trans Telephonic ECG Monitoring (TTEM) reviewed by a Central 
Reading Laboratory.  
Patients may withdraw from the study at any time without having to give a reason and can expect 
to receive regular conventional therapy. 
4. STUDY DESIGN 
4.1. 
OVERALL DESCRIPTION 
This phase IIa trial will be conducted as an international, multicentric, 24 weeks, double-blind, 
placebo-controlled, randomised, parallel group design, trial in 135 patients suffering from 
persistent AF and chronic heart failure. 
After a 1 to 4-week of run-in period without study treatment, patients will be randomised into one 
of the following treatment groups: F373280 1g or placebo for 24 weeks.  
Seven visits are planned for the study: 
- 
Visit 1 (V1): W-4 to W-1: Selection visit (7 to 28 days before the Inclusion Visit) 
- 
Visit 2 (V2): D1: Inclusion visit (start of study treatment)  
- 
Visit 3 (V3): W4 (D28-2/+7D): cardioversion visit (outpatient or hospitalization according 
to clinical practice of the centre) (installation of the Holter ECG device) 
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- 
Visit 4 (V4): W5 (D35 -2/+7D): follow-up visit (removing of Holter ECG device and 
installation of the TTEM) 
- 
Visit 6* (V6): W12 (D84 ± 7D): follow-up visit 
 
 
*see amendment PA05 dated 22OCT2014 
- 
Visit 7 (V7): W16 (D112 ± 7D) : follow-up visit 
- 
Visit 9* (V9): W24 (D168 ± 7D): final study visit 
 
 
*see amendment PA05 dated 22OCT2014 
4.2. 
DISCUSSION OF THE STUDY DESIGN 
4.2.1. Choice of the Study Population 
The target indication of F373280 will be the maintenance of sinus rhythm after cardioversion of 
patients with persistent AF and chronic heart failure. In the present proof of concept study, the 
evaluation will focus on patients within this indication. This target population is justified by: 
- 
The proved efficacy of PUFAs in patients with persistent AF with or without heart failure 
in co-administration with amiodarone (add on therapy) [2] 
- 
The proved efficacy of PUFAs on the improvement of ventricular functional parameters, 
morbi-mortality and duration of hospitalisation in patients with heart failure [3, 4, 5] 
The study aim is to investigate the product effect in patients with: 
- 
Previous history of persistent AF with duration of the current episode from 7 days to 6 
months. 
- 
A systolic heart failure defined by a reduced left ventricular ejection fraction (≥ 30% and ≤ 
45%) or for patients with a LVEF > 45%: 
• an increased left ventricular end-diastolic size (diameter ≥ 60 mm and/or > 32 
mm/m² and/or volume > 97 ml/m²),  
• and/or an increased left ventricular end-systolic size (diameter > 45 mm and/or > 
25 mm/m² and/or volume > 43 ml/m²),  
• and/or a reduced left ventricular outflow tract velocity time integral < 15 cm [23, 
24].  
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According to a sub-group analysis performed in patients with persistent AF associated to 
heart failure (Nodari S. personal data), PUFAs would be effective to prevent recurrence of 
AF after cardioversion in patients with moderately abnormal LVEF. 
- 
A Left Atrial Area (LAA) not severely abnormal (no greater than 40 cm2 as defined in the 
report from the American Society of Echocardiography’s Guideline) [23]. According to a 
sub-group analysis performed in patients with persistent AF associated to heart failure 
(Nodari S. personal data), PUFAs would not be effective to prevent recurrence of AF after 
cardioversion of patients with severely abnormal LAA. 
For the successful rate of ECV, patients should have a stable medical treatment of heart failure 
and should not have any myocardial infarction or unstable angina or unstable ischemic 
coronaropathy assessed by coronarography or cardiac stress test (Echo stress, exercise stress test, 
nuclear or MR perfusion evaluation methods) within 6 months before selection.  
4.2.2. Choice of the Study Design 
As the target indication would be the prevention of AF recurrence after ECV, the study design 
meets 
the 
requirements 
of 
EMA 
guideline 
on 
antiarrhythmics 
in 
AF 
(EMA/CHMP/EWP/213056/2010) [21]. 
As F373280 aims to be a safe treatment for the prevention of AF recurrence, it will not be tested 
as an add-on therapy during the study. To avoid any interaction with the tested product, 
antiarrhythmics class I and III will be forbidden during the study. 
The study design is defined in order to avoid methodological bias. A double blind study is 
appropriate to assess the efficacy and safety of the use of F373280 to prevent recurrence of AF 
episodes. Moreover, this study design is similar to the design of almost all trials that have assessed 
intervention for rhythm control [2, 8, 11, 12].  
According to the target indication, only patients with persistent AF and requiring an ECV will be 
included in order to assess the time to first documented recurrence of AF (or emergence of atrial 
flutter) since cardioversion. 
To confirm the persistent nature of AF, a 24-hour holter monitoring will be performed during the 
selection visit.  
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Eligible participants will enter a selection phase in which anticoagulant treatment (VKA) will be 
adjusted to achieve ideally an International Normalized Ratio (INR) of 2 to 3 before ECV. 
According to guidelines for the management of AF [6], VKA should be given at least 3 weeks 
before cardioversion because of risk of thrombo-embolism due to post-cardioversion.  
Experimental data suggest that the maximal incorporation of n-3 PUFAs in the myocardial cell 
membrane takes up to 28 days to occur [22]. In addition, as shown in Nodari’s study [2], the 
duration of pre-treatment with PUFAs before cardioversion appears to be a contributing factor in 
success. Therefore, before starting follow up for the assessment of AF recurrence, treatment with 
F373280 should be started 28 days before ECV.  
Detection of AF recurrence will be performed using systematic (scheduled) ECG recording, thus 
allowing detection of asymptomatic (about 50% of episodes) as well as symptomatic AF episodes. 
According to previous studies, most of AF recurrences occurred during the first days after 
cardioversion [11, 15]. So that, the heart rhythm will be closely monitored during the first week 
after successful cardioversion using an ambulatory continuous 7-day holter ECG recording in 
order to increase sensibility to detect asymptomatic AF episodes. Thereafter, to improve patient 
compliance, this follow up will be continued using an easier device to carry and to use, i.e. a 
TTEM.  
Finally, during the study, patients will be scheduled for a clinical visit every 4 weeks or 8 weeks 
(with an additional visit 7 days after visit 3 (ECV visit)) in order to ensure a close medical 
monitoring and to assess efficacy and safety parameters. 
4.2.3. Choice of the Dose  
According to a previous study in patients with AF [2], the tested PUFA product (Omacor) at the 
dose of 2 g (i.e. 640 mg of DHA acid) was effective in the prevention of AF after cardioversion. 
Moreover, PUFAs at dosage of 1 g and 2 g were also effective on the improvement of ventricular 
functional parameters, morbi-mortality and duration of hospitalisation in patients with heart 
failure [3, 4, 5].  
From the F373280 phase I study, after a 14-day repeated administration of F373280 (1 g/day), 
observed plasma concentrations of DHA measured before treatment (Cmin) were similar to that of 
an effective dose of Omacor at 2 g/day (60 to 95 mg/ml and 60 to 90 mg/ml, respectively) (phase 
I study of F373280 and [16]). With regard to the rhythm of administration, mean peak/trough 
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fluctuation (baseline corrected) was around 0.3. This value supports a once-daily administration 
allowing a 24-hour plasma exposure in DHA. Therefore, a 1 g daily dose of F373280 is 
considered to be appropriate for this proof of concept study. 
4.2.4. Choice of the Sample Size 
See chapter 13. 
5. STUDY POPULATION 
Each patient fulfilling all the inclusion criteria and none of the non inclusion criteria will be 
eligible. 
5.1. 
INCLUSION CRITERIA 
Demographic Characteristics and Other Baseline Characteristics: 
1. Men or women aged more than 18 years (inclusive) 
2. Patient with current episode of persistent AF between 7 days and 6 months duration for whom 
electrical cardioversion is warranted 
3. Previous history of first documented episode of persistent AF  
4. Previous history of ischemic or non ischemic heart failure 
5. NYHA class I or II chronic heart failure at selection and at inclusion 
6. Left ventricular systolic dysfunction defined at selection and at inclusion by a reduced left 
ventricular ejection fraction (LVEF) ≥ 30% and ≤ 45% or for patients with a LVEF > 45%: 
• an increased left ventricular end-diastolic size  
(diameter ≥ 60 mm and/or > 32 mm/m² and/or volume > 97 ml/m²) 
• and/or an increased left ventricular end-systolic size 
(diameter > 45 mm and/or > 25 mm/m² and/or volume > 43 ml/m²) 
• and/or a reduced left ventricular outflow tract velocity time integral < 15 cm 
7. On appropriate, stable medical treatments for heart failure, including a diuretic and/or 
angiotensin-converting enzyme, and/or angiotensin-receptor blocker and/or mineralocorticoid 
receptor (MR) antagonists, and/or betablockers 
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8. Left atrial area ≤ 40 cm² at selection and at inclusion 
9. Patient treated or having to be treated by vitamin K antagonist 
10. For female patient of child-bearing potential:  
• In all the countries except Italy: 
 
- 
Use of an effective method of contraception (hormonal contraception or intra-uterine 
device) assessed by the investigator for at least 2 months before the selection in the 
study and agreement to go on using it during the whole duration of the study and up to 
1 month after the last dose of the study treatment or 
- 
Documented as surgically sterilized 
• In Italy only: 
- 
Absolute abstention from sexual intercourse during the whole duration of the study and 
for a month after the end of the study or 
- 
Use of double barrier contraception method (use of effective medical contraception 
method) from at least 2 months before the start of the study to the entire duration of the 
study and for a month after the end of the study or 
- 
Documented as surgically sterilized  
 
11. For female patient of child-bearing potential: negative urine pregnancy test at inclusion 
12. For male with a child-bearing potential partner (In Italy only): 
- 
Absolute abstention from sexual intercourse during the whole duration of the study and 
for 3 months after the end of the study or 
- 
Use of double barrier contraception method (use of condom for male and effective 
contraception method for the partner) from the entire duration of the study to 3 months 
after the end of the study. 
 
Ethical /legal considerations: 
13. Having signed his/her written informed consent, 
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14. Affiliated to a social security system, or is a beneficiary (if applicable in the national 
regulation) 
5.2. 
NON INCLUSION CRITERIA 
Criteria related to pathologies: 
1. No previous history of first documented episode of persistent Atrial Fibrillation 
2. More than two successful cardioversions (electrical or pharmacological) in the last 6 months, 
3. Secondary Atrial Fibrillation due to alcohol or severe valvular heart disease (grade III to IV), 
4. NYHA class III or IV heart failure at selection or at inclusion 
5. Thyroid disease uncontrolled by treatment: TSH ± T4L ± T3L to be checked in case of 
treatment for thyroid disease  
6. Myocardial infarction or unstable angina or presence of unstable ischemic coronaropathy 
assessed by coronarography or cardiac stress test (Echo stress, exercise stress test, nuclear or 
MR perfusion evaluation methods) within 6 months before selection 
7. Severe chronic kidney disease (creatinine ≥ 25 mg/L or estimated glomerular filtration rate < 
30 ml/min) at selection 
8. Bradycardia (HR ≤ 50 bpm) 
9. Hyperkalemia or hypokalemia (according to the standards of local laboratories) at selection 
10. Cardiac surgery within 3 months before selection or planned during the study duration 
Criteria related to treatments: 
11. Previously ineffective pharmacological or electrical cardioversion 
12. Concomitant treatment with ranolazine or any anti-arrhythmic drug (within 7 days prior to 
selection), except amiodarone, dronedarone and stable dose of digoxin, beta-blockers, 
calcium-blockers. 
13. Concomitant treatment with oral amiodarone or dronedarone from selection  
14. Concomitant treatment with intravenous amiodarone from selection  
15. Patient requiring a cardiac resynchronization therapy (CRT) or having undergone CRT 
implantation within the last 6 months 
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16. Treatment with any Polyunsaturated Fatty Acid within the last 3 months 
17. Dietary supplement with ω3 or ω6 according to investigator’s judgment 
18. Having undergone any form of ablation therapy for AF 
19. Patient treated with oral anticoagulant treatment other than vitamin K antagonist: new oral 
anticoagulants (dabigatran, rivaroxaban, apixaban), or treated with irreversible antiplatelet 
agents P2Y12 inhibitors such as ticlopidine, clopidogrel or prasugrel  
Others criteria:  
20. Patient liable not to comply with protocol instructions and/or with treatment, in the 
investigator’s opinion, 
21. Patient having taken part in a clinical trial in the preceding 2 months or taking part in a trial at 
the time of selection, 
22. Patient linguistically or mentally unable to understand the nature, objectives and possible 
consequences of the trial, or refusing to patient himself / herself to its constraints, 
23. Patient family member or work associate (secretary, nurse, technician…) of the Investigator, 
24. Patient having forfeited his / her freedom by administrative or legal award or being under 
guardianship, 
25. Breastfeeding female patient. 
5.3. 
NUMBER OF PATIENTS 
Maximum 135  patients (taking into account 15% of non-evaluable patients). 
5.4. 
RECRUITMENT MODALITIES 
Patients will be recruited within the medical consultation of each centre involved in the study. If 
necessary and when authorized by local and national regulation, some specific supports or tools 
will be used to improve the recruitment (announcement, mailing to general practitioners, leaflet, 
website including ClinicalTrials.gov, CRO…). 
Before implementation, the documents will be submitted to and approved by the Ethics 
Committee. 
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5.5. 
 PATIENT IDENTIFICATION 
Patient's code will contain 7 digits: the 2 first digits corresponding to the country number, the 
following 2 digits corresponding to the centre number and the last 3 digits corresponding to the 
patient's chronological order once having signed the written informed consent. 
5.6. 
WITHDRAWAL CRITERIA 
Reasons for a patient's premature withdrawal from the study may be the following: 
• Patient's decision. A patient who wishes to withdraw from the study for any reason may 
do so at any time but must inform the investigator. In all cases, the Investigator should 
attempt to contact the patient as soon as possible for a final assessment in order to: 
- have the patient's decision written on the consent form 
- obtain the reason(s) for withdrawal and report it/them in the case report form 
- evaluate the patient's clinical condition 
- if necessary, take appropriate therapeutic measures: management of an adverse 
effect or concomitant disease, prescription of another treatment. 
• Investigator's decision in the patient's interest, particularly if a serious adverse event 
occurs and is considered by the Investigator liable to threaten the health of the patient. The 
monitor will be informed by phone or fax and a letter or report explaining the withdrawal 
will be forwarded to the monitor as soon as possible. 
• Erroneous inclusion according to the study protocol. The decision to maintain or not the 
patient in the study will be taken jointly by the investigator and the sponsor. Erroneous 
inclusions will not be paid to the investigator. 
• Patients who could not be treated with VKA for at least 3 weeks before ECV or who will 
experience a VKA intolerance during the study. 
• Patients without dyskalemia who will not have INR values ≥ 2 on the 3 last tests 
performed before ECV should not have an ECV and will be excluded from the study. 
However, if only 2 INR values are ≥ 2 among those 3 last tests, an ECV can be performed 
if the presence of atrial thrombosis can be excluded with an ECHO–TE (transesophageal 
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echocardiography) performed on the same day (before ECV) and the patient can continue 
the study.  
• Patients who will not revert to sinus rhythm (i.e. unsuccessful ECV) or with early AF 
relapse or early atrial flutter emergence within the observation period after ECV will be 
considered to have finished follow-up. 
• Occurrence of AF recurrence or atrial flutter emergence that would require, at the 
investigator’s judgement, a cardioversion or an introduction of an anti-arrhythmic because 
of intolerable and/or uncomfortable clinical symptoms for instance. 
5.7. 
REPLACEMENT OF PATIENTS 
Withdrawn patients will not be replaced. 
5.8. 
POST-STUDY EXCLUSION PERIOD  
Patients will not be allowed to participate in another clinical trial during 3 months following the 
study termination. 
5.9. 
STUDY CARD AND LETTER FOR GENERAL PRACTITIONER(S) 
The patient will receive from the Investigating Centre at Visit 1 - Selection Visit:  
- a personal card to be kept all along the study duration and providing the following information: 
patient's name, sponsor's name, study code, EUDRACT number, start date and expected end date 
of the study, complete address of the Investigating Centre with the name and phone number of the 
Investigator and a sponsor 24H/24 phone contact number in case of emergency (French and 
English languages): 33 (0)5 63 35 25 83. For Italy, this card will be in Italian only, without any 
English mention. 
- in Italy, a letter to be given to his/her general practitioner. This letter intends to inform the 
general practitioner(s) (and any other doctors who take care of the patient) that the patient 
participates to the clinical study. It describes the study treatment and includes some information 
on the forbidden treatment during the study.  
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6. STUDY TREATMENT 
The Clinical Pharmacy Department of the Institut de Recherche Pierre Fabre (IRPF) will supply 
the investigational centres with the treatment necessary for the conduct of the trial.  
6.1. 
SOURCE, PRESENTATION AND COMPOSITION OF 
 
INVESTIGATIONAL PRODUCT 
F373280 and placebo will be prepared in Soft Capsules similar presentation.  
• F373280 
Formulation of F373280, 1 g, Soft Capsules: oral administration, oblong size 20, off-white, Soft 
Capsules containing: Panthenyl ester of DHA, gelatine, glycerol, titanium, dioxide, purified water. 
• Placebo 
Formulation of placebo matching tested product, Soft Capsules: oral administration, oblong size 
20, off-white, Soft Capsules containing: paraffin liquid, fish flavour, gelatine, glycerol, titanium, 
dioxide, purified water. 
 
Placebo and F373280 capsules will be packaged in opaque blisters. 
6.2. 
PACKAGING AND LABELLING 
The treatment units will be packed and labelled by the Clinical Pharmacy Department of the IRPF 
according to European Directive and local requirements. 
6.2.1. Packaging 
Each treatment unit will be composed of 3 cases for a 12-week treatment period. 
Two 12-week treatment units will contain 3 cases, each case of 4-week treatment containing:  
10 blister packs of four 1 g F373280 soft capsules or 1 g placebo soft capsules each. 
6.2.2. Labelling 
Investigational Products will be labelled according to the following rules: 
Labelling should comply with the local requirements for Investigational Medicinal Products. 
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On the treatment units and cases, the labels will bear the following indications:  
a) name and address of the sponsor 
b) protocol number 
c) packaging batch number 
d) treatment number 
e) storage conditions 
f) expiry date 
g) pharmaceutical dose form 
h) route of administration 
i) quantity of dosage units 
j) direction for use 
k) legal statements:  
    -“for clinical trial only”, “keep out of the reach and the sight of children”, “please return to 
your doctor any unused product”, respect the prescribed dose” 
On the treatment unit, another label will be affixed with the mention of the Investigator’s name 
and patient’s code (completed by the Investigator). 
In addition, on each case will be mentioned the case number and a detachable label will bear the 
following indications: 
− Protocol number 
− Packaging batch number 
− Expiry date 
− Case number 
− Treatment number 
On the blister pack, the label will mention the protocol number, the packaging batch number, the 
case number and the treatment number. 
6.3. 
DISTRIBUTION TO CENTRE AND STORAGE 
The Clinical Pharmacy Department of the IRPF will supply the Investigational Centre with the 
treatment units along the study according to the need, upon request triggered by the patient’s 
selection.  
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As soon as the Pharmacist or the Investigator receives the trial medication, he/she will check the 
contents and immediately acknowledges the receipt in the IVRS/IWRS. The copy of the 
acknowledgement will be kept in the Investigator’s or the Pharmacist’s file. The same procedure 
will be applied to all further supplies during the course of the trial. 
At the time of the delivery to the Centre, the following information will be provided: 
• Details of storage conditions that should be respected 
• And, upon request and for the 1st delivery only, a letter of release for the Investigational 
Medicinal Product from the Sponsor's Qualified Person 
The CRA will ensure during the monitoring visits that trial medications have been received in 
good conditions and the acknowledgment of receipt has been performed adequately. 
Treatment units should remain intact until dispensation to the patients. They should be kept at 
temperature below 30°C in an appropriate lockable room only accessible to the person authorised 
to dispense them, under the responsibility of the Pharmacist or the Investigator. 
In the case of undue delay in study execution, the Pharmacist or the Investigator should ensure 
that the expiry date has not been exceeded.  
6.4. 
ALLOCATION OF TREATMENTS AND DISPENSATION TO PATIENT 
A randomisation list will be established by the Clinical Pharmacy Department of the IRPF. This 
list will be computer-generated with internal software. The randomisation methodology is 
validated by the Biometry Department before generation. 
Treatments F373280 or placebo will be balanced in a 1:1 ratio. 
As the treatment units are prepared for 12-week treatment periods, the Investigator will have to 
allocate a treatment number at inclusion visit (V2) and another one at visit 6.  
For each patient, the treatment number given at visit 6 will not be the same that the one given at 
inclusion visit (V2). 
The treatment numbers will be given through the IVRS/IWRS. 
At selection visit (V1), practically, once patient’s eligibility is confirmed:  
• The Investigator: 
− Contacts the IVRS/IWRS 
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− Answers the questions related to the patient  
• The IVRS/IWRS company: 
− Confirms this information by fax/email to the Investigator 
− Fills the “Request for Delivery of Investigational Product” form and sends it by email 
and/or fax to the Clinical Pharmacy Department of the IRPF.  
• The Clinical Pharmacy Department of the IRPF sends the corresponding treatment unit to 
the Investigator within 5 days from reception of the email request form. 
 
At inclusion visit (V2), the treatment number to be allocated for the first 12-week period to the 
patient is given by the IVRS/IWRS.  
At visit 6, the Investigator will contact again the IVRS/IWRS to obtain the treatment number for 
the last 12-week period of treatment. 
The Investigator will dispense to the patient the 4-week treatment cases (one or two according to 
the visit) which label indicates the treatment number and the administration period. 
6.5. 
DRUG ADMINISTRATION 
6.5.1. Duration of Treatment 
For a patient completing the study, the theoretical study treatment exposure to F373280 or 
placebo will be 24 weeks. 
If the ECV is postponed by 1 week to allow INR stabilization, the treatment duration will be 25 
weeks. 
6.5.2. Dose Schedule 
One soft capsule of 1g of F373280 or placebo to be taken each day during 24 weeks. 
6.5.3. Route and Conditions of Administration 
The soft capsules are to be taken orally. One soft capsule is to be taken each evening with the 
dinner during 24 weeks.  
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6.6. 
ACCOUNTABILITY ON SITE AND RETURN/DESTRUCTION OF 
 
INVESTIGATIONAL PRODUCT 
The Investigator should maintain accurate written records of drug received, dispensed, returned 
and any remaining treatment units, on the drug accountability form. These records should be made 
available for Clinical Research Associate (CRA) monitoring. The packaging of the medication 
should remain intact until just before the dispensation. 
At each visit, the Investigator will record the number of soft capsules returned by each patient 
using the appropriate page of the e-CRF. 
At the end of the study, all used and unused treatments including packaging should be noted, and 
return is organised by the CRA to the Clinical Pharmacy Department of the IRPF for destruction. 
A copy of the drug accountability form should be provided by the Investigator to the CRA. 
6.7. 
RECALL OF INVESTIGATIONAL PRODUCTS  
In case of recall of investigational products (decided by the Competent Authorities or the 
Sponsor), the Investigator will immediately be informed by the Sponsor. 
The Investigator in collaboration with the Sponsor’s representatives (Study Manager, CRA) must 
urgently: 
• Stop the delivery of the concerned investigational products to the patients. 
• Inform the concerned patients that they must immediately stop taking these investigational 
products and bring them back. 
The Study Manager/CRA organises the return of the recalled products to the Clinical Pharmacy 
Department of the IRPF according to the Sponsor’s procedures. 
7. CONCOMITANT TREATMENTS 
Any existing concomitant treatment (at selection visit), any new concomitant treatment or change 
in the dosage of an existing concomitant treatment during the course of the study must be noted 
on the electronic Case Report Forms (e-CRF). All treatments should be evaluated by the 
Investigator at patient’s selection, and treatment prolongation or stop during the study should be 
considered. 
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For all concomitant treatments taken during the study, the following information must be noted in 
the relevant section(s) of the e-CRF: 
• The name of the treatment and its form 
• The reason for prescription 
• The route of administration 
• The daily dose 
• The duration of treatment. 
7.1. 
VITAMIN K ANTAGONIST TREATMENT 
VKA should be given for at least 3 weeks before ECV and continued for the whole study 
duration. However, VKA should be stopped in case of occurrence of VKA intolerance during the 
study and the patient should be withdrawn from the study. The VKA used will be left to the 
decision of each Investigator according to his/her local practice. 
7.2. 
PROHIBITED TREATMENTS 
- Class I and class III antiarrhythmic treatments: 
• Class I: 
o Class IA: Disopyramide, Procainamide, Quinidine 
o Class IB: Lidocaine, Mexiletine 
o Class IC: Flecainide, Propafenone 
• Class III: Dofetilide, Ibutilide, Sotalol, Amiodarone, Dronedarone. 
- Ranolazine 
- Any PUFA 
- Any oral anticoagulant treatment other than VKA: new oral anticoagulants (dabigatran, 
rivaroxaban, apixaban), or irreversible antiplatelet agents P2Y12 inhibitors such as ticlopidine, 
clopidogrel or prasugrel 
- Dietary supplement with Omega 3 or Omega 6 
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Prohibited treatments at selection must not be prescribed for the duration of the study except in 
case of occurrence of an adverse event or AF episode that requires a corrective treatment in the 
interest of the patient’s health. 
7.3. 
AUTHORISED TREATMENTS 
Other treatments will be authorised during the study duration. 
However, if medication other than study drugs is administered at any time from the start of the 
study, details must be recorded in the e-CRF. During the study, patients must be asked whether 
they have been on a course of prescribed drug treatment or have taken any OTC or herbal drugs 
since the visit. 
8. EVALUATION CRITERIA 
8.1. 
PRIMARY EFFICACY CRITERION  
8.1.1. Time to the first Atrial Fibrillation Recurrence or Atrial Flutter Emergence 
8.1.1.1. 
Definition 
Time to first AF recurrence or atrial flutter emergence is defined by the time to first episode of AF 
or atrial flutter (symptomatic or not) lasting for at least 10 minutes. 
8.1.1.2. 
Schedule 
The heart rhythm follow up will be performed from the end of ECV visit (visit 3) to the final 
study visit (visit 9).  
For randomised patients with spontaneous cardioversion before ECV, the recurrence of AF or the 
emergence of atrial flutter will be assessed after visit 3 (from week 5). 
8.1.1.3. 
Evaluation Methods 
• 7-day holter monitor: 
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The heart rhythm monitoring will be carried out from visit 3 to visit 4 using a 7-day continuous 
ECG (5-leads/2 or 3 channels) ambulatory recording (holter ECG) fixed after ECV visit.  
Following holter monitoring, the heart rhythm will be documented using Trans Telephonic ECG 
Monitoring (TTEM). 
• Trans Telephonic ECG Monitoring: 
The ECG follow up will be documented using the TTEM: one transmission per week from the day 
of visit 4 (end of week 5) to visit 9 (week 24, end of study). The patient will be requested to 
contact the Central Reading Laboratory for transmission of each stored TTEM.  
Moreover, if patient experiences AF or atrial flutter symptoms during this TTEM period, it should 
be documented using the TTEM. 
In case of AF recurrence or atrial flutter emergence and provided that the patient does not require 
a cardioversion or an introduction of an anti-arrhythmic at Investigator’s judgement, the patient 
could be maintained in the study with the treatment in order to assess a spontaneous 
cardioversion. For that purpose the patient will continue to transmit a TTEM once a week. 
• Process of centralisation of ECG (Holter and TTEM) 
ECG (Holter and TTEM) will be centralized by the Central Reading Laboratory. The ECG will be 
validated by a trained technician, then analysed by a cardiologist. The cardiologist interpretation 
will be emailed to the site (or per fax on request of the site). The investigator will be asked to 
review and sign these documents. 
The Holter and TTEM process will be fully described in separate documents. 
8.2. 
SECONDARY EFFICACY CRITERIA 
8.2.1. Numbers of AF episodes in the first week following visit 3 (ECV visit) 
8.2.1.1. 
Definition 
Number of AF episodes will consist in the assessment of AF episodes with duration at least 10 
minutes (NSup10) and of less than 10 minutes (NInf10), respectively. 
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8.2.1.2. 
Schedule 
The heart rhythm follow up will be performed from the end of successful ECV visit (visit 3) to the 
study visit 4.  
8.2.1.3. 
Evaluation Methods 
• 7-day holter monitor: 
The heart rhythm monitoring will start using a 7-day continuous ECG (5-leads/2 or 3 channels) 
ambulatory recording (holter ECG) after ECV visit from visit 3 to visit 4. 
8.2.2. 
Duration of AF episodes in the first week following visit 3 (ECV visit) 
8.2.2.1. 
Definition 
Duration of AF episodes will consist in the sum of duration of each AF episode. 
8.2.2.2. 
Schedule 
The heart rhythm follow up will be performed from the end of successful ECV visit (visit 3) to the 
follow up study visit (visit 4).  
8.2.2.3. 
Evaluation Methods 
Duration of AF episodes will be assessed using the 7-day continuous ECG (5-leads/2 or 3 
channels) ambulatory recording. 
8.2.3. 
Clinical parameters evaluation 
8.2.3.1. 
EHRA score assessment 
8.2.3.1.1. 
Definition 
AF related symptoms will be evaluated by the EHRA (European Heart Rhythm Association) score 
[20]. The following items “during presumed arrhythmia episodes" are checked to determine the 
score: palpitation, fatigue, dizziness, dyspnea, chest pain and anxiety. 
Classification of AF-related symptoms (EHRA score) are as follows: 
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• EHRA I          - ‘No symptoms’ 
• EHRA II         - ‘Mild symptoms’; normal daily activity not affected 
• EHRA III       - ‘Severe symptoms’; normal daily activity affected 
• EHRA IV       - ‘Disabling symptoms’; normal daily activity discontinued  
This classification relates exclusively to the patient-reported symptoms. 
In addition to this score, the frequency will be classified in three groups, namely occasionally 
(less than once per month), intermediate (1/month to almost daily) and frequent at least daily. 
8.2.3.1.2. 
Schedule 
EHRA evaluation will be performed in case of evocative symptoms of arrhythmia. 
8.2.3.1.3. 
Evaluation Methods 
EHRA evaluation will be collected by Central Reading Laboratory during TTEM period. 
 
8.2.3.2. 
Time to first AF recurrence less than 10 minutes 
Time to first AF recurrence less than 10 minutes will be assessed during TTEM period. 
8.2.3.3. 
Recurrence of symptomatic AF  
Recurrence of symptomatic AF will be assessed during TTEM period. 
The number of recurrences of symptomatic AF consists of the number of AF recurrences 
associated with a symptom (palpitation, fatigue, dizziness, dyspnea, chest pain and anxiety) and 
confirmed by an ECG. 
The time to first symptomatic AF recurrence is defined by the time to first episode of 
symptomatic AF. 
8.2.3.4. 
Number and duration of hospitalizations 
• Number and duration of hospitalizations for cardiovascular events 
− Hospitalization for AF treatment 
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− Hospitalization for worsening of heart failure 
− Hospitalization for myocardial infarction 
− All cause of hospitalization 
• Number and duration of hospitalizations for thromboembolic stroke  
 
8.2.4. 
Cardioversion assessment 
• Assessment of spontaneous cardioversion before visit 3 
• Assessment of successful cardioversion at visit 3 (i.e. return to sinus rhythm) 
• Shocks distribution (1, 2 or 3 shocks) 
• Number of patients needing another cardioversion after initial ECV 
8.2.5. 
Evolution of echocardiographic parameters 
8.2.5.1. 
Definition 
The following echocardiographic parameters will be assessed: Left atrial diameter (mm), LAA 
(cm2), Left atrial volume (ml), Left atrial volume/BSA (ml/m2), LVEF (%), Left ventricular end 
diastolic volume/BSA (ml/m2), Left ventricular end systolic volume/BSA (ml/m2), Left 
ventricular end diastolic diameter (mm), Left ventricular end diastolic volume (ml), Left 
ventricular end systolic diameter (mm) and Left ventricular end systolic volume (ml). 
8.2.5.2. 
 Schedule 
Measurements will be performed at visit 1 and visit 2 to check the eligibility of the patient.  
Measurements performed at visit 4, visit 6 and visit 9 are done to follow the echocardiographic 
evolution of the patients in sinus rhythm. 
8.2.5.3. 
Evaluation method 
The echography evaluations will be carried out according to the recommendations for chamber 
quantification drawn up by the American Society of Echocardiography and the European 
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Association of Echocardiography [23]. So, the recommended method for volume measurements is 
to use the biplane method of discs (modified Simpson’s rule) from 2-D measurement. 
8.3. 
BIOMARKER ASSESSMENT: RED BLOOD CELL 
 
CONCENTRATIONS OF DHA 
8.3.1. Definition 
Because of the limited human tissue accessibility for biopsy, red blood cell DHA contents is a 
marker of tissue DHA concentration [13], [14]. 
8.3.2. Blood samples 
8.3.2.1. 
Collection schedule 
Blood samples will be collected to determine the red blood cells (RBC) concentrations of DHA.  
Blood samples will be performed at visit 2 before treatment, visit 3, visit 6 and visit 9. 
Actual sampling times will be individually reported in the e-CRFs. 
8.3.2.2. 
Technical handling 
Two blood samples (2 x 4 ml) will be collected in EDTA tubes. They will be homogenized slowly 
by inverting the tube without shaking, stored between +2°C/+8°C in a fridge (no freezing will be 
allowed) and sent to Analytical Centre in refrigerated conditions (between +2°C and +8°C). 
Analysis will be performed within 2 weeks following reception at the Analytical Centre. 
8.3.3. DHA concentration measurement 
Analytical determination of RBC concentrations of DHA will be carried out by the Analytical 
Centre. 
Lipids will be extracted from red blood cells samples with a mixture of hexane/isopropanol after 
acidification [17]. Total lipid extracts will be saponified and methylated. The fatty acid methyl 
esters (FAME) will be extracted and analyzed by Gas Chromatography. 
Identification of FAME will be based on retention times obtained for FAME prepared from fatty 
acid standards. The area under peaks will be determined using ChemStation Software (Agilent) 
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and results will be expressed as % of total fatty acids. DHA concentration will be calculated using 
the internal standard and expressed as µg/g for red blood cells samples. Thus, omega-3 index will 
be assessed. The omega-3 index represents the content of EPA plus DHA in red blood cells 
(expressed as a percent of total fatty acids). It is a biomarker considered as a new marker of risk 
for death from coronary disease [18]. 
Results of this analytical determination will be kept confidential by the dosing centre until the end 
of the study, and will be provided only at the end of the study (after database lock) in a separate 
file. 
8.4. 
SAFETY ASSESSMENT 
8.4.1. Adverse Events 
At selection, any concomitant disease will be reported on the e-CRF. At each further visit, the 
occurrence of AEs since the last visit will be based on the patient's spontaneous reporting, the 
Investigator's non-leading questioning and his/her clinical evaluation. All AEs will be reported on 
the e-CRF (see section 10). 
8.4.2. Laboratory Investigations 
8.4.2.1. 
Schedule 
Laboratory investigations will be performed at visit 1 (before treatment) and visit 9 (end of 
treatment) or End of Treatment visit. 
At visit 3 and 6, only a standard haematologic dosage will be performed.  
Furthermore the kalemia will be checked before electrical cardioversion at visit 3. 
The total volume of blood samples taken for haematology and biochemistry analysis should not 
exceed 30 ml. 
8.4.2.2. 
Technical Procedures and Parameters 
The following tests will be performed: 
 
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Haematology: 
haematocrit, haemoglobin, RBC count, white blood cells (WBC) count, WBC 
differential counts (% and/or absolute), reticulocytes, platelets.  
 
Biochemistry: 
sodium, potassium, bicarbonate, chloride, alkaline phosphatase, gamma GT, 
albumin, total bilirubin, conjugated bilirubin, creatinine, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), fasting glucose, 
total cholesterol, cholesterol (HDL, LDL), triglycerides, creatine 
phosphokinase (CPK), fibrinogen. 
Blood samples will be taken in the morning in fasting conditions.  
The estimation of GFR at selection relies on the measurement of serum creatinine and the 
Cockcroft- Gault formula: 
Cockcroft-Gault formula 
- with serum creatinine expressed as mg/L:  
in men: 
GFR (ml/min) = [(140-age) x weight / (7.2 x serum creatinine in mg/L)] 
 
in women: 
GFR (ml/min) = [(140-age) x weight / (7.2 x serum creatinine in mg/L)] x 0.85 
 
- with serum creatinine expressed as μmol/l: 
GFR (ml/min) = [(140-age) x weight / serum creatinine in μmol/l] x k,where k = 1.23 for men, 
1.04 for women. 
 
(weight in kg, age in years) 
Additional tests may be done at the Investigator’s discretion, in the patient’s interest. In case of 
any abnormal and/or clinically significant results, the Investigator should order laboratory control 
tests. 
8.4.3. Global Physical Examination 
A global physical examination including the measurement of body weight will be carried out on 
each body system at visit 1, visit 2, visit 3, visit 6, visit 7, and visit 9. 
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The Body surface area (BSA) will be calculated at the same visits using Mostellers’ formula: 
BSA = [(Weight x Height)/3600]1/2 
(Weight in kg, height in cm) 
The physical examination will be globally evaluated as “normal/abnormal”. Further target 
inspection will be undertaken for any abnormal finding. 
8.4.4. Vital Signs 
Vital signs will consist in blood pressure and heart rate at rest.  
8.4.4.1. 
Schedule 
Vital signs will be measured at each visit. 
8.4.4.2. 
Technical Procedure and Parameters 
Systolic blood pressure (SBP) and diastolic blood pressure (DBP), expressed in mmHg, will be 
measured after at least 5 minutes in supine position and after 2 minutes in standing position.  
The heart rate (HR), expressed in beats per minute (bpm), will be measured by auscultation by 
counting the beats for at least 30 seconds, after at least 5 minutes in supine position and after 2 
minutes in standing position. 
Bodyweight will be measured with patient in underwear and with the same balance at each visit.  
8.4.5. Electrocardiogram (ECG)  
8.4.5.1. 
Schedule 
An ECG will be recorded after at least 10 minutes of rest at visit 1, visit 2, visit 3, visit 6, visit 7, 
and visit 9 using a usual standardised 12-lead cardiograph. 
8.4.5.2. 
Technical Procedure and Parameters 
• Electrocardiogram: 
The global interpretation from manual reading (normality, clinical relevance) and HR (bpm), PR 
(ms), QRS (ms), QT (ms), QTcB (ms), QTcF (ms), repolarisation patterns will be reported in the 
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e-CRF. Each print-out will include the patient’s code, date, time, technician's initials and 
investigator's signature. 
In case of thermic paper ECG print out, a photocopy will be made by the centre to ensure safe 
filing. 
• 24 hour-Holter - ECG 
An ambulatory continuous 24-hour ECG (5-leads/2 or 3 channels) will be recorded at selection 
visit using a holter ECG, in order to confirm persistent AF.  
8.4.6. Coagulation parameters 
Coagulation assessment will be evaluated by the following parameters: 
− Prothrombin Time/INR (PT/INR) 
− Activated Partial Thromboplastin Time (aPTT) 
− Thrombin Clotting Time (TCT) 
The recommendations for the controls of INR are the following [25, 26]: 
1) During the pre-cardioversion period, if the anticoagulation by VKA has to be initiated, the 
treatment must be initiated at least 3 weeks prior to cardioversion then the INR will be monitored 
as follow:  
− The adjustment of the dosage of VKA should be performed stepwise by controlling INR 2 
to 3 times a week until stabilization within the target range (2 - 3) on 2 successive tests. 
− When the INR is within the target range (2 - 3) on 2 successive tests, the dose of VKA 
should be maintained. Then the controls of INR will be progressively spaced within a few 
weeks.  
− When INR is stabilized, at least one test should be performed each week. 
− In all cases, an INR control must be performed within 24 h before ECV. 
2) During the pre-cardioversion period, if the anticoagulation by VKA was already initiated, the 
INR will be monitored as follow: 
− One INR per week up to ECV 
− An INR control must be performed within 24 h before ECV 
3) After cardioversion : one INR every 4 weeks 
4) Throughout the duration of the study if INR > 3 the advocated actions are: 
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− No transesophageal echocardiography before cardioversion 
− For asymptomatic patients:  
- 3 < INR < 4: no omission of VKA (dose adjustment if required), no vitamin K 
- 4 ≤ INR < 6: omit one dose of VKA, no vitamin K 
- 6 ≤ INR < 10: interrupt VKA, vitamin K 2 mg orally 
- INR ≥ 10: interrupt VKA, vitamin K 5 mg orally 
For INR ≥ 6, an adverse event has to be reported (asymptomatic overdose).  
Anti-coagulation by VKA should be given at least 3 weeks before ECV and continued for the 
whole study duration. 
aPTT and TCT will be performed at visit 1, visit 2, visit 3, visit 6, visit 7, and visit 9. 
The quantity of blood samples collected at each time for coagulation parameters will be 2 ml. 
Additional tests may be done at the Investigator’s discretion, in the patient’s interest. In case of 
any abnormal and/or clinically significant results, the Investigator should order laboratory control 
tests. 
8.5. 
CONCOMITANT TREATMENTS 
Concomitant treatments will be evaluated at each study visit. 
Requirements related to patient's concomitant treatments started before selection visit and 
continued throughout the trial, or started during the trial, can be found in section 7.  
8.6. 
COMPLIANCE 
The patient will be reminded at each visit to bring back at the following visit any used or unused 
remaining soft capsule, blister and case. 
At each visit (except at visit 4), the Investigator will record the number of supplied and remaining 
soft capsules in the e-CRF. 
9. STUDY PROCEDURES 
Visit 1 - Selection Visit (Week - 4 to Week -1): 
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The patient considered eligible for selection by the Investigator will be informed of the 
characteristics and the consequences of the trial both verbally and by reviewing the patient's 
information sheet and consent form (see section 14.3). If the patient accepts to participate in the 
study, he/she will sign the informed consent form and will keep a copy. 
The patient will be assessed for the following: 
• Demographic characteristics (gender, age, height, body surface area) 
• Personal and medico-surgical history 
• Habits (Tobacco, alcohol consumption, dietary habits including fish consumption…) 
• Cardiovascular diseases, mainly detailed history of Heart Failure and AF characteristics  
• Echocardiography using a two-dimensional echocardiography 
• 12-lead ECG 
• Concomitant diseases, adverse signs or symptoms (able to be used for treatment emergent 
AE determination) 
• Concomitant treatments (authorised, disallowed) 
• Global physical examination/bodyweight 
• Vital signs 
• Biology: haematology, biochemistry, assessment of coagulation parameters: Prothrombin 
Time/INR (PT/INR), Activated Partial Thromboplastin Time (aPTT), Thrombin Clotting 
Time (TCT) 
• Biology assessment of renal function: creatinine or estimated glomerular filtration rate 
If the results of the above assessments are compatible with the selection criteria: 
• A 24-hour continuous ECG ambulatory recording (Holter ECG) device will be installed 
on the patient to monitor the patient heart rhythm. The patient will be requested to bring 
back the device after the termination of 24 hours recording. The recording will be 
transmitted from the Investigational site to the Central Reading Laboratory. The Central 
Reading Laboratory will send his/her assessment regarding the confirmation of persistent 
AF within 2 working days to the Investigator. 
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• The patient will enter the selection and pre-cardioversion periods in which anticoagulant 
(VKA) will be adjusted to achieve ideally an International Normalized Ratio (INR)  in the 
range of 2 to 3 before ECV.  
At the end of the visit, the Investigator will contact the IVRS/IWRS to confirm the patient 
selection (which will automatically order the treatment delivery) and organise the appointment for 
the next visit.  
The patient will receive from the investigational centre the participant card to be kept for all the 
duration of the study. 
Visit 2 - Inclusion Visit (Day 1):  
If the patient's behaviour during the selection period and/or the result of complementary 
examinations, particularly the confirmation of the presence of persistent AF by the Central 
Reading Laboratory during this period and the laboratory tests, are compatible with the inclusion 
criteria, the patient will be assessed for the following: 
• Adverse events 
• Concomitant treatments (authorised, disallowed) 
• Laboratory examination: red blood cell concentrations of DHA and coagulation 
parameters Prothrombin Time/INR (PT/INR), Activated Partial Thromboplastin Time 
(aPTT), Thrombin Clotting Time (TCT) 
• Global Physical examination/bodyweight 
• Vital signs 
• Echocardiography using a two-dimensional echocardiography 
• 12-lead ECG 
• Urine pregnancy test for women of child bearing potential 
If the results of the above assessments are compatible with the inclusion criteria, the patient will 
be included and the investigator will contact the IVRS/IWRS to obtain the treatment unit number 
to be dispensed at visit 2 for the first 12-week period. 
Between this Inclusion visit and the next visit (V3), the INR will be closely monitored (refer to 
paragraph 8.4.6) in order to fulfil the ECV conditions (refer to paragraph 3).  
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At the end of the visit, the Investigator will organise the appointment for the next visit and will 
give the treatment for the next 4-week period (one case of treatment). 
Visit 3 (Week 4: D28 -2/+7 days) cardioversion: 
Patient will be assessed for the following criteria: 
• Adverse events 
• Concomitant treatments (authorised, disallowed) 
• Laboratory examination: Haematology, RBC concentrations of DHA, Prothrombin 
Time/INR (PT/INR), Activated Partial Thromboplastin Time (aPTT), Thrombin Clotting 
Time (TCT) 
• Global Physical examination /bodyweight 
• Vital signs  
• 12-lead ECG 
• Electrocardioversion (ECV): ECV has to be performed 4 weeks after randomization in 
patients with AF. ECV will be performed in the morning, with the patient in the fasting 
state and without dyskalemia. An INR value control must be performed within 24h before 
ECV. INR values ≥ 2 on the 3 last tests performed before ECV are required. However, if 
only 2 INR values are ≥ 2 among those 3 last tests, an ECV can be performed if the 
presence of atrial thrombosis can be excluded with an ECHO–TE (transesophageal 
echocardiography) performed on the same day (before ECV) and the patient can continue 
the study. Anesthesia will be induced and patients will be cardioverted with administration 
of a synchronized, biphasic current. The initial shock will be set at 100 J if the body 
weight is less than 70 kg and at 150 J for higher body weights. Successful cardioversion 
will be defined as recovery of sinus rhythm lasting at least 1 minute after the shock. If 
unsuccessful, a second 200-J shock, and eventually a third 200-J shock, will be 
administered. Failure of ECV is defined as the persistence of AF after the third attempt at 
cardioversion. After the procedure, patients will be monitored on telemetry for at least 6 
hours before discharge.  
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Patients who will not revert to sinus rhythm or with early AF relapse or early atrial flutter 
emergence within the observation period after ECV will be withdrawn from the study and will 
be considered to have finished their follow-up. 
 
At the end of the visit, a 7-day continuous ECG (5-leads/2 or 3 channels) ambulatory recording 
(holter ECG) will be installed on the patient in order to monitor the patient heart rhythm after 
ECV.  
The Investigator will collect all unused cases, blisters and soft capsules, and will count the unused 
capsules for each 4-week treatment period. 
At the end of the visit, the Investigator will organise the appointment for the next visit and give 
the treatment to be taken during the next 8-week period (two cases of treatment). 
Visit 4 (Week 5: D35 -2/+7 days): 
After removal of the continuous ECG ambulatory device, the patient will be assessed for the 
following criteria: 
• Assessment of AE 
• Concomitant treatments (authorised, disallowed) 
• Bodyweight (bodyweight measured at V3 to be used) 
• Vitals Signs 
• Echocardiography using a two-dimensional echocardiography 
At the end of the visit, the patient will be given the TTEM device for cardiac monitoring. The 
patient will be clearly instructed on the frequency and modalities of transmission. The patient will 
be requested to perform one transmission per week from this visit (initial call to perform with the 
patient) to the visit 9 (week 24 – end of study). Moreover, in case of AF or atrial flutter 
symptoms, additional transmissions may be performed.  
Visit 6* (Week 12: D84 ± 7 days) - Visit 7 (Week 16: D112 ± 7 days) : 
*see amendment PA05 dated 22OCT2014 
Patient will be assessed for the following criteria: 
• Adverse events 
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• Concomitant treatments (authorised, disallowed) 
• Laboratory 
examination: 
Prothrombin 
Time/INR 
(PT/INR), 
Activated 
Partial 
Thromboplastin Time (aPTT), Thrombin Clotting Time (TCT). However, in case of 
discontinuation of anticoagulation after ECV due to occurrence of VKA intolerance, the 
monitoring of INR, aPTT and TCT should be stopped. 
• Global Physical examination/bodyweight  
• Vital signs  
• 12-lead ECG 
• The cardiac monitoring will be continued using the TTEM device through one 
transmission per week from the day of visit 4 (end of week 5) to visit 9 (week 24, end of 
study). Moreover, in case of AF or atrial flutter symptoms, additional transmissions may 
be performed. 
The Investigator will collect all unused cases, blisters and soft capsules, and will count the unused 
capsules for each 4-week treatment period. 
In addition, at visit 6: 
• the investigator will contact the IVRS/IWRS to obtain the treatment unit number to be 
dispensed at visit 6 for the last 12-week period. 
• an echocardiography will be performed, an haematology examination will be done and the 
RBC concentration of DHA will be measured.  
At the end of each visit, the Investigator will organise the appointment for the next visit and give 
the treatment to be taken during the next treatment period: one case at visit 6 and two cases at visit 
7. 
Visit 9* - End-of-Study Visit (Week 24: D168 ± 7 days):  
*see amendment PA05 dated 22OCT2014 
Patient will be assessed for the following: 
• Adverse events 
• Concomitant treatments (authorised, disallowed) 
• Global Physical examination/bodyweight 
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• Vital signs 
• 12-lead ECG 
• Laboratory examination: haematology, biochemistry, assessment of coagulation 
parameters: Prothrombin Time/INR (PT/INR), Activated Partial Thromboplastin Time 
(aPTT), Thrombin Clotting Time (TCT), Red blood cell concentration of DHA. 
• Urine pregnancy test for women of childbearing potential 
• Echocardiography using a two-dimensional echocardiography 
The Investigator will collect all unused cases, blisters and soft capsules, and will count the unused 
soft capsules. 
 
The total volume of blood collected should be about 90 ml for the study duration (30 ml for the 
total volume of haematology and biochemistry, 2 ml for each blood samples for coagulations 
parameters and 4 ml for each blood samples of DHA). 
10. ADVERSE EVENTS: DEFINITION AND REPORTING 
10.1. ADVERSE EVENTS 
10.1.1. Definition of Adverse Events 
An AE is any adverse change from the patient's baseline condition, i.e. any subjective signs and 
symptoms or change in a concomitant disease present at the Selection Visit considered or not 
related to the treatment. 
AE includes intercurrent signs, symptoms, illnesses and significant deviations from baseline for 
vital signs and laboratory values which may occur during the course of the clinical study. 
All laboratory tests for which abnormal results are collected after study treatment initiation should 
be repeated until the values return to normal or to a stable status. Abnormal results are defined as 
those falling out of the laboratory normal ranges and that are clinically significant. The frequency 
of such checks should be defined by the Investigator according to the degree of abnormality. 
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In all cases, the aetiology should, as much as possible, be identified and Pierre Fabre Médicament 
notified. 
10.1.2. Grading of Adverse Events 
Adverse or intercurrent events are graded as follows: 
• Mild: awareness of signs or symptoms, but easily tolerated 
• Moderate: uncomfortable enough to cause interference with usual activity 
• Severe: incapacity with inability to work or do usual activity 
10.1.3. Reporting of Adverse Events 
The records of AE in the e-CRF describe the nature (diagnosis, signs and symptoms), severity, 
onset date, stop date, outcome and actions taken, and relationship to study treatment (in the 
Investigator's opinion). It must be specified whether the event is serious or not. 
10.2. SERIOUS ADVERSE EVENTS (SAE) 
10.2.1. Definition 
A SAE includes, but is not necessarily restricted to, any event which: 
• Results in death (whatever may be the cause) 
• Is life-threatening 
• Results in persistent or significant disability/incapacity 
• Requires the patient's hospitalisation or prolongation of current hospitalisation * 
• Is a congenital anomaly or birth defect 
Other events such as cancer and any additional adverse experience or abnormal laboratory values 
occurring during the study period, defined by the protocol as serious or which the Investigator 
considers significant enough or that suggest a significant hazard, contra-indications, side effect or 
precaution, must be handled as serious adverse events. 
Any overdosage meeting a seriousness criteria should be reported as a SAE (see section 10.3). 
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Any pregnancy occurring during/after exposure to the study drug(s) should be reported on the 
SAE notification form (see section 10.4). 
* any hospitalisation, or prolongation of hospitalisation due to the circumstances listed below: 
− planned (as per protocol) medical/surgical procedure 
− preparation for routine health assessment/procedure (e.g. routine colonoscopy) 
− planned medical/surgical admission (planned prior to entry into study trial, appropriate 
documentation required) 
− administrative or social reasons (e.g. lack of housing, economic inadequacy, care-giver 
respite, family circumstances) 
will not be reported as a SAE. 
10.2.2. Reporting of SAE 
All Serious Adverse Events, according to the above-mentioned definitions and regardless of 
treatment or relationship to study drug, and occurring once the informed consent form has been 
signed, must be reported by the Investigator as soon as he/she is informed of the event. 
The Investigator must notify the Sponsor of this event by sending, within 24 hours, the 
"Notification of serious adverse event" form ("first notification") with all the available 
information about the event (see appendix 17.2), to the Sponsor's Corporate Vigilances e-mail 
dedicated box: 
HQ.pharmacovigilance@pierre-fabre.com 
 
 In case it is not possible to send the report by e-mail it can be sent by FAX at the 
following number: 
+ 33 1 49 10 80 90 
In case of non-inclusion, the reporting period ends when the non-inclusion is documented. 
10.2.3. Follow-up of SAE 
The Investigator must draw-up a specific clinical report and use the "Notification of serious 
adverse event" form ("follow-up") (see appendix 17.2) and collect the results of the carried out 
examinations and the reports of hospitalisation. 
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The serious adverse events must be followed up until resolution or stabilisation. 
10.2.4. SAE Occurring After the Study 
Any SAE occurring during 30 days following the end of the study for the patient should be 
notified to the Sponsor. 
Must also be notified to the Sponsor any event occurring at any time after the end of the study for 
the patient which may be related to the study treatment in the Investigator's opinion. 
10.3. REPORTING OF OVERDOSAGE TO THE SPONSOR 
For the purpose of this trial, an overdosage will be defined as any dose exceeding the planned 
prescribed dose of the study drug or the administration of any dose of an associated product that is 
considered both excessive and medically important. 
In the absence of seriousness criteria, the overdosage and associated adverse event if any, are 
reported only on the Adverse Event page of the e-CRF. If the definition of seriousness criteria is 
met, the SAE notification form must also be transmitted to the Sponsor. 
10.4. REPORTING OF PREGNANCY TO THE SPONSOR 
Pregnancies discovered in the period in between the informed consent form signed but before any 
study drug exposure are not to be reported to the Sponsor unless associated to a seriousness 
criteria (e.g. serious adverse event study-protocol related procedure). If pregnancy is confirmed, 
the women must not be administered the study drug and must be withdrawn immediately from the 
study.  
If pregnancy is suspected while the patient is receiving study treatment, the study drug should be 
discontinued immediately until the result of the pregnancy testing is known. If pregnancy is 
confirmed, then the study treatment is permanently discontinued in an appropriate manner and the 
patient is withdrawn from the study.  
The Investigator must report to the Sponsor any pregnancy which occurs during or after the 
patient has been exposed to the study drug and until 30 days after the last study drug 
administration. The Investigator must immediately notify the Sponsor using the SAE notification 
form and also report the pregnancy on the AE page of the e-CRF. 
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Women who become pregnant after exposure to the study drug must be followed by the 
Investigator until the completion/termination of the pregnancy. If the pregnancy goes to term, the 
outcome will have to be reported to the Sponsor (baby's healthy status). 
10.5. SPONSOR'S RESPONSIBILITIES FOR SAFETY REPORTING 
 
PURPOSES 
Sponsor will submit expedited and periodic reports to both Competent Authorities and Ethics 
Committees per corporate standard operating procedures as regards to the EU directive 
2001/20/EC taking into account local specific requirements. 
11. DATA COLLECTION AND STUDY MONITORING 
11.1. DATA COLLECTION 
11.1.1. Case Report Form 
An e-CRF will be used to record all patient data required by the protocol except the central ECG 
(Holter ECG, TTEM) and DHA data which will be transferred from vendors to the subcontractor 
as electronic data files that will be loaded into the study database.  
The e-CRF should be fully validated, compliant with ICH-GCP requirements and European 
regulations and should include a traceability system for data corrections and deletions (audit trail). 
Prior to the start of the study, the Investigator will complete a "Delegation of significant study-
related duties" form. The signature and initials of all personal in charge of e-CRF completion 
should be recorded on this form. Each person involved in e-CRF completion, review, correction 
and / or validation will be trained and will have an individual login and access code to the e-CRF. 
Training sessions will be held by the subcontractor for all participants using this tool. An e-CRF 
user manual will be available for investigators and CRAs.  
All the information included into the e-CRF will be recorded from source documents onto the e-
CRF by an authorised person. 
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The Investigator is responsible for the management and accuracy of the information on the e-
CRF. At each monitoring visit, the e-CRF(s) should be at the CRA's disposition for review and 
validation.  
At the end of the study, a CD-ROM containing the pdf version of all e-CRFs (including audit-
trail) will be sent by the subcontractor to the Sponsor and to the investigational sites for archiving. 
The subcontractor must store all study data for at least 15 years after the end of the study and 
ensure their legibility and accessibility during all the storage period. 
11.1.2. Source Documents 
A source document is an original record or certified copy of an original record of clinical findings, 
observations or any other medical or paramedical activities performed during the clinical trial, 
necessary for the transcription and the verification of the collected data. 
Source documents along with all other trial-related documents (copies of all "informed consent" 
forms, e-CRFs CD-ROM, drug inventories and any correspondence related to the study) must be 
kept in the investigator's file throughout the study, and then, must be stored in the study centre's 
archives for a period of at least 15 years or as per local legal requirements, whatever is the 
longest.  
For further details see section 15.2. 
11.2. STUDY MONITORING 
11.2.1. Monitoring visits 
On-site visits will be carried out by a representative of the Sponsor's staff (Study Manager or 
CRA) prior to study initiation and at regular intervals (every 4 to 6 weeks) throughout the study. 
Additional visits and communication by telephone fax or meeting may be performed if necessary. 
Any site visit performed by the Sponsor's representatives will be recorded in the Investigator's 
study file. 
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11.2.1.1. Site Preselection Visit 
Before selecting a centre for the study, a visit will be carried out by the CRA and/or the Study 
Manager to ensure that the Investigator has the necessary capacities (availability, patient's 
recruitment, environment), technical means and staff to carry out the study. 
11.2.1.2. Initiation Visit 
Before the start of the study at all investigational sites, an initiation visit will be carried out by the 
CRA to check at the latest that: 
• The Investigator: 
− has received the technical protocol, administrative and financial agreement signed by all 
parties 
− has received the written statement of the Ethics Committee approval and the list of its 
members and their functions 
• The original dated and signed curriculum vitae of the investigator(s) has been collected 
• Laboratory normal ranges have been collected  
• All study materials are available on the study site 
• All participants agree with the monitoring procedures and know the study procedures 
• All participants are aware of a possible audit or inspection 
The CRA has also to provide training on the study protocol requirements and study specific 
procedures. 
11.2.1.3. Follow-up Visits 
Throughout the study, regular follow-up visits will be carried out by the CRA to check 
compliance with GCP, patient’s informed consents, strict application of the protocol, conformity 
of the data entered on the e-CRF with the source documents and ensure its correct completion, 
adverse events reporting, proper retention, storage and management of the study medication, as 
well as the source and other trial-related documents. 
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11.2.1.4. Closing Visit 
At the end of the study, a final visit will be carried out by the CRA to: 
• Verify that the e-CRFs CD-ROM with pdf files are correctly stored 
• Control the accountability of intact and used treatment units and return them to the 
Clinical Pharmacy Department of the IRPF for destruction 
• Obtain the last data clarifications and/or solutions if any 
• Collect the patient's consent forms in sealed envelopes (except in case of specific country 
requirements),  
• Make an on-site review of all study documentation and complete it if necessary 
• And finally, remind the Investigator of his regulatory obligations, study document 
archiving process and duration. 
11.2.2. Direct Access to Source Documents 
In accordance to the requirements of the GCP, all Sponsor representatives (Study Manager, CRA 
and Auditors) have to be given a direct access to all source and study data to perform quality 
monitoring/audit, thus ensuring accuracy and completeness of data).  
Investigators are reminded that all Sponsor representatives keep professional confidentiality with 
regards to the patient data. 
11.3. INDEPENDENT DATA MONITORING COMMITTEE 
An Independent Data Monitoring Committee (IDMC) will be established to assess at intervals the 
progress of the clinical trial, the compliance with the inclusion criteria, the quality of follow up, 
the quality of primary end point measures, the safety data. The IDMC will thereafter recommend 
to the Sponsor whether to continue, modify, or stop the study.  
The IDMC operating procedures will be described in an independent document.  
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12. DATA MANAGEMENT  
All clinical data related to the study will be collected and saved in a computerised database by the 
Data Management Department of the subcontractor and under the supervision of the Data 
Manager of Pierre Fabre Biometry (PFB) according to the following procedures.  
12.1. DATA ENTRY 
All required data will be collected by the Investigator or authorised designee (duly identified into 
the delegation task list) on the e-CRFs.  
The e-CRFs used for this study will be developed and maintained by the Data Management 
Department of the subcontractor and approved by the Sponsor.  
Electronic data (Holter ECG, TTEM and DHA) will be transferred by the 3rd party vendor 
according to the specifications given by the Data Manager of the subcontractor. These data will be 
captured and handled in accordance with the European GCP ICH E6 guideline. 
12.2. DATA CLEANING 
The subcontractor will define in the Data Validation Plan for reviewing and querying data, 
descriptions of both manual and electronic edit checks. Upon Sponsor approval, the subcontractor 
will program the checks.  
The subcontractor will review the data over the course of the study, working with the Sponsor to 
identify data inconsistencies. The Investigator will be asked to resolve queries by making changes 
directly into the e-CRF.  
12.3. DATA CODING 
Adverse events, concomitant diseases, medical/surgical histories will be coded by the 
subcontractor using the MedDRA dictionary (latest version in use). 
Concomitant medication will be coded by the subcontractor using the WHO-DRUG dictionary 
(latest version in use).  
The Sponsor Clinical Development Physician will validate the coding. 
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12.4. DATA STORAGE 
Computer data files as well as their modifications will be archived by the subcontractor and kept 
available upon request of the Sponsor. 
12.5. DATABASE LOCK 
The validated database will be locked by the subcontractor upon request of the Data Manager of 
PFB following the completion of all steps required, i.e. data entry and check of all data, resolution 
of all queries, validation of the coding, Clinical and Products Safety databases reconciliation and 
validation committee.  
Then, the subcontractor will transfer the locked database in SAS format to the Data Manager of 
PFB who assume storage on the PFB secured server. 
13. STATISTICAL ANALYSIS 
After the database lock and the randomisation code release, the statistical analysis will be 
performed by PFB or under the supervision of the statistician of PFB using SAS® software, 
according to the Statistical Analysis Plan approved by the Validation Committee. 
13.1. GENERAL CONSIDERATIONS 
The main objective of the study is to assess the efficacy of F373280 versus placebo on the 
maintenance of sinus rhythm after direct ECV in patients with persistent AF and chronic heart 
failure. 
Only the primary analysis of the primary efficacy criterion, on which is based the sample size 
justification, may lead to a causal interpretation. All other statistical results are to be regarded 
within a descriptive perspective. 
The statistical significance level of the various two sided tests of all analyses will be 5 %. 
13.2. SAMPLE SIZE 
Assuming an AF recurrence or atrial flutter emergence rate of 85% under placebo and 65% under 
active group, i.e. a clinically relevant difference ∆ of 20%, a sample size of 64 assessable patients 
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per group is required, using a log-rank test of survival curves with a 80 % power and a 5 % two-
sided significance level. 
According to the previous assumptions and assuming a rate of not assessable patients of 15%, a 
minimum of 76 patients will have to be randomised per group. 
Due to the premature stop of the recruitment 135 patients were finally randomised. 
13.3. PROTOCOL DEVIATIONS 
Prior to the database lock and the randomisation code release, the Validation Committee members 
will review the protocol deviations and will classify them as either minor or major. A protocol 
deviation will be considered major when it is likely to bias significantly the treatment effect 
estimate based on the primary efficacy criterion. 
Patients with major deviation(s) will be excluded from the Per Protocol data set (see section 13.4). 
A listing of all protocol deviations will be provided for all randomised patients, including the type 
(major/minor) of protocol deviations according to the decisions made by the members of the 
Validation Committee. 
The number and percentage of patients with major protocol deviations will be tabulated by 
treatment group and type of major protocol deviations on the Full Analysis Set defined in section 
13.4. 
13.4. DATA SETS ANALYSED 
The following 3 data sets will be analysed (as defined by the Validation Committee):  
 
• The Safety Set composed of all randomised patients having received at least one dose of 
the study treatment. This data set will be used to perform analyses of Safety. 
• The Full Analysis Set (FAS) composed of all randomised patients having received at least 
one dose of the study treatment and with a successful cardioversion observed at visit 3. 
This data set will be used to perform analyses of Efficacy.  
• The Per Protocol Set (PP) which is the subset of the Full Analysis Set composed of all 
patients with a primary efficacy criteria available and without any major protocol 
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deviation or other source of bias for primary criteria analyses. This data set will be used to 
perform the supportive analysis of the primary efficacy criterion. 
13.5. HANDLING OF DROPOUTS AND MISSING DATA 
13.5.1. Dropouts 
The number of patients who withdraw from the study after their randomisation will be provided 
by treatment group for all treated patients (Safety Set). All withdrawn patients will be further 
described regarding their time to dropout and reasons for withdrawal. 
13.5.2. Repositioning of Visits 
No repositioning of visits will be done. 
13.5.3. Missing Data 
Missing values will not be substituted by estimated values, but considered as missing in statistical 
analysis. 
13.6. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Before the first trial drug intake, patient’s background, medical and surgical history, demographic 
data and disease characteristics will be described by treatment group on the Safety Set. 
- Quantitative parameters will be described by treatment group and overall using the 
following: number of patients, number of missing data, mean, standard deviation, 
minimum, median and maximum values. 
- Qualitative parameters will be described by treatment group and overall using 
frequencies. 
Concomitant diseases, as well as medical and surgical histories will be tabulated descriptively by 
treatment group and overall using the MedDRA codes of System Organ Classes and preferred 
terms. 
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If more than 10% of patients are excluded from the FAS and PP set, the description of patients by 
treatment group at selection and inclusion will be repeated on the FAS and PP set for all 
parameters. 
No statistical test of comparability of treatment groups at baseline will be performed.  
13.7. EFFICACY ANALYSIS  
13.7.1. Primary Criterion  
13.7.1.1. Primary Analysis 
The primary criteria, time to first recurrence of AF or atrial flutter emergence, will be analysed 
using the Kaplan Meier method and compared with the Log rank test. Hazard ratios and 95% 
confidence intervals will be estimated with the Cox regression model. 
The primary analysis will be performed on the FAS. 
13.7.1.2. Supportive Analysis 
The primary analysis will be repeated on the PP set. 
13.7.1.3. Additional Analysis 
To take into consideration the sample size reduction, the predictive probability of success with 
the expected sample size based on observed data, the predictive power and the conditional 
power will be provided to support the statistical decision. 
13.7.2. Secondary Criteria 
All secondary analyses will be performed on the FAS. If more than 10% of patients are excluded 
from the PP set, the secondary analyses will be repeated on the PP set.  
13.7.2.1. Numbers of Atrial Fibrillation Episodes in the first week following V3 
Both the numbers of AF episodes (symptomatic or not) lasting for at least 10 minutes and with 
duration less than 10 minutes (NSup10 and NInf10) will be described by treatment group and 
compared by the chi-square test (or CMH test adjusted for centre) or Fisher’s exact Test. 
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13.7.2.2. Duration of Atrial Fibrillation Episodes in the first week following V3 
The duration of all AF Episodes will be described by treatment group and compared using the 
Student t (or using an ANOVA with treatment and centres effects) or Wilcoxon test. 
13.7.2.3. Time to first AF recurrence less than 10 minutes or symtomatic 
The time to the first AF recurrence less than 10 minutes and the time to the first symptomatic AF 
recurrence will be analysed as the primary analysis.  
13.7.2.4. Clinical parameters evaluation 
The EHRA score will be described by treatment group and analysed using a chi-squared test (or 
CMH test adjusted for centre) or Fisher’s exact Test.  
The frequency of presumed arrhythmia will be described by treatment group. 
The number of recurrence of symptomatic AF, of hospitalizations (for cardiovascular events, for 
thromboembolic stroke and for all causes), of spontaneous cardioversion, of successful 
cardioversion (including number of shocks distribution) and the number of patients needing 
cardioversion after initial ECV will be described by treatment group and compared using a chi-
square test or a Fisher Test (if the numbers are relevant).  
The duration of hospitalizations for cardiovascular events, for thromboembolic stroke and for any 
cause will be described by treatment group and compared using the Student t (or using an 
ANOVA with treatment and centre effects) or Wilcoxon test. 
The echocardiographic parameters values will be described at each time (V1, V2, V4, V6 and V9) 
and changes described from V4 to V9 and from V2 to V9. 
13.7.2.5. Biomarker analysis: red blood cell concentrations of DHA 
Values and changes from baseline for red blood cell concentration of DHA will be performed by 
treatment group and assessment time. 
13.8. SAFETY ANALYSIS 
The Safety Set will be used to perform all analyses of the safety criteria. 
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13.8.1. Adverse Events 
Any adverse event having been reported during the study for a given patient will be classified by 
preferred term and corresponding system organ class using the MedDRA terminology. 
Adverse events will be classified as: 
• Treatment emergent adverse events, i.e., any adverse event which occurs or worsens on 
study treatment during the randomised period. 
• Or non treatment emergent adverse events, i.e., any adverse event which occurs during the 
run-in period (before V2) or is reported as concomitant disease with the same intensity. 
For each study period, any patient with at least one reported adverse event will be classified as a 
patient: 
• With at least one adverse event 
• With at least one treatment emergent adverse event 
• With one TEAE 
• With two TEAEs 
• With at least three TEAEs 
• With at least one related TEAE 
• With an adverse event leading to the study treatment discontinuation (definitive or 
temporary) 
• With an adverse event leading to withdrawal 
• With at least one serious adverse event. 
Numbers and percentages of patient with at least one reported treatment emergent adverse event 
will be tabulated by treatment group: 
• By system organ class 
• By system organ class and preferred term 
• By system organ class and preferred term, taking into consideration its most severe 
intensity 
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• And by system organ class and preferred term, taking into consideration the most severe 
relationship to the study treatment. 
Recurring adverse events (i.e., adverse events classified with the same preferred term) for a given 
patient will only be counted once and only their most severe intensity or most severe relationship 
to the study treatment will be tabulated. 
The number and percentage of patient with at least one most common (reported in 1% patients in 
any group) drug related TEAE ("not excluded or unassessable") will be tabulated by Preferred 
Term and Treatment group in decreasing order for the treatment group (for all patients). 
The number and percentage of patients with at least one reported most common treatment 
emergent adverse event will also be plotted by treatment group. This graphical representation will 
highlight the frequencies of the most severe intensities reported by system organ class and 
preferred term. 
SAE will also be described on an individual basis: treatment group, patient's code, sex and age, 
Investigator's reported term, preferred term, time of onset according to the time of the first study 
treatment administration, duration, action taken regarding the study treatment administration, use 
of a corrective treatment, outcome and relationship to the study treatment in the Investigator’s 
opinion. 
13.8.2. Clinical Laboratory Evaluation  
For each laboratory parameter, data will be tabulated by treatment group and assessment time. 
The absolute changes post-trial drug administration - baseline (the baseline value being the value 
measured on the last blood sample collected before the first trial drug administration) will be 
calculated and tabulated by parameter, treatment group and post-trial drug administration 
assessment time. Results of retests performed post-trial drug administration will not be analysed 
and tabulated. They will only be displayed in individual data listings. 
For all biochemistry parameters, scatter plots highlighting individual results will display the 
baseline and week 24 of the laboratory measurements for each patient by locating the point 
defined by the baseline value on the abscissa and respectively week 24 value in the ordinate.  
For all haematology parameters, scatter plots highlighting individual results will display the 
baseline and week 4, week 12 and week 24 of the laboratory measurements for each patient by 
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locating the point defined by the baseline value on the abscissa and respectively week 4, week 12 
and week 24 value in the ordinate.  
Each treatment group will be differently identified. The first bisecting line (45° line), the lines of 
lower and upper normal range, the lines of Potentially Clinically Significant Change (PSC) range 
and Clinically noteworthy abnormal laboratory value (CNALV) range added on the plots (see 
Appendix 17.3). 
For all blood laboratory parameters, shift tables will be provided to depict the numbers of  patients 
with post-trial drug administration variations at each assessment time as compared to the baseline 
values (measured on the last blood sample collected before the first trial drug administration) by 
treatment group. A 3-point scale (low, normal, high) will be used as defined by the normal ranges 
in use in the laboratory in charge of the assays. 
CNALV (see in Appendix 17.3) will be identified and described on an individual basis. If 
relevant, five separate individual data listings by treatment group will be provided: 
• CNALV for haemoglobin (including corresponding individual results of erythrocytes and 
haematocrit) 
• CNALV for neutrophils or leucocytes (including corresponding individual results of 
basophils, eosinophils, lymphocytes and monocytes) 
• CNALV for platelets (including corresponding individual results of erythrocytes and 
leucocytes) 
• CNALV for liver function parameters (including corresponding individual results of 
gamma-GT) 
• CNALV for serum creatinine  
13.8.3. Global Physical Examination 
Recorded data of the global physical examination performed will not be tabulated as any 
abnormal findings post-randomisation should be reported as AEs (if clinically significant). 
Physical examination assessments will be provided in the listings of individual data. 
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13.8.4. Vital Signs, Physical Findings and Other Observations Related to Safety 
13.8.4.1. Vital Sign Measurements Over Time 
For each parameter (systolic blood pressure, diastolic blood pressure and HR in supine and 
standing positions), descriptive statistics over time of values and changes from baseline will be 
tabulated by treatment group and assessment time. 
13.8.4.2. Body weight 
Descriptive statistics over time of values and changes from baseline will be tabulated by treatment 
group and assessment time. 
13.8.4.3. Individual Patient Changes 
The number and percentage of patient with at least one Predefined Potentially Clinically 
Significant Change (PSC) and with at least one PSC Leading to Clinically Significant Value 
(PSCV) will be tabulated by treatment group (see Table 1 in Appendix 17.3).  
According to the pharmacological drug profile mentioned previously in this Protocol, the changes 
from baseline to the maximum and/or minimum post-baseline value could be categorized and 
tabulated by treatment group with frequencies and decreasing cumulative percentages. 
If there is a signal of a drug effect toward one direction rather than the other, additionally shift 
tables of variations from baseline to the maximum or minimum post-baseline value could be also 
provided (see Table 2 to 4 in Appendix 17.3). 
An individual data listing of patients with symptomatic or asymptomatic orthostatic hypotension 
will be provided by treatment group (see Table 5 in Appendix 17.3). 
13.8.5. ECG 
Frequencies on the clinical interpretation (normal, abnormal CS or NCS) will be presented by 
treatment group and assessment time. Individual tabulated data for ECG abnormalities will be also 
displayed. 
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13.8.6. Coagulation parameters 
Scatter plots highlighting individual results for coagulation parameters (prothrombin time/INR, 
activated partial thromboplastin time and thrombin clotting time) before and after study treatment 
administration will be produced. 
13.9. CONCOMITANT TREATMENTS 
Concomitant treatments will be tabulated by treatment group within a descriptive perspective. 
They will be classified by therapeutic area according to the WHO-DRUG dictionary using the 
"anatomical therapeutic chemical" classification on the safety set. 
13.10. COMPLIANCE 
 
The percentage of compliance will be described by treatment group using the quantity 
 
100
_
_
_
(%)
×
=
n
consumptio
l
Theoretica
n
consumptio
actual
Estimated
Compliance
 
 
 
with: Estimated actual consumption = number of tablets provided at the start of study (Visit 2) 
minus number of tablets returned at the end of study (Visit 9) 
Theoretical consumption = number of days of treatment intake planned between the start and the 
end of study (168 days ± 7days) 
 
13.11. INTERIM ANALYSIS AND DATA MONITORING 
No analyses of efficacy data are planned for IDMC that ensures that the overall probability of type 
I error is controlled. No Type I error and sample size adjustments are necessary. Any 
recommendations of the IDMC to alter study conduct will be based on safety, so IDMC 
monitoring of the study will not affect the statistical operating characteristics of the final analysis. 
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The IDMC will review, two times during the study period (after the first 30 subjects will have 
been randomized and when the first 80 subjects will have terminated their study participation), 
safety data results across treatment groups and judges whether the overall safety and feasibility 
(not futility) of the trial remain acceptable. 
14. GENERAL ETHICAL CONSIDERATIONS  
14.1. ETHICAL CONDITIONS 
This study is performed in accordance with the principles stated in the Declaration of Helsinki 
(1964) and subsequent amendments and in accordance with the Good Clinical Practice Guideline 
(CPMP/ICH/135/95). 
14.2. ETHICS COMMITTEE AND LEGAL REQUIREMENTS 
All the documents required by National Regulations and any other informative documents that 
may be requested are submitted for review to an Ethics Committee whose procedures and 
operations meet the GCP and National Legal Requirements. 
Depending on National Regulations, the application is submitted to the Ethics Committee by the 
Sponsor (or representative) or by the Investigator. 
A copy of the formal written approval from the Ethics Committee is provided to the Sponsor 
(directly by the Ethics Committee or via the Investigator) with a list of names and qualifications 
of its members. 
The request for authorisation by the Competent Authority or its notification if required (depending 
on National Regulations) is carried out by the Sponsor. 
The screening of patients does not start before the approval of the Ethics Committee has been 
obtained and the study authorised by the Competent Authority or notified to the Competent 
Authority (depending on National Regulations). 
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14.3. PATIENT'S INFORMATION LEAFLET AND INFORMED CONSENT 
 
FORM 
An information must be given to the patients before their decision to participate or abstain from 
participation. 
This information is based on the elements set out in the Declaration of Helsinki and the ICH GCP 
Guidelines. It must also describe the measures taken to safeguard patient’s privacy and protection 
of personal data, according to European Directive 95/46 EC or other local regulation. 
Restraints and risks must be explained, as well as the right to discontinue participation in the 
study at any stage, without affecting their further relationship with the Investigator and/or their 
future care. 
The written information and consent form must be submitted to the patient with an oral 
explanation. It must be agreed and signed by the patient before any study-related procedure starts. 
This information and consent procedure is under the Investigator’s responsibility. 
The information and consent document are made in triplicate: the original copy is kept by the 
Investigator, one copy is given to the patient and the last copy is kept by the Clinical Quality 
Assurance Unit of the Sponsor in a sealed envelope at the end of study (except in case of specific 
country requirement). 
Specific areas of the Sponsor’s copy are not triplicated to avoid the reading of the patient’s 
surname (except the first 3 letters), first name, address and signature.  
If any information becomes available during the trial that may be relevant to the patient’s 
willingness to keep on participating in the trial, an updated written informed consent must be 
submitted to the patient to confirm  agreement to continue participating. 
14.4. PERSONAL DATA PROTECTION 
All information from this study (excluding data from the informed consent) is entered into a 
computer under the Sponsor’s responsibility in accordance with the French law, "Loi 
Informatique et Libertés" (January 6, 1978, and subsequent amendments) and with the European 
Directive 95/46/CE. 
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14.5. INSURANCE POLICY 
In accordance with the provisions of the law and the GCP, the Sponsor Pierre Fabre Médicament, 
has an insurance policy intended to guarantee against possible damage resulting from the research. 
The studies and/or experiments performed on behalf of the Sponsor Pierre Fabre Médicament are 
specifically and expressly guaranteed. 
It is advisable to underline that non compliance with the Research Legal Conditions is a cause for 
guarantee exclusion. 
15. ADMINISTRATIVE PROCEDURES 
15.1. PROTOCOL AMENDMENT 
Neither the Investigator nor the Sponsor may alter the protocol without the authorisation of the 
other party.  
All changes to the protocol are subject to an amendment which must be dated and signed by both 
parties and must appear as an amendment to the protocol. 
Substantial amendments are submitted for approval / authorisation to the Ethics Committees and 
Competent Authorities. 
Urgent amendments are submitted for approval / authorisation to the Ethics Committees and 
Competent Authorities, but could be implemented immediately under specific conditions defined 
with the Sponsor. 
15.2. SOURCE DOCUMENTS, INVESTIGATOR'S FILE STORAGE 
The Investigator: 
• Keeps all trial-related documents in appropriate file folders. Records of patient, original 
informed consent forms, source documents, a CD Rom containing a pdf copy of e-CRF, 
drug inventory, Ethics Committees and Sponsor correspondence pertaining to the study 
must be kept on file. 
• Retains all documents relating to the screening (consent and investigation results) of all 
patients included in the trial or not. 
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• Retains a list of the patient’s names, addresses (and/or number of medical file), code 
numbers to allow checking of data reported on e-CRFs with those from source documents. 
• Authorises direct access to source documents for monitoring, audits and inspections. 
• The trial-related documents must be retained as strictly confidential at the Investigator’s 
site for at least 15 years or according to local requirements, whatever is the longest after 
the completion or discontinuation of the trial (European Directive 2003/63/EC). 
15.3. END OF THE STUDY 
15.3.1. Definition of the End of Study 
The end of study is the last visit of the last patient undergoing the trial. 
Any change to this definition during the study, for whatever reason, must be notified as a 
substantial amendment. 
15.3.2. Early Study Termination 
15.3.2.1. Early Study Termination Decided by the Sponsor 
The Sponsor may discontinue the study at any time for any of the following reasons: 
• Lack of recruitment 
• Deviations from good clinical practice and/or regulations 
• Poor product safety 
• New information that could jeopardise the patient’s safety 
• Stopping of the development … 
15.3.2.2. Early Study Termination Decided by the Competent Authorities 
The Competent Authorities may suspend or prohibit a study if they consider that either the 
conditions of authorisation are not being met or has doubt about the safety or scientific validity of 
the study. 
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15.4. AUDIT 
The Sponsor is responsible for making sure that both its representatives (Study Manager, CRA...) 
and the Investigator fulfil the requirements as specified by the GCP Guideline.  
An audit can be organised internally at Pierre Fabre Médicament and at the investigational site 
where the e-CRFs are matched against source documents. 
All study documentation must be directly accessible to auditors. 
The practical conditions for the audit are discussed between the Investigator and the Clinical 
Quality Assurance Department. 
Oral information about the audit results are given to the Investigator. 
15.5. INSPECTION 
The Health Authorities may inspect any investigation site or the Sponsor in the course of the study 
or after its completion, to verify the conduct of the study and quality of the data. The Investigator 
must provide to the inspectors direct access to study documents. 
15.6. CONFIDENTIALITY 
The present materials (protocol and related documentation, e-CRF, Investigator's Brochure) 
contain confidential information.  
Except if agreed in writing with the Study Manager, the Investigators must hold such information 
confidential, and must not disclose it to others (except where required by Applicable Law). 
15.7. CLINICAL STUDY REPORT 
Data analysis and clinical study report writing are under the Sponsor’s responsibility.  
Upon data analysis completion, a final report including a review of the objectives and methods, a 
presentation and a discussion of the results is drawn up according to ICH Guidelines (Structure 
and Content of Clinical Study Reports, ICH-E3, CPMP/ICH/137/95). 
The report is a clinical and statistical integrated report. It must be signed by the Sponsor's 
representative(s) and the Coordinating Investigator. 
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15.8. STUDY RESULTS COMMUNICATION 
Upon completion of the study, the global results of the Research are communicated to the 
Investigator. According to the Local Regulation, the patient can ask the Investigator for the 
results. 
15.9. STUDY RESULTS PUBLICATION 
The information and data collected during the conduct of this clinical study are considered 
confidential and are used by the Sponsor in connection with the development of the study drug. 
This information may be disclosed if deemed necessary by the Sponsor. 
To allow the use of the information derived from this clinical study and to insure compliance with 
Current Regulations, the Investigator must provide the Sponsor with complete test results and all 
data collected during the study.  
Only the Sponsor may make study information available to physicians and to Regulatory 
Agencies, except as required by Current Regulations. 
All the results of this study including data, reports, discoveries and inventions resulting from the 
study, are the property of the Sponsor. 
In the event the Sponsor chooses to publish study data, the manuscript must be provided to the 
author(s) at least 30 days prior to the expected date of submission to the intended publisher. 
The Investigator(s) can reserve the right to publish or present study data; if so, the manuscript or 
abstract must be provided to the Sponsor for review at least 30 days prior to the expected date of 
submission to the intended publisher or of planned presentation. 
In addition, if necessary, (the) Investigator(s) shall withhold publication for an additional 60 days, 
to allow the filing of a patent application, or to allow the Sponsor to take any measures he deems 
appropriate to establish and preserve his proprietary rights. 
It is agreed that publication of study results by each site shall be made only as part of a 
publication of the study results obtained by all sites performing the protocol, once the study is 
completed and finalised.  
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The authors list is agreed by all Investigators prior to publication. The names of the authors are 
provided according to their participation in the design of the protocol as well as their recruitment 
of eligible and analysable patients. 
 
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16. REFERENCES 
 
[1]. 
F373280 INVESTIGATOR'S BROCHURE, version October 2013 
 
[2]. 
NODARI S., TRIGGIONAI M., CAMPIA U., MANERBA A., MILESI G., CESANA 
M.B., GHEORGHIADE M., DEI CAS L. 
n-3 Polyunsaturated Fatty Acids in the prevention of atrial Fibrillation Recurrences after 
electrical cardioversion. A prospective, Randomised study 
Circulation, 2011; 124:1100-1106 
 
[3]. 
NODARI S., TRIGGIANI M., CAMPIA U., MANERBA A., MILESI G., CESANA 
M B., GHEORGHIADE M., DEI CAS L. 
Effects of n-3 polyunsaturated fatty acids on left ventricular function and functional 
capacity in patients with dilated cardiomyopathy 
J. Am. Coll. Cardiol. 2011;57;870-879 
 
[4]. 
MOERTL D., HAMMER A., STEINER S., HUTULEAC R., VONBANK K., 
BERGER R. 
Dose-dependant effects of omega-3-polyunsaturated fatty acids on systolic left ventricular 
function, endothelial function, and markers of inflammation in chronic heart failure of non 
ischemic origin: A double-blind, placebo-controlled, 3-arm study  
American Heart Journal 2011; 161:915.e1-915.e9 - volume 161, number 5 
 
[5]. 
GISSI-HF INVESTIGATORS 
Effects of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GSSI-
HF Trial): a randomised, double-blind, placebo-controlled trial 
The lancet on line - August 2008 
 
[6]. 
CAMM A.J., KIRCHHOF P., LIP G.Y., SCHOTTEN U., SAVELIEVA I., ERNST 
S., VAN GELDER I.C., AL-ATTAR N., HINDRICKS G., PRENDERGAST B., 
HEIDBUCHEL H., ALFIERI O., ANGELINI A., ATAR D., COLONNA P., DE 
CATERINA R., DE SUTTER J., GOETTE A., GORENEK B., HELDAL M., 
HOHLOSER S.H., KOLH P., LE HEUZEY J.Y., PONIKOWSKI P., RUTTEN F.H. 
Guidelines for the management of atrial fibrillation: the Task Force for the Management of 
Atrial Fibrillation of the European Society of Cardiology (ESC). 
European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery, 
Eur Heart J. 2010 Oct;31(19):2369-429 
 
 
[7]. 
KOWEY PR, REIFFEL JA, ELLENBOGEN KA, NACCARELLI GV, PRATT CM. 
Efficacy and safety of prescription omega-3 fatty acids for the prevention of recurrent 
symptomatic atrial fibrillation: a randomised controlled trial. 
JAMA. 2010;304:2363–2372. 
 
 
 
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[8]. 
BIANCONI L., CALO L., MENNUNI M., SANTINI L., MOROSETTI P., 
AZZOLINI P., BARBATO G., BISCIONE F., ROMANO P., SANTINI M.  
N-3 polyunsaturated fatty acids for the prevention of arrhythmia recurrence after electrical 
cardioversion of chronic persistent atrial fibrillation: a randomised, double-blind, 
multicentre study  
Europace (2011) 13, 174-181 
 
[9]. 
OMACOR® SUMMARY PRODUCT CARACTERISTICS (SPC) dated 17/02/2012 
 
[10]. 
BEPANTHENE ® SUMMARY PRODUCT CARACTERISTICS (SPC) 
 
[11]. 
TOUBOUL P, BRUGADA J, CAPUCCI A, CRIJNS HJ, EDVARDSSON N, 
HOHNLOSER SH.  
Dronedarone for prevention of atrial fibrillation: a dose-ranging study.  
Eur Heart J 2003;24(16):1481-7. 
 
[12]. 
LE HEUZEY JY AND ALL.  
A Short-Term, Randomised, Double-Blind, Parallel-Group Study to Evaluate the Efficacy 
and Safety of Dronedarone versus Amiodarone in Patients with Persistent Atrial 
Fibrillation: The DIONYSOS Study. 
J Cardiovasc Electrophysiol. 
 
[13]. 
METCALF G.R., JAMES J.M., GIBSON A.R., EDWARDS J., STUBBERFIELD J., 
STUKLIS R., YOUNG D.G., ROBERTS-THOMSON K. & CLELAND G.L.M.L. & 
OKEN H. 
Effects of fish-oil supplementation on myocardial fatty acids in humans.  
Am J Clin Nutr (2007); 85 : 1225. 
 
[14]. 
ARTERBURN M.L. & OKEN H. 
Distribution, interconversion and dose response of n-3 fatty acids in humans.  
Am J Clin Nutr (2006);83 : 1469-1473S. 
 
[15]. 
TIELEMAN RG, VAN GELDER IC, CRIJNS HJ, DE KAM PJ, VAN DEN BERG 
MP, HAAKSMA J, VAN DER WOUDE HJ, AND ALLESSIE MA. 
Early recurrences of atrial fibrillation after electrical cardioversion: a result of 
fibrillation-induced electrical remodelling of the atria? 
J. Am. Coll. Cardiol. 1998;31;167-173 
 
[16]. 
SALM P, TAYLOR PJ, KOSTNER K 
Simultaneous quantification of total eicosapentaenoic acid, docosahexaenoic acid and 
arachidonic acid in plasma by high-performance liquid chromatography-tandem mass 
spectrometry.  
Biomed Chromatogr 2011 Jun;25(6):652-9. 
 
[17]. 
LEGRAND P., SCHMITT B., MOUROT J., CATHELINE D., CHESNEAU G., 
MIREAUX M., KERHOAS N., WEILL P. 
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The consumption of food products from linseed-fed animals maintains erythrocyte omega-
3 fatty acids in obese human.  
Lipids, 2010, 45, 11-19. 
 
[18]. 
HARRIS WS, VON SCHACKY C. 
The Omega-3 Index: a new risk factor for death from coronary heart disease? 
 Prev Med. 2004 Jul; 39(1):212-20 
 
[19]. 
ABSTRACT: P5161.  
NODARI S, MANERBA A., MADURERI A., BERLINGHIERI N., PULCINI E., 
FRATTINI S., METRA M, DEI CAS L. 
Effects of Polyunsaturated Fatty Acids n-3 (PUFA n-3) in the prophylaxis of atrial 
fibrillation relapses after external electric cardioversion 
World Congress of Cardiology 2006, 2-6 September, Barcelona – Spain 
[20]. 
KIRCHHOF P., AURICCHIO A., BAX J., CRIJNS H., CAMM J., DIENER HC., 
GOETTE A., HINDRICKS G., HOHNLOSER S., KAPPENBERGER L., KUCK 
KH., LIP HYG., OLSSON B., MEINERTZ T., PRIORI S., RAVENS U., 
STEINBECK G., SVERHAGE E., TIJSSEN J., VINCENT A., BREITHARDT G. 
Outcome parameters from a consensus conference organized by the German Atrial Fibrillation 
Competence NETwork and the European Heart Rhythm Association. 
Europace 2007, 9, 1006-1023 
[21]. 
EUROPEAN MEDICINES AGENCY 
Addendum to the guideline on antiarrhythmics on atrial fibrillation and atrial flutter. 
EMA/CHMA/EWP/213056/2010 
[22]. 
OWEN AJ, PETER-PRZYBOROWSKA BA, HOY AJ, MCLENNAN PL. 
Dietary fish oil dose- and time-response effects on cardiac phospholipid fatty acid composition. 
Lipids. 2004;39:955–961 
[23]. 
ROBERTO M. LANG, MICHELLE BIERIG, RICHARD B. DEVEREUX, FRANK 
A. FLACHSKAMPF*, ELYSE FOSTER, PATRICIA A. PELLIKKA, MICHAEL H. 
PICARD, MARY J. ROMAN, JAMES SEWARD, JACK SHANEWISE, SCOTT 
SOLOMON, KIRK T. SPENCER, MARTIN ST. JOHN SUTTON, WILLIAM 
STEWART. 
 
Recommendations for chamber quantification 
 
Eur J Echocardiography (2006) 7, 79-108 
[24]. 
JOHN J.V. MCMURRAY, STAMATIS ADAMOPOULOS, STEFAN D. ANKER, 
ANGELO 
AURICCHIO, 
MICHAEL 
BÖHM, 
KENNETH 
DICKSTEIN, 
VOLKMAR FALK, GERASIMOS FILIPPATOS, CÂNDIDA FONSECA, MIGUEL 
ANGEL GOMEZ-SANCHEZ, TINY JAARSMA, LARS KØBER, GREGORY Y.H. 
LIP, ALDO PIETRO MAGGIONI, ALEXANDER PARKHOMENKO, BURKERT 
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M. PIESKE, BOGDAN A. POPESCU, PER K. RØNNEVIK, FRANS H. RUTTEN, 
JUERG SCHWITTER, PETAR SEFEROVIC, JANINA STEPINSKA, PEDRO T. 
TRINDADE, ADRIAAN A. VOORS, FAIEZ ZANNAD, ANDREAS ZEIHER 
ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012 
European Heart Journal (2012) 33, 1787–1847 
[25]. 
AGENCE NATIONALE DE SECURITE DU MEDICAMENT ET DES PRODUITS 
DE SANTE (ANSM). 
 
Bon usage des médicaments antivitamine K (AVK) 
 
Actualisation – Juillet 2012 
[26]. 
GILLES PERNOD, ANNE GODIER, CLAIRE GOZALO, BENJAMIN TREMEY, 
PIERRE SIE 
French clinical practice guidelines on the management of patients on vitamin K 
antagonists in at-risk situations (overdose, risk of bleeding, and active bleeding) 
Thrombosis Research 126 (2010) e167–e174 
 
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17. APPENDICES 
 
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17.1. DECLARATION OF HELSINKI 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
ETHICAL PRINCIPLES FOR MEDICAL RESEARCH INVOLVING 
HUMAN SUBJECTS 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 29th WMA 
General Assembly, Tokyo, Japan, October 1975 35th WMA General Assembly, Venice, Italy, October 1983 41st 
WMA General Assembly, Hong Kong, September 1989 48th WMA General Assembly, Somerset West, Republic of 
South Africa, October 1996 52nd WMA General Assembly, Edinburgh, Scotland, October 2000 53th WMA General 
Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 55th WMA General Assembly, Tokyo 
2004 (Note of Clarification on Paragraph 30 added) 59th WMA General Assembly, Seoul, October 2008 
 
A. INTRODUCTION  
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of 
ethical principles for medical research involving human subjects, including research on identifiable 
human material and data. The Declaration is intended to be read as a whole and each of its constituent 
paragraphs should not be applied without consideration of all other relevant paragraphs.  
2. Although the Declaration is addressed primarily to physicians, the WMA encourages other participants 
in medical research involving human subjects to adopt these principles.  
3. It is the duty of the physician to promote and safeguard the health of patients, including those who are 
involved in medical research. The physician's knowledge and conscience are dedicated to the fulfilment 
of this duty.   
4. The Declaration of Geneva of the WMA binds the physician with the words, “The health of my patient 
will be my first consideration,” and the International Code of Medical Ethics declares that, “A physician 
shall act in the patient's best interest when providing medical care.”  
5. Medical progress is based on research that ultimately must include studies involving human subjects. 
Populations that are underrepresented in medical research should be provided appropriate access to 
participation in research.  
6. In medical research involving human subjects, the well-being of the individual research subject must 
take precedence over all other interests.  
7. The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic interventions 
(methods, procedures and treatments). Even the best current interventions must be evaluated continually 
through research for their safety, effectiveness, efficiency, accessibility and quality.  
8. In medical practice and in medical research, most interventions involve risks and burdens.  
9. Medical research is subject to ethical standards that promote respect for all human subjects and protect 
their health and rights. Some research populations are particularly vulnerable and need special 
protection. These include those who cannot give or refuse consent for themselves and those who may be 
vulnerable to coercion or undue influence.  
10. Physicians should consider the ethical, legal and regulatory norms and standards for research involving 
human subjects in their own countries as well as applicable international norms and standards. No 
national or international ethical, legal or regulatory requirement should reduce or eliminate any of the 
protections for research subjects set forth in this Declaration.  
 
B. PRINCIPLES FOR ALL MEDICAL RESEARCH  
11. It is the duty of physicians who participate in medical research to protect the life, health, dignity, 
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integrity, right to self-determination, privacy, and confidentiality of personal information of research 
subjects.  
12. Medical research involving human subjects must conform to generally accepted scientific principles, be 
based on a thorough knowledge of the scientific literature, other relevant sources of information, and 
adequate laboratory and, as appropriate, animal experimentation. The welfare of animals used for 
research must be respected.   
13. Appropriate caution must be exercised in the conduct of medical research that may harm the 
environment.  
14. The design and performance of each research study involving human subjects must be clearly described 
in a research protocol. The protocol should contain a statement of the ethical considerations involved 
and should indicate how the principles in this Declaration have been addressed. The protocol should 
include information regarding funding, sponsors, institutional affiliations, other potential conflicts of 
interest, incentives for subjects and provisions for treating and/or compensating subjects who are 
harmed as a consequence of participation in the research study. The protocol should describe 
arrangements for post-study access by study subjects to interventions identified as beneficial in the 
study or access to other appropriate care or benefits.   
15. The research protocol must be submitted for consideration, comment, guidance and approval to a 
research ethics committee before the study begins. This committee must be independent of the 
researcher, the sponsor and any other undue influence. It must take into consideration the laws and 
regulations of the country or countries in which the research is to be performed as well as applicable 
international norms and standards but these must not be allowed to reduce or eliminate any of the 
protections for research subjects set forth in this Declaration. The committee must have the right to 
monitor ongoing studies. The researcher must provide monitoring information to the committee, 
especially information about any serious adverse events. No change to the protocol may be made 
without consideration and approval by the committee.  
16. Medical research involving human subjects must be conducted only by individuals with the appropriate 
scientific training and qualifications. Research on patients or healthy volunteers requires the 
supervision of a competent and appropriately qualified physician or other health care professional. The 
responsibility for the protection of research subjects must always rest with the physician or other health 
care professional and never the research subjects, even though they have given consent.  
17. Medical research involving a disadvantaged or vulnerable population or community is only justified if 
the research is responsive to the health needs and priorities of this population or community and if 
there is a reasonable likelihood that this population or community stands to benefit from the results of 
the research.   
18. Every medical research study involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and communities involved in the research in 
comparison with foreseeable benefits to them and to other individuals or communities affected by the 
condition under investigation.  
19. Every clinical trial must be registered in a publicly accessible database before recruitment of the first 
subject.  
20. Physicians may not participate in a research study involving human subjects unless they are confident 
that the risks involved have been adequately assessed and can be satisfactorily managed. Physicians 
must immediately stop a study when the risks are found to outweigh the potential benefits or when 
there is conclusive proof of positive and beneficial results.  
21. Medical research involving human subjects may only be conducted if the importance of the objective 
outweighs the inherent risks and burdens to the research subjects.  
22. Participation by competent individuals as subjects in medical research must be voluntary. Although it 
may be appropriate to consult family members or community leaders, no competent individual may be 
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enrolled in a research study unless he or she freely agrees.  
23. Every precaution must be taken to protect the privacy of research subjects and the confidentiality of 
their personal information and to minimize the impact of the study on their physical, mental and social 
integrity.   
24. In medical research involving competent human subjects, each potential subject must be adequately 
informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional 
affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort 
it may entail, and any other relevant aspects of the study. The potential subject must be informed of the 
right to refuse to participate in the study or to withdraw consent to participate at any time without 
reprisal. Special attention should be given to the specific information needs of individual potential 
subjects as well as to the methods used to deliver the information. After ensuring that the potential 
subject has understood the information, the physician or another appropriately qualified individual 
must then seek the potential subject’s freely-given informed consent, preferably in writing. If the 
consent cannot be expressed in writing, the non-written consent must be formally documented and 
witnessed.  
25. For medical research using identifiable human material or data, physicians must normally seek consent 
for the collection, analysis, storage and/or reuse. There may be situations where consent would be 
impossible or impractical to obtain for such research or would pose a threat to the validity of the 
research. In such situations the research may be done only after consideration and approval of a 
research ethics committee.   
26. When seeking informed consent for participation in a research study the physician should be 
particularly cautious if the potential subject is in a dependent relationship with the physician or may 
consent under duress. In such situations the informed consent should be sought by an appropriately 
qualified individual who is completely independent of this relationship.  
27. For a potential research subject who is incompetent, the physician must seek informed consent from the 
legally authorized representative. These individuals must not be included in a research study that has 
no likelihood of benefit for them unless it is intended to promote the health of the population 
represented by the potential subject, the research cannot instead be performed with competent persons, 
and the research entails only minimal risk and minimal burden.   
28. When a potential research subject who is deemed incompetent is able to give assent to decisions about 
participation in research, the physician must seek that assent in addition to the consent of the legally 
authorized representative. The potential subject’s dissent should be respected.  
29. Research involving subjects who are physically or mentally incapable of giving consent, for example, 
unconscious patients, may be done only if the physical or mental condition that prevents giving 
informed consent is a necessary characteristic of the research population. In such circumstances the 
physician should seek informed consent from the legally authorized representative. If no such 
representative is available and if the research cannot be delayed, the study may proceed without 
informed consent provided that the specific reasons for involving subjects with a condition that renders 
them unable to give informed consent have been stated in the research protocol and the study has been 
approved by a research ethics committee. Consent to remain in the research should be obtained as soon 
as possible from the subject or a legally authorized representative.  
30. Authors, editors and publishers all have ethical obligations with regard to the publication of the results 
of research. Authors have a duty to make publicly available the results of their research on human 
subjects and are accountable for the completeness and accuracy of their reports. They should adhere to 
accepted guidelines for ethical reporting. Negative and inconclusive as well as positive results should 
be published or otherwise made publicly available. Sources of funding, institutional affiliations and 
conflicts of interest should be declared in the publication. Reports of research not in accordance with 
the principles of this Declaration should not be accepted for publication.  
 
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C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE  
31. The physician may combine medical research with medical care only to the extent that the research is 
justified by its potential preventive, diagnostic or therapeutic value and if the physician has good 
reason to believe that participation in the research study will not adversely affect the health of the 
patients who serve as research subjects.   
32. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the 
best current proven intervention, except in the following circumstances:  
• 
The use of placebo, or no treatment, is acceptable in studies where no current proven intervention 
exists; or  
• 
Where for compelling and scientifically sound methodological reasons the use of placebo is 
necessary to determine the efficacy or safety of an intervention and the patients who receive 
placebo or no treatment will not be subject to any risk of serious or irreversible harm.  Extreme 
care must be taken to avoid abuse of this option.  
33. At the conclusion of the study, patients entered into the study are entitled to be informed about the 
outcome of the study and to share any benefits that result from it, for example, access to interventions 
identified as beneficial in the study or to other appropriate care or benefits.  
34. The physician must fully inform the patient which aspects of the care are related to the research. The 
refusal of a patient to participate in a study or the patient’s decision to withdraw from the study must 
never interfere with the patient-physician relationship.  
35. In the treatment of a patient, where proven interventions do not exist or have been ineffective, the 
physician, after seeking expert advice, with informed consent from the patient or a legally authorized 
representative, may use an unproven intervention if in the physician's judgement it offers hope of 
saving life, re-establishing health or alleviating suffering. Where possible, this intervention should be 
made the object of research, designed to evaluate its safety and efficacy. In all cases, new information 
should be recorded and, where appropriate, made publicly available.  
 
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17.2. SAE REPORT FORM 
 
 
 
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N O T I F I C A T I O N  O F  S E R I O U S  A D V E R S E  E V E N T  ( S A E )  O R  P R E G N A N C Y   
T O  P I E R R E  F A B R E  C O R P O R A T E  V I G I L A N C E S  D I V I S I O N   
 
TO 
BE 
TRANSMITTED 
TO 
THE 
CORPORATE 
VIGILANCES 
DIVISION 
BY 
E-MAIL 
WITHIN 
24H 
TO 
HQ.pharmacovigilance@pierre-fabre.com OR BY FAX WITHIN 24H – Fax N°: 33 (0) 1.49.10.80.90 
Transmission date  
 
 
  
 
  
 
 
 
(ddmmyyyy) 
Country :  
........................................
 
 
 
   SAE N° 
 
 
 
                      FIRST NOTIFICATION           FOLLOW-UP   N° 
 
 SUBJECT CHARACTERISTICS  
 
 
 
 
 
 
 
 
Birth date  
 
 
 
 
 
 
 
 
  
 
 
Gender 
 
1=M,    2=F 
   Height 
 
 
 
cm 
 Weight 
 
 
 
 
 
kg 
 
 
 DESCRIPTION OF THE EVENT 
The serious adverse event resulted in : 
 Death (whatever may be the cause) 
 Hospitalisation (*) or extension thereof 
 Life threatening 
 Invalidity or disability 
 
 Congenital abnormality or abnormal pregnancy outcome 
 Cancer 
 Other  (any other serious clinical or laboratory event 
     according to the investigator or the protocol, overdosage 
      meeting seriousness criteria, suicide attempts) 
Other fact to be notified : 
 Pregnancy exposure 
Nature of the event (if clinical nature, indicate the diagnosis or the major symptom) : 
........................................................................................................................................................................................................... 
........................................................................................................................................................................................................... 
........................................................................................................................................................................................................... 
AE onset date  |__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
 
Seriousness onset date  |__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
 
Summary description (if clinical cause, significant history, progression of event, available laboratory results, etc...) : 
 
 
 
 
 
 
(*) Except hospitalisations with durations and goals planned in the protocol 
 
 THE SAE IN RELATION TO THE TRIAL 
                                                      TREATMENT NUMBER         |___|___|___|___|___|___| 
• Time of occurrence of SAE 
 
 During the selection or run-in period 
 
 During the administration phase of the study treatment 
 
 After the administration phase of the study treatment 
• Date of first study treatment administration 
• Date of last study treatment administration 
   before the occurence of SAE 
|__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
 
|__|__|  |__|__|  |__|__|__|__| (ddmmyyyy) 
• Was the blind broken ?       Yes         No          Not applicable 
   If yes, or if this is an open study, drug(s) administered : 
 
 
 
 
 
  Conditions of administration (cycles(s), daily dose(s), route(s) of administration, etc..) :  
 
 
 
 
 
 
 
 
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Transmission date 
 
 
 
 
 
 
 
 
 
 
  (ddmmyyyy) 
Country : ............................................ 
 
 
 
  SAE N° 
 
 
 
                     FIRST NOTIFICATION           FOLLOW-UP   N° 
 
 CONCOMITANT MEDICATION SINCE TRIAL INITIATION and UP UNTIL THE OCCURRENCE OF THE SAE 
     (EXCEPT THE TREATMENTS GIVEN FOR THE SAE)  
 
Trade name  
(or INN) 
 
Daily dose 
 
Start date 
(dd/mm/yy) 
Ongoing at 
occurence of the 
event 
 
Stop date 
(dd/mm/yy) 
Route of 
admin. 
 
Indication 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 MEASURES TAKEN FOLLOWING THE SAE 
• Study treatment 
 
 No change 
 
 Dosage modification, specify :……………………………..….      Modification Date : 
 
 Temporarily discontinued                                                       Readministration date : 
 
 Withdrawn                                                                                                  End date : 
 
 Not applicable 
 
____/____/_____ 
 ____/____/_____ 
 ____/____/_____ 
• The event led to : 
 
 Prescription of corrective or symptomatic treatments: 
 
 
Trade name  
(or INN) 
 
Daily dose 
 
Start date 
(dd/mm/yy) 
Ongoing at 
occurence of the 
event 
 
Stop date 
(dd/mm/yy) 
Route of 
admin. 
 
Indication 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 Discontinuation of concomitant treatments: 
 
 
Trade name  
(or INN) 
 
Daily dose 
 
Start date 
(dd/mm/yy) 
Ongoing at 
occurence of the 
event 
 
Stop date 
(dd/mm/yy) 
Route of 
admin. 
 
Indication 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
___/___/____ 
 
___/___/____ 
 
 
 
 
 Others, specify : 
 
 
 OUTCOME 
         Not recovered/Not resolved                  Recovering/Resolving               Recovered/Resolved 
         Recovered/Resolved with sequelae     Fatal                                          Unknown 
 
                In case of death, has an autopsy been conducted ?       Yes         No 
 
 INVESTIGATOR CAUSALITY ASSESSMENT (investigator’s assessment to be done as soon as possible) 
Study drug:                                                                         Related to study protocol: 
 Not Suspected                 Suspected                             Not Suspected                          Suspected                   
Comments: ............................................................................................................................................................. 
 
Enclose in the notification the results of carried out examinations, reports of hospitalisation, etc... 
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17.3. PREDEFINED LIMITS OF LABORATORY AND VITAL SIGN 
POTENTIALLY CLINICALLY SIGNIFICANT CHANGES AND VALUES  
List of Predefined Potentially Clinically Significant Change For Laboratory Values(¤) 
 
 
PARAMETERS 
UNIT 
PSC 
 
 
 
Decrease 
Increase 
MUSCLE 
Creatine  Phosphokinase 
U / l 
- 
236 
KIDNEY 
Creatinine 
Urea 
Uric acid 
Phosphate 
Calcium 
µmol/l 
mmol/l 
µmol/l 
mmol/l 
mmol/l 
- 
- 
- 
0.39 
0.30 
35 
3.2 
119 
0.39 
0.30 
ELECTROLYTES 
Sodium 
Potassium 
Chloride 
Bicarbonate 
mmol/l 
mmol/l 
mmol/l 
mmol/l 
8 
1.1 
8 
7 
8 
1.1 
7 
8 
METABOLISM/ 
NUTRITIONAL 
Glucose (random) 
Albumin 
Protein 
Cholesterol 
HDL cholesterol 
LDL cholesterol 
Triglycerides 
mmol/l 
g/l 
g/l 
mmol/l 
mmol/l 
mmol/l 
mmol/l 
3 
6 
11 
- 
0.91 
2.17 
- 
3.7 
6 
10 
1.97 
0.85 
2.04 
2.91 
ERYTHROCYTES 
Erythrocyte count 
Haemoglobin 
Haematocrit 
MCV  
MCH (Fe) 
MCHC (Fe) 
T/l 
g/l 
1 
fl 
fmol 
mmol/l 
0.7 
20 
0.06 
7 
0.19 
2 
0.7 
- 
0.06 
7 
0.19 
2 
LEUKOCYTES 
Leukocyte count 
G/l 
4.2 
3.8 
DIFFERENTIAL 
COUNT 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
G/l 
G/l 
G/l 
G/l 
G/l 
3.47 
1.76 
- 
- 
- 
3.19 
1.63 
0.49 
0.41 
0.14 
URINE 
Specific gravity 
pH 
- 
- 
0.017 
2 
0.015 
2 
LIVER 
Total bilirubin 
ASAT (SGOT) 
ALAT (SGPT) 
Gamma GT 
Alkaline phosphatase 
µmol/l 
U/l 
U/l 
U/l 
U/l 
- 
- 
- 
- 
-- 
10 
N x (23/36) 
N x (28/45) 
N x (25/38) 
N x (30/95) 
 
N = upper limit of normal range 
 
(¤) Delta-limits from « Routine Laboratory Tests in Clinical Trials » W. Leigh Thompson, Rocco 
L. Brunelle, Gregory G. Enas, Patrick J. Simpson and Randy L. Walker Lilly Research 
Laboratories, Lilly Corporate Centre, Indianapolis, Indiana in « Clinical Trials and Tribulations » 
1988. 
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Definition of Clinically Noteworthy Abnormal Laboratory Values (CNALV) 
 
 
PARAMETERS 
CNALV 
HAEMOGLOBIN 
 
• Decrease of at least 2g/dl and value < 10 g/dl whatever the baseline 
value 
• If missing baseline : value <10g/dl 
NEUTROPHILS 
• < 1 500/mm3 whatever the baseline value 
WBC 
(if missing value for neutrophils) 
• < 3 000/mm3 whatever the baseline value 
PLATELETS 
• < 100 000/mm3 whatever the baseline value 
SERUM CREATININE 
• Increase of at least 30 % as compared to baseline value and 
value > 150 µmol/l whatever the baseline value 
• If missing baseline : value > 150 µmol/l 
LIVER FUNCTION TESTS 
 
 
ALAT 
 
 If normal baseline :  
 
 
•ALAT > 2 N 
 If abnormal baseline : 
→if baseline value ≤ 2.5 N : 
  
• increase of at least 100 % as compared to baseline value 
→ if baseline value > 2.5 N :  
 
 
• value > 5 N 
and/or 
ASAT 
 
  If normal baseline :  
 
 
• ASAT > 2 N 
  If abnormal baseline : 
→ if baseline value ≤ 2.5 N : 
  
• increase of at least 100 % as compared to baseline value 
→ if baseline value > 2.5 N :  
 
 
• value > 5 N 
and/or 
Alkaline phosphatase (AP) 
 
  If normal baseline :  
 
 
• AP > 1.25 N 
  If abnormal baseline :  
 
 
• AP > 2 N 
and/or 
Total bilirubin (TB) 
  If normal baseline :  
 
 
• TB > 1.5 N 
  If abnormal baseline :  
 
 
• TB > 2 N 
N=upper limit of normal range 
International consensus Meeting. International Journal of Clinical Pharmacology, Therapy and Toxicology, 1990;28:317-322 
Standardisation of definitions and criteria of causality assessment of adverse drug reactions: drugs-induced liver disorders: report 
of an Standardisation of definitions and criteria of causality assessment of adverse drug reactions: drugs-induced cytopenia. 
International Journal of Clinical Pharmacology, Therapy and Toxicology, 1991;29:75-81 
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Cardiovascular Safety 
 
Table 1: Predefined Limits for Potentially Clinically Significant Changes (PSC) and PSC 
Leading to Clinically Significant Values (PSCV) 
 
Parameter 
PSC 
PSCV 
SBP 
Increase ≥ 20 mmHg 
Decrease ≥ 20 mmHg 
SBP ≥ 160 mmHg and increase ≥ 20 mmHg 
SBP ≤ 90 mmHg and decrease ≥ 20 mmHg 
DBP 
Increase ≥ 10 mmHg 
Decrease ≥ 10 mmHg 
DBP ≥ 100 mmHg and increase ≥ 10 mmHg 
DBP ≤ 50 mmHg and decrease ≥ 10 mmHg 
HR 
Increase ≥ 10 bpm 
Decrease ≥ 10 bpm 
HR ≥ 110 bpm and increase ≥ 10 bpm 
HR ≤ 50 bpm and decrease ≥ 10 bpm 
 
Table 2: Predefined Classes for changes from Baseline to the Maximum (and/ or Minimum) 
Post-baseline Value 
Classes of Change from Baseline to the Maximum 
Post-baseline Value 
Classes of Change from Baseline to the 
Minimum Post-baseline Value 
SBP  mmHg 
DBP  mmHg 
HR bpm 
SBP  mmHg 
DBP  mmHg 
HR bpm 
All 
All 
All 
All 
All 
All 
≥  0 
≥  0 
≥  0 
≤  0 
≤  0 
≤  0 
>  0 
>  0 
>  0 
<  0 
<  0 
<  0 
≥ 10 
≥  5 
≥ 10 
≤ -10 
≤ - 5 
≤ -10 
≥ 20 
≥ 10 
≥ 20 
≤ -20 
≤ -10 
≤ -20 
≥ 30 
≥ 15 
≥ 30 
≤ -30 
≤ -15 
≤ -30 
≥ 40 
≥ 20 
 
≤ -40 
≤ -20 
 
 
≥ 25 
 
 
≤ -25 
 
 
≥ 30 
 
 
≤ -30 
 
 
Table 3: Classes for Vital Signs Maximum or Minimum Values 
Classes  for  the Maximum Post-baseline Value 
for each parameter 
Classes  for  the Minimum Post-baseline Value 
for each parameter 
SBP  mmHg 
DBP  mmHg 
HR bpm 
SBP  mmHg 
DBP  mmHg 
HR bpm 
< 120 
< 80 
≤ 50 
≤ 90 
≤ 50 
≤ 50 
[120 ;140[ 
[80;90[ 
]50 ;75[ 
[90 ;120[ 
[50;80[ 
]50 ;75[ 
[140;160[ 
 [90;100[ 
[75;100[ 
[120;140[ 
 [80;90[ 
[75;100[ 
≥ 160 
≥ 100 
≥ 100 
≥ 140 
≥ 90 
≥ 100 
 
Table 4: Classes for Maximum or Minimum of BP in its entirety 
Classification of Maximum Values for Blood 
Pressure (mmHg) 
Classification of Minimum Values Blood 
Pressure (mmHg) 
SBP < 140 and DBP < 90 
SBP > 90 and DBP > 50 
SBP [140;160[ and DBP < 100 
or DBP [90;100[ and SBP < 160 
SBP ≤  90 or DBP ≤  50 
SBP ≥ 160 or DBP ≥ 100 
 
 
Table 5: Definition of orthostatic hypotension 
Orthostatic Hypotension * 
SBP Decrease ≥ 20 mmHg or DBP Decrease ≥ 10 mmHg between supine and standing positions 
* Consensus Committee of the American Autonomic Society and the American Academy of Neurolog :Consensus statement on the definition of 
orthostatic hypotension, pure autonomic failure and multiple system atrophy. Neurology 1996;46:1470-3. 
 
 
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SAP_001.pdf: 
C o nfi de nti al  
F 3 7 3 2 8 0 C A 2 0 1  
Pi erre F a bre Mé dic a me nt 
Re prese nte d b y: I nstit ut de Rec herc he Pierre F a bre  
4 5, Pl ace A bel G a nce 
F -9 2 1 0 0 B o ul o g ne
C LI NI C A L S T U D Y R E P O R T 
E F FI C A C Y A N D S A F E T Y S T U D Y O F F 3 7 3 2 8 0 F O R M AI N T E N A N C E O F 
SI N U S R H Y T H M A F T E R E L E C T RI C A L C A R DI O V E R S I O N I N P A TI E N T S 
WI T H P E R SI S T E N T A T RI A L FI B RI L L A TI O N A N D C H R O NI C H E A R T 
F AI L U R E 
1 6.  A P P E N DI C E S  (c o nti n ue d)
1 6. 1. S T U D Y I N F O R M A TI O N  (c o nti n ue d) 
1/ 4 0
1 6. 1. 9   DO C U M E N T A TI O N O F S T A TI S TI C A L M E T H O D S  


2/ 4 0


C o nfi de nti al  
F 3 7 3 2 8 0 C A 2 0 1  
St atistic al A n al ysis Pl a n  –  V ersi o n  2  -  1 5/ 0 6/ 2 0 1 7  
2 /3 9  
3.
V E R SI O NI N G
Versi o n  D ate  
A ut h or  
( Fi rst & 
L ast 
n a me)  
P a ges o r secti o ns 
c o ncer ne d  
N at ure( *)  
Re as o n(s) f or c h a n ge 
( * *) 
1 
1 4/ 0 6/ 2 0 1 7 
Méla nie 
G R O C  
All  
C 
2 
1 5/ 0 6/ 2 0 1 7  
Méla nie 
G R O C  
Secti o n 2  
M 
Res p o nsi bilit y “ A u dit or” 
c ha n ge d i nt o “ Re vie wer”  
2 
1 5/ 0 6/ 2 0 1 7  
Méla nie 
G R O C  
Secti o n 1 4. 1. 4 
M 
M o dificati o n of patie nts 
s u b gr o u ps wit h vas c ular 
or car di ac t hera pe utic 
pr oce d ures ( del eti o n of  
o nset restricti o n 
“ < 3 m o nt hs”) 
( *) C: Cre ati o n, M: M o dific ati o n, A: A d diti o n, D: Deleti o n 
( * *) 
3/ 4 0
If t he m o dific ati o ns are re q ueste d by exter n al re pr ese nt atives ( a ut h orities), s pecify t he 
or g a nis m n a m e. 


C o nfi de nti al  
F 3 7 3 2 8 0 C A 2 0 1  
 
St atistic al A n al ysis Pl a n  –  V ersi o n  2  -  1 5/ 0 6/ 2 0 1 7  
3 /3 9  
 
4.  
T A B L E O F C O N T E N T S  
 
1.  
TI T L E P A G E  ........................................................................................................................... 1 
2.  
SI G N A T U R E S  ......................................................................................................................... 1 
3.  
V E R SI O NI N G ......................................................................................................................... 2  
4.  
T A B L E O F C O N T E N T S  ........................................................................................................ 3 
5.  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N O F T E R M S  ........................................ 5 
6.  
I N T R O D U C TI O N ................................................................................................................... 6 
7.  
A N A L Y SI S S E T S  .................................................................................................................... 9 
8.  
I N F E R E N TI A L P RI N CI P LE S  .............................................................................................. 9 
9.  
D E VI A TI O N S  ........................................................................................................................ 1 0 
1 0.  H A N D LI N G O F MI S SI N G D A T A A N D A N A L Y SI S O F  D R O P -O U T S  ........................ 1 0 
1 0. 1.  D R O P -O U T S  ....................................................................................................................... 1 0 
1 0. 2.  R E P O SI TI O NI N G O F VI S I T S ............................................................................................ 1 0 
1 0. 3.  MI S SI N G D A T A ( O T H E R T H A N D R O P -O U T)  ............................................................... 1 1 
1 1.  D E S C RI P TI V E S T A TI S TI C S  ............................................................................................. 1 3 
1 2.  DI S P O SI TI O N O F P A TI E N T S  ........................................................................................... 1 3 
1 3.  D E M O G R A P HI C A N D O T H E R B A S E LI N E C H A R A C T E R I S TI C S ........................... 1 3 
1 4.  A N A L Y SI S O F E F FI C A C Y  ................................................................................................ 1 5 
1 4. 1.  P RI M A R Y C RI T E RI O N  ..................................................................................................... 1 5 
1 4. 1. 1.  Pri mar y A n al ysis  ............................................................................................................... 1 6 
1 4. 1. 2.  S u p p orti ve A nal ysis .......................................................................................................... 1 6  
1 4. 1. 3.  A d diti o nal A nal yses .......................................................................................................... 1 6  
1 4. 1. 4.  Se nsiti vit y A nal ys es  .......................................................................................................... 1 7 
1 4. 2.  S E C O N D A R Y C RI T E RI A  .................................................................................................. 1 7 
1 4. 2. 1.  N u m bers of Atrial Fi brillati o n/ Fl utter E pis o des i n t he first wee k f oll o wi n g V 3  ............. 1 7 
1 4. 2. 2.  D urati o n of Atrial Fi brillati o n/ Fl utter E pis o des i n t he first wee k f oll o wi n g V 3 .............. 1 8 
1 4. 2. 3.  Ti me t o  first A F rec urr e n ce / fl utter e mer ge n ce less t ha n 1 0 mi n utes d uri n g 
T T E M peri o d  ..................................................................................................................... 1 8 
1 4. 2. 4.  Ti me t o first s y m pt o matic A F rec urre n ce / fl utter e mer ge n ce d uri n g T T E M 
peri o d ................................................................................................................................. 1 8  
1 4. 2. 5.  Cli nical para meters e val u ati o n  .......................................................................................... 1 8 
1 4. 2. 5. 1.  E H R A sc ore  .................................................................................................................... 1 8 
1 4. 2. 5. 2.  Pres u m e d arr h yt h mia  ...................................................................................................... 1 9 
1 4. 2. 5. 3.  Rec urre n ce of s y m pt o matic A F  ...................................................................................... 1 9 
1 4. 2. 5. 4.  N u m ber a n d d ur ati o n of h os pitalizati o ns ....................................................................... 1 9  
1 4. 2. 5. 5.  Car di o versi o n assess me nt  .............................................................................................. 2 0 
1 4. 2. 5. 6.  E v ol uti o n of ec h ocar di o gra p hic para meters ................................................................... 2 0  
1 5.  C O M P LI A N C E  ..................................................................................................................... 2 1
4/ 4 0
 


C o nfi de nti al  
F 3 7 3 2 8 0 C A 2 0 1  
 
St atistic al A n al ysis Pl a n  –  V ersi o n  2  -  1 5/ 0 6/ 2 0 1 7  
4 /3 9  
 
1 6.  BI O M A R K E R A N A L Y SI S  .................................................................................................. 2 1 
1 6. 1.  R E D B L O O D C E L L C O N C E N T R A TI O N S O F D H A  ....................................................... 2 1 
1 7.  S A F E T Y A N A L Y SI S  ............................................................................................................ 2 1 
1 7. 1.  E X T E N T O F E X P O S U R E  ................................................................................................... 2 2 
1 7. 2.  A D V E R S E E V E N T S  ........................................................................................................... 2 2 
1 7. 3.  VI T A L SI G N S  ..................................................................................................................... 2 4 
1 7. 4.  L A B O R A T O R Y D A T A  ...................................................................................................... 2 4 
1 7. 5.  C O A G U L A TI O N P A R A M E T E R S  ..................................................................................... 2 6 
1 7. 6.  E C G  ...................................................................................................................................... 2 6 
1 7. 7.  P H Y SI C A L E X A MI N A TI O N  ............................................................................................. 2 6 
1 7. 8.  C O N C O MI T A N T M E DI C A TI O N S  .................................................................................... 2 7 
1 8.  C H A N G E S SI N C E P R O T O C O L R E D A C TI O N  ............................................................... 2 7 
1 9.  D A T A P R O C E S SI N G  ........................................................................................................... 2 7 
2 0.  A P P E N DI X  ............................................................................................................................ 2 7 
5/ 4 0
 


C o nfi de nti al  
F 3 7 3 2 8 0 C A 2 0 1  
 
St atistic al A n al ysis Pl a n  –  V ersi o n  2  -  1 5/ 0 6/ 2 0 1 7  
5 /3 9  
 
5.  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N O F T E R M S  
a P T T :  
a P T T : Acti vate d partial t hr o m b o plasti n ti me  
A E  
A d verse E v e nt  
A F  
Atrial Fi brillati o n  
A P  
Al kali ne P h os p hatase  
A T C  
A nat o mical T her a pe utic C he mical classificati o n  
B P  
Bl o o d Press ure  
B S A  
B o d y S urface Area  
C N A L V  
Cli nicall y N ote w ort h y A b n or mal La b orat or y Val u e  
C R F  
Case Re p ort Fr o m  
D B P  
Diast olic Bl o o d Press ure  
D H A  
D oc osa he x ae n oic aci d  
eC R F  
Electr o nic case r e p ort f or m  
E C G  
Electr ocar di o gra m  
E C V  
Electr ocar di o versi o n  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
H L G T  
Hi g h -Le vel Gr o u p Ter m  
H L T  
Hi g h -Le vel Ter m  
H R  
Heart Rate  
I C H 
I nter nati o nal c o nfer e nce o n har m o nisati o n of tec h nical re q uire me nts f or 
re gistrati o n of p har m ace uticals f or h u ma n use 
I D M C 
I n d epe n de nt Data M o nit ori n g C o m mittee  
IN R  
I nter nati o nal n or malize d rati o 
IV R S  
I nteracti ve v oice r es p o ns e s yste m 
J N C 
J oi nt Nati o nal C o m mittee 
Me d D R A  
Me dical Dicti o nar y f or R e g ul at or y Acti vities  
N Y H A  
Ne w Y or k H eart A ss ociati o n 
P S C  
Pre defi ne d P ote ntiall y Cl i nicall y Si g nifi ca nt C ha n ge 
P S C V  
P S C lea di n g t o Cli nicall y Si g nifica nt Val u e  
P T  
Preferre d Ter m  
S A E  
Seri o us A d verse E v e nt  
S A P  
Statistical A nal ysis Pla n  
S A S  
Statistical A nal ysis S yste m  
S B P  
S yst olic Bl o o d Press ure  
S D  
Sta n dar d De viati o n  
S E M  
Sta n dar d Er r or of Mea n 
S O C  
S yste m Or ga n Class  
T B  
T otal Bilir u bi n  
T C T  
T hr o m bi n cl otti n g ti me  
T E A E  
Treat me nt E mer ge nt A d v erse E ve nt  
T T E M  
Tra ns Tele p h o ni c E C G m o nit ori n g  
W B C  
W hite Bl o o d Cells  
W H O Dr u g  
W orl d Healt h Or ga nisati o n Dr u g  
6/ 4 0


C o nfi de nti al  
F 3 7 3 2 8 0 C A 2 0 1  
 
St atistic al A n al ysis Pl a n  –  V ersi o n  2  -  1 5/ 0 6/ 2 0 1 7  
6 /3 9  
 
 
6.  
I N T R O D U C TI O N 
 
T his d oc u me nt d escri bes t he fi nal statistical a n al ysis of t he st u d y t h at will be perf or me d after 
t he l oc k of t he cli nical data base a n d t he ra n d o mi sati o n c o de release o n t he t otal n u m ber of 
st u d y patie nts .  
T his statistical a nal ysis pla n will be a p pr o ve d b ef ore  t he fi nal Dat a Re vie w Meeti n g , a n d 
fi nalise d a n d si g n e d pri or t o t he fi nal ra n d o misati o n c o de rel ease.  
 
St u d y desi g n  
T his p hase IIa trial is c o n d ucte d as a n i nter nati o nal, m ultice ntric, 2 4 w ee ks, d o u ble - bli n d, 
place b o -c o ntr olle d,  ra n d o mise d,  parallel  gr o u p  desi g n,  st u d y o n  patie nts  s ufferi n g  fr o m  
persiste nt A F a n d c hr o ni c heart fail ure.  
 
St u d y o bjecti ves  
T he pri mar y o bjecti ve of t he st u d y is t o assess t he efficac y of F 3 7 3 2 8 0 o n t he mai nte na nce of  
si n us r h yt h m after direct E C V i n patie nts wit h persiste nt A F a n d c hr o nic heart fail ure. 
 
T he sec o n d ar y o bjecti ves of t he st u d y are t o ass ess:  
• t he efficac y of F 3 7 3 2 8 0 o n t he effici e nc y of direct E C V 
• t he eff ect of F 3 7 3 2 8 0 o n ec h ocar di o gra p hi c para meters 
• t he safet y a n d t olera bilit y of F 3 7 3 2 8 0 
 
St u d y tre at me nt  
After a 1 t o  4-wee k r u n -i n peri o d, patie nts are ra n d o mise d i nt o o ne of t he f oll o wi n g treat me nt 
gr o u ps: F 3 7 3 2 8 0 1 g or place b o 1 g f or 2 4 wee ks. T he treat me nt start s 4 wee ks bef ore E C V 
a n d E C V is perf or m e d i n patie nts wit h n o s p o nta ne o us car di o versi o n a n d wit h I N R le v els  
sta bilize d as me nti o ne d i n t he pr ot oc ol. T he f oll o w- u p is of 2 0 wee ks after a s uccessf ul E C V 
(at visit 3 – car di o versi o n visit) or after a s p o nt a ne o us C V. 
 
Pri m ar y effic ac y c rit eri o n 
T he pri mar y criteri o n is t he ti me t o first Atrial Fi brillati o n rec urre nce or Atrial Fl utter 
e mer ge n ce defi ne d b y t h e ti me t o first e pis o de of Atrial Fi brillati o n or atrial fl utter lasti n g f or 
at least 1 0 mi n utes d uri n g t he f oll o w u p of 2 0 wee ks after  visit 3 ( E C V visit).  
 
T he car diac m o nit ori n g is perf or me d usi n g: 
- A 7 -da y c o nti n u o us E C G a m b ulat or y rec or di n g ( H olter E C G) bet wee n visit 3 ( E C V visit) 
a n d visit 4 ( wee k 5) i n patie nts car di o verte d t o si n us r h yt h m. 
- A Tra ns T ele p h o nic E C G M o nit ori n g ( T T E M): 
* bef ore pr ot oc ol a me n d me nt  P A 0 5 : wit h a dail y tra ns missi o n fr o m wee k 6 t o wee k 
8; t he n e ver y t w o da ys fr o m wee k 9 t o wee k 2 4, a n d at a n yti me i n case of A F s y m pt o ms 
* after pr ot o c ol a me n d m e nt P A 0 5: wit h  o ne tra ns missi o n per wee k fr o m t he da y of 
visit 4 (e n d of wee k 5) t o visit 9 ( wee k 2 4). 
 
 
S a m ple size  
Ass u mi n g a n A F r ec urre n ce r ate of 8 5 % u n der place b o a n d 6 5 % u n der acti ve gr o u p, i.e. a  
cli nicall y r ele va nt differ e nce ∆ 
7/ 4 0
of 2 0 %, a sa m ple size of 6 4 assessa ble patie nts per gr o u p is  


C o nfi de nti al  
F 3 7 3 2 8 0 C A 2 0 1  
 
St atistic al A n al ysis Pl a n  –  V ersi o n  2  -  1 5/ 0 6/ 2 0 1 7  
7 /3 9  
 
re q uire d, usi n g a l o g-r a n k test of s ur vi val c ur ves wit h a 8 0 % p o wer a n d a 5 % t w o-si de d 
si g nifica n ce  le vel. Acc or di n g  t o  t he  pre vi o us  ass u m pti o ns  a n d  ass u mi n g  a  rate  of  n ot  
assessa ble patie nts  of 1 5 %, a mi ni m u m of 7 6 patie nts ha ve t o be ra n d o mise d per gr o u p. 
D ue t o l o w recr uit me nt,  it  was  deci de d t o st o p  pre mat urel y t he  st u d y.  1 3 5 patie nts  were 
fi nall y r a n d o mise d (i nstea d of 1 5 2 i nitiall y pla n ne d).  
 
 
I nteri m S af et y re vie ws/I D M C rec o m me n d ati o ns 
T hree  I D M C w ere pla n n e d t o pr o vi de i n de pe n d e nt safet y re vie w a n d trial g ui da n ce d uri n g t he 
c o urse of t he o n g oi n g tri al  (after t he first 3 0 ra n d o mise d patie nts, w he n t h e first 8 0 patie nts 
ha ve ter mi nate d t heir st u d y partici pati o n a n d t he n 1 3 0 patie nts ). D u e t o t he pre mat ure st o p of 
t he  recr uit me nt,  o nl y  t h e  first  t w o  meeti n gs  t o o k  place  wit h  I D M C  rec o m me n dati o ns  t o  
c o nti n ue t he st u d y. 
 
 
 
 
 
 
 
 
 
8/ 4 0
 


C o nfi de nti al  
F 3 7 3 2 8 0 C A 2 0 1  
 
St atistic al A n al ysis Pl a n  –  V ersi o n  2  -  1 5/ 0 6/ 2 0 1 7  
8 /3 9  
 
S T U D Y F L O W -C H A R T  ( P R O T O C O L V E R SI O N 9 2 8/ 0 9/ 2 0 1 6) 
F 3 7 3 2 8 0 C A 2 0 1  
V 1  
V 2  
V 3  
V 4  
 
V 6  
V 7  
 
V 9  
W e e k s  
W- 4 t o W - 1 
D 1  
W 4  
( 28 -2 D / + 7 D) 
W 5  
( 3 5 -2 D/ + 7 D)  
 
W 1 2  
( 8 4 +/-7 D)  
W 1 6  
( 1 1 2 +/-7 D)  
 
W 2 4  
( 1 6 8 +/-7 D)  
  
  
  
  
  
  
  
  
  
  
O ut p ati e nt or H o s pit ali z ati o n ( 1)  
  
  
X  
  
 
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
I nf or m e d c o n s e nt 
X  
  
  
  
  
  
  
  
  
D e m o gr a p hi c c h ar a ct eri sti c s  
X  
  
  
  
  
  
  
  
  
M e di c o -s ur g i c al hi st or y 
X  
  
  
  
  
  
  
  
  
C o n c o mit a nt di s e a s e  
X  
  
  
  
  
  
  
  
  
C o n c o mit a nt tr e at m e nt  
X  
X  
X  
X  
X  
X  
X  
X  
X  
H a bit s  
X  
  
  
  
  
  
  
  
  
Gl o b al p h y si c al e x a mi n ati o n ( b o d y w ei g ht)  
X  
X  
X  
 
X  
X  
X  
X  
X  
E c h o c ar di o gr a p h y  
X  
X  
  
X  
  
X  
  
  
X  
Eli gi bilit y crit eri a c h e c k  
X  
X  
  
  
  
  
  
  
  
Bl o o d pr e s s ur e, h e art r at e  
X  
X  
X  
X  
X  
X  
X  
X  
X  
1 2 -L e a d  E C G R e c or di n g  
X  
X  
X  
  
X  
X  
X  
X  
X  
I N R  
 
 
                   
  
X  
 
 
X  
                     ( 2) 
a P T T, T C T  
X  
X  
X  
  
X  
X  
X  
X  
X  
Bi o c h e mi str y  
X  
  
  
  
  
  
  
  
X  
H a e m at ol o g y  
X  
  
X  
  
  
X  
  
  
X  
Uri n ar y pr e g n a n c y t e st  
  
X  
  
  
  
  
  
  
X  
R e d Bl o o d C ell c o n c e ntr ati o n s of D H A  
  
X  
X  
  
  
X  
  
  
X  
Tr e at m e nt n u m b er all o c ati o n  
  
X  
  
  
  
X  
  
  
  
I V R S/I W R S 
X  
X  
  
  
 
X  
  
  
  
E C V ( 3)  
  
  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Dr u g a d mi ni str ati o n  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
A d v er s e e v e nt s r e c or di n g  
  
X  
X  
X  
X  
X  
X  
X  
X  
H olt er E C G  
                ( 4) 
  
 
                ( 5) 
 
 
 
 
 
T T E M ( 6)  
  
  
 
 
 
  
  
  
  
( 1) O ut p ati e nt or h o s pit ali z ati o n a c c or di n g t o cli ni c al pr a cti c e of t h e c e ntr e (l e s s or m or e t h a n 2 4 h o ur s)  
( 2) I n c a s e of V K A i ntr o d u cti o n: I N R 2 t o 3 ti m e s a w e e k u ntil st a bili z ati o n , t h e n w e e kl y u ntil t h e E C V, t h e n e v er y 4 w e e k s  aft er E C V  
( 3) I n p ati e nt s wit h A F 
( 4) 2 4 -h o ur H olt er E C G  
( 5) 7 -d a y H olt er E C G  
( 6) T T E M: o n e tr a n s mi s si o n  p er w e e k fr o m t h e d a y of vi sit 4 ( e n d of w e e k 5) t o vi sit 9 ( w e e k 2 4) a n d at a n y ti m e i n c a s e of A F or atri al fl utt er s y m pt o m s . 
T T E M o n c e a w e e k e v e n i n c a s e of A F r e c urr e n c e or atri al fl utt er e m er g e n c e f or at l e a st 1 0 mi n ut e s . 
 
V 5 et V 8 w er e c a n c ell e d  i n t h e a m e n d m e nt P A 0 5  
 
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C o nfi de nti al  
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St atistic al A n al ysis Pl a n  –  V ersi o n  2  -  1 5/ 0 6/ 2 0 1 7  
9 /3 9  
 
7.  
A N A L Y SI S  S E T S  
 
T he f oll o wi n g a nal ysis sets will be defi ne d:  
 T he Scree ne d p atie nts  Set  w hic h c o nsists of all patie nts  w h o ha ve si g ne d a n i nf or me d 
c o nse nt, 
 T he R a n d o mise d P atie nts  Set  w hic h c o nsists of all patie nts w h o ha ve si g n e d a n i nf or me d 
c o nse nt, a n d are assi g ne d a treat me nt n u m ber,  
 T he S af et y Set c o m pose d of all ra n d o mise d patie nts ha vi n g ta ke n at least o ne d ose of t he 
st u d y treat me nt. T his set will be use d t o perf or m a nal yses of Safet y . 
 T he F ull A n al ysis Set ( F A S)  c o m p ose d of all ra n d o mise d patie nts ha vi n g recei v e d at least 
o ne d ose of t he st u d y treat me nt a n d wit h a s uccessf ul car di o versi o n o bser v e d at visit 3. A 
s uccessf ul car di o versi o n will be defi ne d as eit her s p o nta ne o us car di o versi o n bef ore V 3 or 
s uccessf ul E C V perf or m e d at V 3 (earl y rela pse wit hi n t he o bser vati o n peri o d after E C V will 
be c o nsi der e d as n o n s uccessf ul). T his set will be use d t o perf or m a nal yses of Efficac y.  
 T he Per Pr ot o c ol Set ( P P)  w hic h is t he s u bset of t he F ull A nal ysis Set c o m p ose d of all F A S 
patie nts wit h o ut a n y maj or pr ot oc ol de viati o n or ot her s o urce of bias f or pri mar y criteri a 
a nal ys es.  T his set will be use d t o perf or m t he s u p p orti ve a nal ysis of t he pri mar y effi cac y 
criteri o n. 
 
Patie nts fr o m Ra n d o mise d Pa tie nts Set, Safet y Set , F ull A nal ysis Set or P P set will be a nal yse d as 
treate d (i e as treat me nt  act uall y r ecei ve d at t he ra n d o misati o n). I n case of err or of treat me nt 
dis pe nsati o n d uri n g t he st u d y peri o d, t he assi g n m e nt of patie nt treat me nt gr o u p will be disc usse d 
d uri n g t he d ata r e vie w m eeti n g.  
Ra n d o mise d patie nts n ot treate d will be a nal yse d as ra n d o mise d (i e as treat me nt all ocate d at t he 
ra n d o misati o n). 
 
8.  
I N F E R E N TI A L P RI N CI P LE S  
 
O nl y t he test o n t he pri mar y criteri o n, o n w hi c h is base d t he sa m ple size j u stificati o n, ma y l ea d t o 
a ca usal i nter pretati o n. All ot her statistical res ults are t o be re gar de d as e x pl orat or y. 
Statistical tests will be t w o -si de d a n d t he si g nifica nce le vel will be set t o 5 %. 
I n or d er t o o btai n statistical m o delli n g c o n ver ge n ce a n d bala n ce n u m ber of ra n d o mise d patie nts , 
P ola n d  ( wit h o nl y f o ur ra n d o mise d patie nts) will be gr o u pe d wit h t he c o u ntr y t h at ra n d o mise d t he 
sec o n d l o west n u m b er of patie nts (H u n gar y ). C ate g orical varia bl e “ C o u ntr y” will be a nal yse d 
wit h 4 le vels f or str atifie d  statistical tests a n d st atistical m o deli n g: Ital y, S pai n , Czec h Re p u blic  
a n d H u n gar y.
1 0/ 4 0
 


C o nfi de nti al  
F 3 7 3 2 8 0 C A 2 0 1  
 
St atistic al A n al ysis Pl a n  –  V ersi o n  2  -  1 5/ 0 6/ 2 0 1 7  
1 0 /3 9  
 
 
9.  
D E VI A TI O N S  
 
A fi nal data re vie w m eeti n g will be  hel d, pri or t o data base l oc k , i n or der t o re vie w pr ot oc ol 
de viati o ns . T hese will be classifie d as mi n or or m aj or.  
A  pr ot oc ol d e viati o n  will  be  c o nsi dere d  as maj or  w he n  it  is  li kel y  t o  bias  si g nifica ntl y  t he  
treat me nt effect esti mate base d o n t he pri mar y effi cac y criteri o n.  
Maj or pr ot oc ol de vi ati o ns  a n d ot her s o urce s of bias f or pri mar y criteri o n a nal yses , as  well as 
a d diti o nal reas o ns of e x cl usi o n fr o m a nal ysis sets  will be i de ntifie d usi n g t he list of pre-defi ne d 
reas o ns  f or  e x cl usi o n  fr o m  a nal ysis  sets  f or  t he  st u d y des cri be d  i n  a  s pecific  d oc u me nt  
“ Pre defi n e d reas o ns f or e x cl usi o n fr o m a nal ysis sets“ se parat el y fr o m t he st atistical a nal ysis pla n.   
 
A listi n g of all de viati o ns a n d a listi n g of a d diti o nal reas o ns f or e x cl usi o n fro m statistical a nal ysis 
will be pr o vi de d f or all ra n d o mise d patie nts, i ncl u di n g t he t y pe ( maj or/ mi n or) as vali date d d uri n g 
t he data  re vie w  meeti n g .  T his  listi n g  s h o ul d  be  pr o vi de d  pri or  t o  t he  data base  l oc k  a n d  t he  
ra n d o misati o n c o de r elease. 
T he  n u m ber  a n d  p erce nta ge  of  p atie nts  wit h  m aj or  pr ot oc ol  d e viati o ns  will  be  ta b ulate d  b y  
treat me nt gr o u p a n d t y p e of maj or  pr ot oc ol de vi ati o ns o n  t he ra n d o mise d patie nts set defi ne d i n  
secti o n 7 . T he n u m ber a n d perce nt a ge of patie nts wit h mi n or pr ot oc ol de viati o ns will be als o 
ta b ulate d b y treat me nt gr o u p a n d t y p e of mi n or de viati o ns o n t he ra n d o mise d patie nts set. 
 
T he  n u m ber  a n d  p erce nta ge  of  patie nts  wit h  reas o n  of  e x cl usi o n  fr o m  a nal ysis  sets  will  be  
ta b ulate d b y treat me nt gr o u p a n d t y p e of reas o n of e x cl usi o n o n t he ra n d o mise d patie nts set. 
 
1 0.  H A N D LI N G O F MI S SI N G D A T A A N D A N A L Y SI S O F  D R O P -
O U T S  
1 0. 1.  D R O P- O U T S 
 
Res ults of criteria r e p orte d o ver ti me will be prese nte d o n t he o bser ve d cas es ( O C).  
 
1 0. 2.  R E P O SI TI O NI N G O F VI SI T S 
 
F or pre mat ur e wit h dr a w al s, patie nts’  d ata  at t he e n d of st u d y visit will be i m p ute d t o   t he ne xt 
e x pecte d visit  ( O bser ve d Case a p pr oac h). F or e x a m ple, if  a patie nt dr o ps o ut of t h e st u d y after 
Visit 6 ( Wee k 1 2), t he n t he e n d of st u d y visit will i m ple me nt t he  visit 7 ( Wee k 1 6). 
 
U nsc he d ule d m eas ur e me nts will be ta ke n i nt o acc o u nt f or a n al ysis i n case of missi n g ori gi nal 
meas ure me nt
1 1/ 4 0
. 


C o nfi de nti al  
F 3 7 3 2 8 0 C A 2 0 1  
 
St atistic al A n al ysis Pl a n  –  V ersi o n  2  -  1 5/ 0 6/ 2 0 1 7  
1 1 /3 9  
 
U nsc he d ule d m eas ure me nts  will be ta ke n i nt o acc o u nt f or i n di vi d ual detecti o n of a b n or malities.  
 
I n case of se ver al p ost-baseli ne retests ar o u n d a sa me visit, t he first a vaila ble meas ure me nt at t he 
visit will be ke pt f or all a nal yses.  
 
 
1 0. 3.  MI S SI N G D A T A ( O T H E R T H A N D R O P- O U T) 
 
 F or S af et y a n al yses: 
 
F or  safet y  a n al ys es,  missi n g  val ues  will  be  re place d  b y  c orres p o n di n g val ue  of  re p ositi o ne d  
u nsc he d ule d meas ure me nt if a n y.     
 
F or  la b or at or y data,  i n t he  case t hat a n  u p per li mit  is  me nti o ne d  i n  t he  ass ociate d  c haracter  
varia ble,  m issi n g n u meric al val ue  will  be  re place d  b y  t he  li mit  me nti o ne d  i n  t he  c h aracter  
varia ble . ( F or l o w er li mit, m issi n g n u meric val ue will be re place d b y t he l o wer li mit).  
E x a m ple: f or a meas ur e of A L A T wit h a c haract er varia ble “ < 6”, missi n g n u meric val ue will be 
re place d b y 6. 
 
Missi n g b o d y w ei g ht : f or cr eati ni ne cleara nce esti mati o n, missi n g b o d y wei g ht will be re place d 
b y t he b o d y w ei g ht meas ure d at t he nearest visit.  
 
Re place me nt  of  missi n g  or  i nc o m plete  dates  prese nte d  hereafter  is  defi ne d  i n  a  c o nser v ati ve  
a p pr oac h.  
 
 Missi n g d ates of first or l ast tri al dr u g i nt a ke 
Missi n g dates of t he first trial dr u g i nta k e will be c o nsi dere d e q u al t o t he i ncl usi o n da y.  
Missi n g dates  of  last  trial  dr u g i nta ke  will  be  disc usse d  b y t he  m e m bers  of  t h e  data  re vi e w  
meeti n g  a n d e xtra p olate d  usi n g all i nf or mati o n rec or de d. 
 
 Missi n g d ates of st art of a d verse e ve nt  
I n case of c o m pletel y missi n g date, it will be esti mate d b y t h e date of first i nta ke of st u d y dr u g 
 
If t he da y a n d t he m o nt h are missi n g, 
- 
If t h e year is t he sa me as t he year of first i nta ke, it will be esti mate d b y t he date of first i nta ke 
of st u d y dr u g 
- 
If t he year is pri or t o t he year of first i nta ke, it will be esti mate d b y t he 3 1 D ece m ber 
- 
If t he year is after t he year of first i nta ke, it will be esti mate d b y t he 1st J a n uary 
 
If o nl y t h e da y is missi n g, 
- 
1 2/ 4 0
If t he m o nt h/ year are t h e sa me as t he m o nt h/ year of first i nta k e, it will be esti mate d b y t he 
date of first i nta ke of st u d y dr u g 


C o nfi de nti al  
F 3 7 3 2 8 0 C A 2 0 1  
 
St atistic al A n al ysis Pl a n  –  V ersi o n  2  -  1 5/ 0 6/ 2 0 1 7  
1 2 /3 9  
 
- 
If t he m o nt h/ year ar e pri or t o t he m o nt h/ year of first i nta ke, it will be esti mate d b y t he last d a y 
of t he m o nt h 
- 
If t he m o nt h/ year are after t o t he m o nt h/ year of first i nta ke, it will be esti mate d b y t he first da y 
of t he m o nt h 
 
If after i m p utati o n, t he esti mate d start date is aft er t he e n d dat e of t he a d verse e ve nt, it will be 
re place d b y t he e n d d ate of t he a d verse e v e nt 
 
 Missi n g d ates of e n d of a d verse e ve nt  
F or a d v erse e v e nts t hat are n ot “ o n g oi n g” at t he e n d of t he st u d y (i.e. wit h a n o utc o me ot her t ha n 
“ N ot rec o v er e d/ n ot res ol ve d” or “ R ec o veri n g/res ol vi n g”): 
I n case of missi n g date, it will be esti mate d b y t he last a vaila ble date (last visit or last u nsc he d ule d 
e x a m date) 
 
If t he da y a n d t he m o nt h are missi n g, 
- 
If t he year is t he s a me as t he year of last a vail a ble date, it will be esti mate d b y t h e last 
a vaila ble date  
- 
If t he year is pri or t o t he year of l ast a vaila ble d ate, it will be esti mate d b y t he 3 1 Dece m ber 
 
If o nl y t h e da y is missi n g, 
- 
If t he m o nt h/ year are t he sa me as t he m o nt h/ year of last a vaila ble d ate, it will be esti mate d b y 
t he last a vaila ble dat e 
- 
If t he m o nt h/ year are pri or t o t he m o nt h/ year of l ast a vaila ble dat e, it will be esti mate d b y t he 
last da y of t he m o nt h 
If after i m p utati o n, t he esti mate d e n d date is b ef ore t he start date of t he a d verse e ve nt, it will be 
re place d b y t he start dat e of t he a d verse e v e nt 
 
 Missi n g  se verit y or rel ati o ns hi p t o st u d y dr u g of a n a d verse e ve nts 
If t he ma xi mal se verit y of a n A E, as re p orte d b y t he i n vesti gat or, is missi n g, a ma xi mal se verit y 
“se ver e” will be i m p ute d.  
 
If  t h e  relati o ns hi p  t o  st u d y  dr u g,  as  re p orte d  b y  t he  i n vesti gat or,  is  missi n g,  a  relatio ns hi p 
“s us pecte d ” will be i m p ute d.  
 
 
 C o nc o mit a nt me dic ati o ns  
W he n t he start date is partiall y or c o m pletel y missi n g, t he sa me r ules as f or start a n d e n d d ate of 
a d verse e ve nt will be a p plie d , e x ce pt i n case of c o nfir mati o n of pre vi o us me dicati o n i n t he C RF 
(tic ke d b o x) t hat will be esti mate d at t he earliest date .
1 3/ 4 0
 


C o nfi de nti al  
F 3 7 3 2 8 0 C A 2 0 1  
 
St atistic al A n al ysis Pl a n  –  V ersi o n  2  -  1 5/ 0 6/ 2 0 1 7  
1 3 /3 9  
 
 
1 1.  D E S C RI P TI V E S T A TI S TI C S  
 
S u m mar y statistics will be prese nt e d b y treat me nt gr o u p a n d visit w he n a p pr o priate, a n d will 
c o nsist of val ues f or: 
- q ua ntitati ve para meters : n u m ber of missi n g data, n u m ber of patie nts, mea n, sta n dar d de vi ati o n 
(s d), me dia n, l o wer a n d u p per q uartiles, mi ni m u m a n d ma xi m u m, 9 5 % c o nfi de nce i nter v al  ar o u n d 
t he mea n ( w h e n rel e va nt)  
- q ualitati ve para m eters : n u m ber of missi n g dat a, a n d n u m ber a n d p erce nta ge of patie nts. 
 
 
M ea n c ha n ges  a n d  sta n dar d  err or  of  mea n  ( S E M)  will  be  als o re pres e nte d  gra p hicall y  fr o m  
baseli ne o ver ti me  f or rel e va nt criteria.  
 
Calc ulate d statistics ( mea n, s d, me dia n , l o wer a n d u p per q uartiles a n d 9 5 % c o nfi de nce i nter val)  
will dis pla y at m ost o ne m ore si g nifica nt fi g ure t h a n t he o bser v e d data. 
 
F or perce nt a ges, o ne d eci mal di git will be gi ve n. 
 
I n di vi d ual dat a listi n gs will be pr o vi de d f or all a n al yse d criteria.  
 
1 2.  DI S P O SI TI O N O F P A TI E N T S  
 
T he n u m ber of s cree ne d patie nts (w h o ha ve si g ne d a n i nf or me d c o ns e nt ) a n d ra n d o mise d patie nts , 
a n d reas o ns f or n o n r a n d o misati o n will be pr o vi de d o n t he Scree ne d patie nts set.  
T he n u m ber of patie nts i n eac h a nal ysis set detaile d i n secti o n 2 will be pr o vi de d b y treat me nt 
gr o u p a n d b y c o u ntr y a n d ce ntre f or ra n d o mise d pati e nts.  
T he n u m ber of ra n d o mi se d patie nts b y visit d o ne will be als o ta b ulate d b y treat me nt gr o u p  f or 
ra n d o mise d patie nts. 
 
T he n u m ber a n d perce nta ge of patie nts w h o wit h dre w pre mat urel y fr o m  t he st u d y after t heir 
ra n d o misati o n will be pr o vi de d b y treat me nt  gr o u p a n d reas o ns of dr o p o ut o n t he ra n d o mise d 
patie nts  set. 
 
1 3.  D E M O G R A P HI C A N D O T H E R B A S E LI N E C H A R A C T E R I S TI C S 
 
Bef ore t he first trial dr u g i nta k e, me di cal a n d s ur gical hist or y, d e m o gra p hic  data ( ge n d er, a ge, 
wei g ht,  hei g ht  a n d  B S A)  a n d  disease  c haract eris tics  (left atrial  area  i n  c m 2
1 4/ 4 0
, left  ve ntric ular  
ejecti o n  fracti o n  i n  %,  d urati o n  of  c urre nt  A F  u p  t o  selecti o n  visit  ( da ys), ti me  fr o m first 


C o nfi de nti al  
F 3 7 3 2 8 0 C A 2 0 1  
 
St atistic al A n al ysis Pl a n  –  V ersi o n  2  -  1 5/ 0 6/ 2 0 1 7  
1 4 /3 9  
 
d oc u me nte d persiste nt A F  u p t o selecti o n visit , ti me fr o m heart fail ure di a g n osis  u p t o selecti o n 
visit , N Y H A gr a de) will be descri b e d b y treat me nt gr o u p o n t he F ull A nal ysis  Set.  
 
T hese data , e x ce pt diseas e c har acteristics a n d baseli ne efficac y criteria will als o be descri b e d o n 
t he Safet y set. 
 
If m ore t ha n 1 0. 0 % patie nts of t he F A S are e x cl u de d fr o m t he Per Pr ot oc ol Set, de m o gra p hic data, 
disease c h aracteristics a n d baseli ne efficac y criteria will be re peate d o n t he P P  Set.  
 
T he  a ge  i n  years  will  be  calc ulate d  as  t h e  i nt e ger  part  of  [(refere nce  start  dat e*  - date  of  
birt h)/ 3 6 5. 2 5]. * See a p pe n dix 1  
 
F or listi n gs of i n d i vi d ual data, t he a ge prese nte d f or ra n d o mise d a n d n o n treate d p atie nts will be 
( date of ra n d o misati o n   - date  of birt h) a n d t he a ge f or n ot  ra n d o mis e d patie nts will be ( date of 
i nf or me d c o nse nt si g nat ure dates - d ate  of birt h).  
 
T he B MI will be calc ul ate d as wei g ht ( k g) / [ hei g ht ( m)]² r o u n de d t o 1 deci mal place. 
 
T i me fr o m first d oc u me nte d persiste nt A F a n d ti me fr o m heart fail ure dia g n osis u p t o selecti o n  
visi t will be calc ulate d i n m o nt hs as (selecti o n visit date – e ve nt d ate + 1 )/ 3 0. 4, r o u n de d t o  o n e 
d eci mal place. 
 
B o d y w ei g ht, B S A , left atrial area a n d left ve ntri c ular ejecti o n fracti o n at scree ni n g a n d i ncl usi o n 
visits will be descri b e d b y tr eat me nt gr o u p o nl y f or b aseli ne v al ues ( i.e. last val ues meas ure d 
bef ore t h e first a p plicati o n of st u d y dr u g).  
 
 
C o nc o mita nt  diseases  at  selecti o n,  as  w ell  as  me dical  a n d  s ur gical  hist or y  will  be  ta b ul ate d  
descri pti vel y b y tr eat me nt gr o u p usi n g t he Me d D R A S yste m Or ga n Classes a n d preferre d ter ms  
o n t he Safet y Set . 
 
C o nc o mita nt treat me nts ta ke n bef ore  first st u d y dru g i nta ke d ate will be ta b ulate d des cri pti vel y 
( n u m ber a n d p erce nta ge of patie nts) b y treat me nt gr o u p o n t he Safet y S et . T he y will be classifie d 
b y t her a pe utic area acc or di n g t o t he W H O -D R U G dicti o nar y usi n g t he "a nat o mical t hera p e utic 
c he mical" ( A T C) clas sifi cati o n, b y W H O-D R U G A T C 1  a n d A T C 2 c o des. 
C o nc o mita nt treat me nts ta ke n bef or e first st u d y dr u g i nta ke date a n d li n ke d t o t he st u d y pat h ol o g y 
will be als o ta b ulate d as a b o ve.  
 
A n y f act or w hic h c o ul d bias t he treat me nt effect esti mate, li ke de m o gra p hic da ta or a n y ot her 
baseli ne  c h ar acteristics  will  be  ca uti o usl y  e x a mi ne d  i n  or der  t o  deter mi ne  w h et her  t he  
ra n d o misati o n faile d a n d affect t he i nter pretati o n of t he pri mar y res ults. If t his descri pti ve a nal ysis 
pr o vi des a n y cl ues o n p ot e ntial i m bala nces, f urt h er statistical i n vesti gati o ns will be carri e d o ut.  
1 5/ 4 0
 


C o nfi de nti al  
F 3 7 3 2 8 0 C A 2 0 1  
 
St atistic al A n al ysis Pl a n  –  V ersi o n  2  -  1 5/ 0 6/ 2 0 1 7  
1 5 /3 9  
 
 
1 4.  A N A L Y SI S O F E F FI C A C Y  
 
U nless ot her wise s pecifie d, the efficac y a nal ysis will be perf or me d o n t he F A S.  
Baseli ne v al ues will be t he latest val ue meas ure d bef ore t h e first st u d y dr u g  i nta ke.  
1 4. 1.  P RI M A R Y C RI T E RI O N 
 
T he pri mar y efficac y criteri o n is  t he ti me t o first rec urre nce of A F or atri al fl utter e mer ge nce.  
T he ti me t o first r ec urre nce of A F or atrial fl utter e mer ge nce is d efi ne d b y t h e ti me b et wee n t he 
date of E C V visit ( visit 3)  a n d t he date of t he first rec urre n ce of A F or atrial fl utter e mer ge nce  
o ver t he peri o d V 3- V 9.  
T he first rec urr e nce of A F or atrial fl utter is d efi ne d as t he first e pis o de of A F (s y m pt o matic or 
n ot) or atrial fl utter e mer ge n ce  lasti n g f or at least 1 0 mi n utes fr o m visit 3. 
 
F or r a n d o mise d patie nts wit h s p o nta ne o us car di o v ersi o n bef ore E C V, t he rec urre nce of A F or t he 
e mer ge n ce of atrial fl utter will be assesse d fr o m visit 3 ( wee k 5). 
 
T he pri mar y efficac y criteri o n will be calc ul ate d i n a c o nser v ati ve a p pr o ac h:  
- 
If first T T E M meas ure m ent is t he first  c o nfir me d  A F /fl utter al ert t he n t he d a y after t he e n d 
date of H olter will be c o nsi dere d as t he o ns et da y of first A F rec urre n ce  or atrial fl utter 
e mer ge n ce.  
- 
If  T T E M   meas ure me nt is n ot a vaila ble t he da y b ef ore t h e  first c o nfir m e d A F /fl utter al ert , 
t he n t he da y aft er t he pr e vi o us T T E M will be c o nsi dere d as t he o ns et da y of first A F 
rec urre nce or atrial fl utter e mer ge nce. 
- 
If a n A F/fl utter al ert i n T T E M meas ure me nt w as n ot c hec ke d at least 1 0 mi n utes after o n 
t he sa me da y, it will be c o nsi dere d as t he o ns et da y of t he first A F /fl utter o nl y if A F /fl utter 
is c o nfir me d wit h t he ne xt meas ure me nt.  
 
 
If t he patie nt has a pre m at ure E O T at a visit X ( or i n bet wee n visits X-1 a n d X), t he ce ns ori n g 
ti me will be at visit X. If t h e patie nt t o o k pr o hi bited treat me nt lea di n g t o n o n rec urre n ce / n o n 
e mer ge n ce pri or t o pr e mat ure E O T, t he ce ns ori n g ti me will be t he start date of t he pr o hi bite d 
treat me nt.  
If n o r ec urre n ce of A F or atrial fl utter e mer ge nce ca n be ascertai ne d b y last meas ure me nt d a y a n d 
t he patie nt has n ot alrea d y bee n ce ns ore d acc or di n g t o t he r ule descri be d a b o ve, t he patie nt will be 
ri g ht-ce ns or e d at t he last meas ure me nt d a y. 
 
1 6/ 4 0
 


C o nfi de nti al  
F 3 7 3 2 8 0 C A 2 0 1  
 
St atistic al A n al ysis Pl a n  –  V ersi o n  2  -  1 5/ 0 6/ 2 0 1 7  
1 6 /3 9  
 
1 4. 1. 1.  Pri m ar y A n al ysis 
T he pri mar y criteri o n , ti me t o first rec urre n ce of A F or atrial fl utter e m er ge n ce, will be d escri be d 
u si n g s ur vi val c ur ves acc or di n g t o t he K a pla n M eier met h o d. S ur vi val c ur ves will be p erf or me d 
b y  treat me nt  gr o u p.  T h e  ti me  t o  first  rec urre n ce  of  A F  or  atrial  fl utter  e mer ge n ce will  be  
c o m pare d b et wee n treat me nt gr o u ps usi n g  wit h t he L o g ra n k test.  
T he dis tri b uti o n of ti me t o first rec urre nce of A F or atrial fl utter e mer ge n ce will be des cri be d b y 
treat me nt gr o u p usi n g K a pla n-Meier met h o ds, re p orti n g Q 1, Q 3, m e dia n,  a n d t he 9 5 % c o nfi de nce 
i nter val ( CI).  
S ur vi val rates ( patie nts still i n si n usal rh yt h m ) will  be descri be d b y treat me nt gr o u p  at se veral 
ti me p oi nts (i ncl u di n g 1 wee k, 1, 2, 3 a n d 4 m o nt hs). 
Hazar d rati os a n d 9 5 % c o nfi de nce i nter v als ( base d o n t he Wal d test ) will be esti mate d wit h a C o x 
re gressi o n m o d el. T he P H R E G pr oce d ure i n S A S wit h o pti o n TI E S = E X A C T will be use d t o fit 
t he C o x pr o p orti o nal hazar ds m o del.  
 
1 4. 1. 2.  S u p p orti ve A n al ysis  
T he pri mar y a n al ysis will be re peate d o n t he P P set.  
 
1 4. 1. 3.  A d dit i o n al A n al yses  
T o ta ke i nt o c o nsi der ati o n t he sa m ple size re d ucti o n, t he pre dicti ve pr o ba bilit y of s uccess  wit h  t he 
e x pecte d sa m ple size b ase d o n o bser ve d d ata, a n d t he c o n diti o nal p o w er will be pr o vi de d t o 
s u p p ort t he statistical decisi o n. Differe nt p ossi bl e tr ue  treat me nt effects will be ass u me d f or t he  
calc ulati o n s of c o n diti o nal p o wer (e x pecte d cli nicall y rel e v a nt differe n ce of 2 0 % , a n d o bs er ve d 
differe n ce) . 
1 7/ 4 0
 


C o nfi de nti al  
F 3 7 3 2 8 0 C A 2 0 1  
 
St atistic al A n al ysis Pl a n  –  V ersi o n  2  -  1 5/ 0 6/ 2 0 1 7  
1 7 /3 9  
 
1 4. 1. 4.  S e nsiti vit y A n al yses 
Pri mar y a nal ysis of t he mai n criteri o n (s ee secti o n 1 4. 1. 1 ) will be c o n d uct e d o n t he s u b gr o u ps of 
patie nts defi ne d as:  
 
•  F A S patie nts wit h a D H A baseli ne < = me dia n of t he D H A at bas eli ne  
•  F A S patie nts wit h a D H A baseli ne > me di a n of t he D H A at b aseli ne  
N ote : T he me dia ns se par ati n g s u b gr o u ps will be calc ulate d o n t he F A S. 
 
•  F A S patie nts wit h vas c ul ar or car diac t h era p e utic pr oce d ures i de ntifie d i n  t he data re vie w 
meeti n g r e p ort  
•  F A S patie nts wit h o ut vasc ular  or  car diac  t h era pe utic  pr oce d ures  i de ntifie d  i n  t he  dat a  
re vie w meeti n g re p ort 
 
Ot her C o x m o dels will be use d t o i n vesti gate t he i nfl ue nce of Treat me nt * c o u ntr y, Treat me nt * 
Baseli ne  i nteracti o ns ( D H A  baseli ne),  a n d  t o  e val uate  t he  i nfl ue nce  of  s o me  pr o g n ostic  or  
de m o gr a p hic  f act ors  ( ge n der,  a ge,  B S A),  baseli ne  c haracteristics  of  t h e  disease  (d urati o n  of  
c urre nt A F u p t o selecti o n visit ,  ti me fr o m first d oc u me nte d persiste nt A F u p t o selecti o n visit, 
Ti me  fr o m  heart  fail ur e  dia g n osis  u p  t o  selecti o n  visit,  N Y H A  gra de ,  left  atrial  area,  Left  
ve ntric ular ejecti o n fr acti o n   o n t he F ull A nal ysis Set. 
 
R O C c ur ves will be als o c o nstr ucte d acc or di n g t o D H A a n d ti me t o first rec urre n ce t hres h ol ds 
(f or e xa m ple, p ositi ve/ ne gati ve D H A vs first rec urre nce < =/ > 1 wee k ). 
 
1 4. 2.  S E C O N D A R Y C RI T E RI A  
All sec o n dar y a nal yses will be perf or me d o n t he F A S.  
1 4. 2. 1.  N u m bers of Atri al Fi brill ati o n/ Fl utter E pis o des i n t he first w ee k f oll o wi n g 
V 3 
1 8/ 4 0
T he t otal n u m ber of A F /fl utter e pis o des (s y m pt o m atic or n ot, lasti n g f or at l east 1 0 mi n utes or l ess 
t ha n 1 0 mi n utes) d uri n g t he 7- da y h olter  m o nit ori n g will be des cri be d b y treat me nt gr o u p a n d 
c o m pare d b y t he C o c hra n -Ma ntel -Hae nszel test a dj uste d b y c o u ntr y. 


C o nfi de nti al  
F 3 7 3 2 8 0 C A 2 0 1  
 
St atistic al A n al ysis Pl a n  –  V ersi o n  2  -  1 5/ 0 6/ 2 0 1 7  
1 8 /3 9  
 
1 4. 2. 2.  D ur ati o n of Atri al Fi brill ati o n/ Fl utter E pis o des i n t he first w ee k f oll o wi n g 
V 3 
T he d urati o n of all A F /fl utter  e pis o des d uri n g t h e 7- da y h olter   m o nit ori n g will be descri be d b y 
treat me nt gr o u p a n d c o m pare d usi n g a n o n-para metric a nal ysis of c o varia nce ( bas e d o n ra n ks) 
a dj uste d f or c o u ntr y.  
 
1 4. 2. 3.  Ti me t o first A F rec u rre nce / fl utter e mer g e nce less t h a n 1 0 mi n utes d uri n g 
T T E M pe ri o d 
T he ti me t o t he first A F r ec urr e nce / fl utter e m er ge nce less t h a n 1 0 mi n utes will be a nal yse d as t he 
pri mar y a nal ysis.  
 
1 4. 2. 4.  Ti me t o first s y m pt o m atic A F re c urre nce / fl u tter e mer ge nce d u ri n g T T E M 
peri o d 
T he ti me t o t he first s y m pt o matic A F rec urre nce / fl utter e mer ge nce * will be a nal yse d as t he 
pri mar y a nal ysis.  
*  Sy m pt o m atic  A F  rec urre nce/ Fl utter  e mer ge n ce  will  be  defi ne d  as  A F  rec urre nce / Fl utter 
e mer ge n ce  ass oci ate d w it h at le ast o ne sy m pt o m ( p al pit ati o n, f ati g ue, dizzi ness, dys p ne a, c h est 
p ai n a n d a nxiety) i n E H R A ev al u ati o n. 
 
1 4. 2. 5.  Cli nic al p ar a mete rs e v al u ati o n 
1 4. 2. 5. 1.  E H R A sc ore 
A F r elate d s y m pt o ms were  e val u ate d b y t he E H R A  ( E ur o pea n Heart R h yt h m Ass ociati o n) sc ore. 
T he f oll o wi n g ite ms “ d uri n g pres u me d arr h yt h mia e pis o des " are c hec k e d t o deter mi ne t he s c ore: 
pal pitati o n, fati g ue, dizzi ness, d ys p n ea, c h est pai n a n d a n xiet y. 
Classificati o n of A F -relat e d s y m pt o ms ( E H R A sc ore) are as f oll o ws: 
•  
1 9/ 4 0
E H R A I           - ‘ N o s y m pt o ms’ 


C o nfi de nti al  
F 3 7 3 2 8 0 C A 2 0 1  
 
St atistic al A n al ysis Pl a n  –  V ersi o n  2  -  1 5/ 0 6/ 2 0 1 7  
1 9 /3 9  
 
•  E H R A II          - ‘ Mil d s y m pt o ms’; n or mal dail y acti vit y n ot affecte d 
•  E H R A III        - ‘ Se ver e s y m pt o ms’; n or mal dail y acti vit y affecte d 
•  E H R A I V        - ‘ Disa bli n g s y m pt o ms’; n or mal dail y acti vit y disc o nti n ue d  
T he ma xi m u m E H R A sc ore will be des cri be d b y treat me nt  gr o u p a n d a n al yse d usi n g t he C oc hra n-
Ma ntel -Hae nszel statistics (r o w  m ea n  sc ores) stratifie d b y c o u ntr y effect  usi n g m o difie d ri dit 
sc ores.  
I n a d diti o n t o t his sc ore, t he fre q ue nc y of s y m pt o ms  will  be classifie d i n t hree gr o u ps, na mel y 
occasi o nall y (less  t ha n o nce per m o nt h), i nter me diate ( 1/ m o nt h t o al m ost dail y) a n d fre q u e nt at 
least dail y, a n d will be descri be d b y treat me nt gr o u p. 
 
1 4. 2. 5. 2.  Pres u m e d arr hyt h mi a 
A pres u me d arr h yt h mia will be defi ne d as a n E H R A sc ore e q u al t o II, III or I V. 
T he fre q u e nc y of pres u m e d arr h yt h mia ( will be descri be d b y treat me nt gr o u p. 
 
1 4. 2. 5. 3.  Rec urre nc e of sy m pt o m atic A F 
T he n u m ber of r ec urre n ces of s y m pt o matic A F c o nsists of t he n u m ber of A F rec urre n ce s d uri n g 
T T E M peri o d  ass ociate d wit h at least o ne s y m pt o m (p al pitati o n, fati g ue, dizzi ness , d ys p nea, c hest 
pai n a n d a n xiet y) i n E H R A e val uati o n. 
T he n u m ber o f rec urre n ce of s y m pt o matic A F will be des cri be d b y treat me nt gr o u p a n d c o m pare d 
usi n g t he C oc hr a n-Ma ntel -Hae nszel test stratifie d b y c o u ntr y. 
 
1 4. 2. 5. 4.  N u m ber a n d d ur ati o n of h os pit aliz ati o ns 
2 0/ 4 0
H os pi talizati o ns f or car di o vasc ular e ve nts will be c haracterise d b y:  


C o nfi de nti al  
F 3 7 3 2 8 0 C A 2 0 1  
 
St atistic al A n al ysis Pl a n  –  V ersi o n  2  -  1 5/ 0 6/ 2 0 1 7  
2 0 /3 9  
 
− H os pitalizati o n f or A F tr eat me nt  
− H os pitalizati o n f or w orse ni n g of h eart fail ure 
− H os pitalizati o n f or m y o car dial i nfarcti o n  
T he n u m ber of h os pitali zati o ns (f or car di o vas c ular e v e nts, f or t hr o m b o e m b olic str o ke a n d f or all 
ca uses) will be descri be d b y treat me nt gr o u p a n d c o m pare d usi n g C o c hra n -Ma ntel -H ae nszel test 
stratifie d b y c o u ntr y. 
T he d urati o n of h os pitalizati o ns f or car di o vas c ular e ve nts, f or t hr o m b oe m b olic str o ke a n d f or a n y 
ca use will be des cri be d b y treat me nt gr o u p a n d c o m pare d usi n g a n o n-para m etric a nal ysis of 
c o varia n ce ( b ase d o n r a n ks) a dj uste d f or c o u ntr y. 
 
1 4. 2. 5. 5.  C ar di oversi o n assess m e nt 
T he n u m ber of s p o nta n e o us car di o versi o n  bef ore visit   3, of s uccessf ul car di o versi o n (i ncl u di n g 
n u m ber of  s h o c ks distri b uti o n) at visit 3 a n d t he n u m ber of p atie nts nee di n g a n ot her car di o versi o n 
after i nitial E C V will be descri b e d b y treat me nt gr o u p a n d c o m pare d  usi n g C oc hra n -Ma ntel -
Hae nszel test stratifie d b y c o u ntr y. 
 
1 4. 2. 5. 6.  Ev ol uti o n of ec h oc ar di o gr a p hic p ar a m eters 
T he  f oll o wi n g  ec h ocar di o gra p hi c  para meters  w ere  ass esse d:  Left  atrial  dia meter  ( m m),  L A A  
(c m2), Left atrial v ol u me ( ml), Left atri al v ol u me/ B S A ( ml/ m2), L V E F ( %), Left v e ntric ular e n d 
diast olic  v ol u me/ B S A  ( ml/ m 2),  Left  ve ntric ul ar  e n d  s yst olic  v ol u me/ B SA  ( ml/ m 2),  Left  
ve ntric ular  e n d  diast oli c  dia meter  ( m m),  Left  ve ntric ular  e n d  di ast olic  v ol u me  ( ml),  Left  
ve ntric ular e n d s yst olic dia meter ( m m) a n d Left v e ntric ular e n d s yst olic v ol u me ( ml).  
T he ec h ocar di o gra p hic p ara meters val ues will be descri be d at eac h ti me ( V 1, V 2, V 4, V 6 a n d V 9) 
a n d c ha n ges descri b e d fr o m V 4 t o last val ue (V 9 ) a n d fr o m V 2 t o last val ue (V 9 ). 
2 1/ 4 0
 


C o nfi de nti al  
F 3 7 3 2 8 0 C A 2 0 1  
 
St atistic al A n al ysis Pl a n  –  V ersi o n  2  -  1 5/ 0 6/ 2 0 1 7  
2 1 /3 9  
 
1 5.  C O M P LI A N C E  
 
Esti mati o n of c o m plia nce will be prese nte d b y treat me nt gr o u p o n t he F ull A nal ysis Set. T he 
a nal ysis of c o m plia nce will be p urel y d escri pti ve.  
 
O nl y t he gl o bal c o m plia nce ( ie f or t he w h ole d ur ati o n of st u dy) will be esti mate d. 
 
Trial dr u g c o m plia nce will be e val uat e d, f or eac h patie nt, b y treat me nt gr o u p, b y calc ulati n g: 
(esti mate d n u m ber of ta blets act uall y ta k e n di vi de d b y t he oreti cal n u m ber of ta blets t o be ta ke n) x 
1 0 0 (r o u n de d at 1 di git). 
T he n u m ber of ta blets act uall y ta k e n d uri n g t he st u d y will be esti mate d as: n u m ber of ta blets 
deli vere d mi n us n u m ber of ta blets ret ur n e d.  
I n case of trial dr u g b o x es n ot ret ur ne d or partiall y br o u g ht bac k, trial dr u g c o m plia nce will be 
c o nsi dere d u n k n o w n a n d missi n g.  
T he t he oretical n u m ber of ta blets t o be ta ke n will be calc ulate d ta ki n g i nt o acc o u nt t he act ual 
n u m ber of da ys b et wee n dates of visits  V 2 a n d V 9 c o nsi deri n g t he dail y d ose sta ble  
 
C o m plia nce will be ta b ulate d usi n g c o nti n u o us scale a n d acc or di n g t o a 3 -scale as: < 8 0, [ 8 0 – 
1 0 0], a n d > 1 0 0 %. 
 
A n e xtra p olati o n of t he c o m plia nce will be als o calc ulate d c o nsi deri n g t h e n ot ret ur ne d blisters as 
ta ke n. 
 
1 6.  BI O M A R K E R A N A L Y SI S    
1 6. 1.  R E D B L O O D C E L L C O N C E N T R A TI O N S O F D H A 
Val ues a n d c ha n ges fr o m baseli ne f or re d bl o o d cell c o nce ntrati o n of D H A will be perf or me d b y 
treat me nt gr o u p a n d assess me nt ti me o n t he F A S. 
 
1 7.  S A F E T Y A N A L Y SI S  
 
T he safet y a nal ysis will be prese nt e d o n t he Safet y Set  a n d will be descri pti ve.  
2 2/ 4 0
Baseli ne Meas ur es: T he baseli ne will be t he last val ue meas ure d b ef ore  t he first i nta ke of st u d y 
dr u g. I n partic ular, i n cas e of ret est, t his retest will be use d. 


C o nfi de nti al  
F 3 7 3 2 8 0 C A 2 0 1  
 
St atistic al A n al ysis Pl a n  –  V ersi o n  2  -  1 5/ 0 6/ 2 0 1 7  
2 2 /3 9  
 
Val ues meas ure d t he sa m e d a y as t he first i nta ke will be c o nsi dere d bef ore t he f irst i nta ke of st u d y 
dr u g ( pla n ne d i n t he e ve ni n g wit h di n ner). 
Res ults of retests perf or me d p ost -trial dr u g a d mi nistrati o n will n ot be a nal yze d a n d ta b ulate d 
(e x ce pt i n case of missi n g val u e f or t ec h nical pr o ble m). T he y will o nl y b e dis pla ye d i n i n di vi d ual 
data listi n gs.  
 
1 7. 1.  E X T E N T O F E X P O S U R E 
 
E xte nt of e x p os ure t o t he trial dr u g e x presse d i n da ys will be ta b ulate d as q ua ntitati ve data, b y  
treat me nt gr o u p a n d gl o b all y. 
 E xte nt of e x p os ure t o t he trial dr u g is defi ne d as t he ti me i nter val b et wee n t he act ual d at e of first 
trial dr u g a d mi nistrati o n (i ncl u d e d) a n d t he act u al date of last trial dr u g a d mi nistrati o n (i ncl u de d), 
i.e., as t he q ua ntit y ” d ate of last trial dr u g a d mi nistrati o n – date of first trial dr u g a d mi nistrati o n + 
1 da y”. ( I nc o m plet e or u nk n o w n d ates of first a n d l ast tri al dr u g a p plicati o ns  will be s u bstit ute d 
as detaile d i n secti o n 1 0. 3 ). 
 
1 7. 2.  A D V E R S E E V E N T S 
 
A n y a d v erse  e ve nt  ha vi n g bee n  re p orte d  d uri n g  t he  st u d y f or  a  gi ve n  s u bject/ patie nt will  be 
classifie d usi n g t h e Me d D R A ter mi n ol o g y o n t he Safet y Set.  
 
A n y rec or de d A E will be re gar de d as Treat me nt E mer ge nt ( T E A E)  if it occ urs or w orse ns after 
t he first a d mi nistrati o n (i ncl u de d) of t he st u d y dr u g. 
 
T he occ urre n ce of a n a d v erse e v e nt will be defi ne d b y t he a p peara nce of a ne w si n gl e e ve nt, t he 
rea p pear a nce of a pr e vi o usl y rec o vere d e v e nt or t he w orse ni n g of a persist e nt e ve nt (relati ve t o its 
pre vi o us stat us). 
 
If t he se verit y is missi n g, a se verit y of “se vere” will be assi g ne d. 
 
Missi n g or i nc o m plete d ates will be i m p ute d f or t he calc ul ati o n of T E A E as descri be d i n secti o n 
1 0. 3 , b ut will be prese nte d as re p orte d i n t he eC R F i n t he data listi n gs.  
 
 
A s u m mar y t a ble will be pr o d uce d gi vi n g t he n u m ber (a n d p erce nta ge f or p atie nt) of:  
 P atie nts wit h at least o ne A E  
 P atie nts wit h at least o ne T E A E  
 Patie nts wit h at least o n e rel ate d T E A E (i.e. rel ati o ns hi p t o t he st u d y dr u g ot her t ha n “ N ot 
s us pecte d”) 
 P atie nts wit h at least o ne A E lea di n g t o defi niti ve st u d y dr u g disc o nti n uati o n  
 P atie nts wit h at least o ne Seri o us A E ( S A E)  
 Occ urre nces of  A Es  
 
2 3/ 4 0
Occ urre nces of  T E A Es  


C o nfi de nti al  
F 3 7 3 2 8 0 C A 2 0 1  
 
St atistic al A n al ysis Pl a n  –  V ersi o n  2  -  1 5/ 0 6/ 2 0 1 7  
2 3 /3 9  
 
 Occ urre nces  of relate d T E A Es  
 Occ urre nces  of A Es lea di n g t o defi niti ve st u d y dr u g disc o nti n uati o n 
 Occ urre nces  of S A Es  
 
T he n u m ber a n d per ce nt a ge of patie n ts wit h at least o ne A E occ urre d bef ore first a d mi nistrati o n 
wil l be ta b ulate d b y Me d D R A S yste m Or ga n Class ( S O C), Preferre d Ter m ( P T) a n d Treat me nt 
Gr o u p.  
 
N u m bers a n d per ce nta ges of s u bjects wit h at least o ne re p orte d treat me nt e mer ge nt a d verse e ve nt 
will be ta b ulate d b y treat me nt gr o u p  ( b y decreasi n g or d er of fre q ue nc y i n t he ver u m gr o u p).  a n d: 
•  B y s yste m or ga n class a n d preferre d t er m  
•  B y s yste m or ga n class, preferre d t er m, a n d t he m ost se vere i nte nsit y  
•  A n d b y s yste m or ga n class, preferre d ter m a n d t he m ost se vere relati o ns hi p t o t he st u d y dr u g. 
" T he n u m ber a n d p erc e nta ge of patie nt s wit h at least o ne dr u g relate d T E A E (i.e. rel ati o ns hi p t o 
t he st u d y dr u g ot her t ha n “ N ot s us pecte d") will be ta b ulate d b y S O C, Preferre d Ter m a n d 
Treat me nt gr o u p i n decr easi n g or d er f or t he treat me nt gr o u p ( b y decreasi n g or der of fre q u enc y i n  
t he ver u m gr o u p). 
 
T he n u m ber a n d per ce nt a ge of patie nts wit h at least o ne T E A E, a n d t he n u m ber of occ urre n ces of 
T E A Es, will be ta b ulate d b y M e d D R A S O C, Preferre d Ter m, seri o us n ess a n d Treat me nt Gr o u p  
( b y d ecr easi n g or d er of fr e q ue nc y i n t he v er u m gr o u p). 
T he  n u m ber  a n d  per ce nta ge  of  patie n ts  wit h  at  least  o n e  relate d  T E A E,  a n d  t h e  n u m ber  of  
occ urr e nces of relate d T E A Es, will be ta b ulate d b y Me d D R A S O C, Preferre d Ter m, seri o us ness 
a n d Treat me nt Gr o u p ( b y decreasi n g or der of fre q ue nc y i n t he ver u m gr o u p). 
 
 
Seri o us A d verse E ve nts ( S A Es)  
 
Seri o us a d vers e e ve nts will als o be descri b e d o n a n i n di vi d ual basis: treat me nt gr o u p, patie nt ’s 
c o de, se x a n d a ge, i n vesti gat or's re p ort e d ter m, preferre d ter m, date of o ns et acc or di n g t o t he d ate 
of t he first st u d y treat m e nt a d mi nistrati o n, d urati o n, acti o n ta ke n re gar di n g t he st u d y treat me nt 
a d mi nistrati o n, use of a c orrecti ve treat me nt, o ut c o me a n d relati o ns hi p t o t he st u d y treat me nt i n 
t he i n vesti gat or’s o pi ni o n. 
 
A Es le a di n g t o t he defi niti ve disc o nti n u ati o n  
All A Es  ha vi n g  le d  t o  t he  defi niti ve  disc o nti n uati o n  of  t he  trial  dr u g   will  be  liste d  a n d  
e x ha usti vel y des cri be d, o n a n i n di vi d ual basis, b y treat me nt gr o u p, i n e x actl y t he sa me wa y as 
seri o us a d verse e v e nts pre vi o usl y d escri b e d, d uri n g t he st u d y (fr o m t he dat e of t he first trial dr u g 
i nta ke o n war ds). 
2 4/ 4 0
 


C o nfi de nti al  
F 3 7 3 2 8 0 C A 2 0 1  
 
St atistic al A n al ysis Pl a n  –  V ersi o n  2  -  1 5/ 0 6/ 2 0 1 7  
2 4 /3 9  
 
De at hs  
Deat hs will be als o liste d a n d e x ha usti vel y des cri b e d, o n a n i n di vi d ual basis. 
 
All A Es will be i ncl u de d i n t he listi n gs of i n di vi d ual data.  
 
1 7. 3.  VI T A L SI G N S  
 
Descri pti ve statistics o ver ti me of val ues a n d c h a n ges fr o m bas eli ne of s u pi ne S yst olic Bl o o d 
Press ure ( S B P m m H g), Diast olic Bl o o d Press ure ( D B P m m H g) a n d Heart Rate ( H R b p m) will be 
ta b ulate d b y treat me nt gr o u p a n d assess me nt ti me.  
Fi g ures : mea n c ha n ges a n d sta n dar d err or of mea n ( S E M) will be re pres e nte d gra p hicall y fr o m 
baseli ne o ver ti me.  
T he scales of vertical a xis will  be:  
 
S B P m m H g  
D B P m m H g  
H R b p m  
Fr o m -1 5 t o + 1 5  
Fr o m -1 0 t o + 1 0  
Fr o m -1 5 t o + 1 5  
 
 
P S C a n d P S C V f or s u pi ne p ar a meters  
T he  n u m ber  a n d  perce nta ge  of  p atie nts  wit h  at  least  o ne  Pre defi n e d  P ote ntiall y  Cli nicall y  
Si g nifica nt C ha n ge ( P S C) a n d wit h at least o ne P S C Lea di n g t o Cli nicall y Si g nifi ca nt Val ue  
( P S C V) will be ta b ulate d b y treat me nt gr o u p (cf A p pe n di x 2, Ta ble 1).  
 
 
Ort h ost atic H y p ote nsi o n 
T he  n u m ber  a n d  perce nta ge  of  p atie nts  e x pe rie nci n g  at  least  o ne  p ost- baseli ne  ort h ostatic 
h y p ote nsi o n  (cf  A p p e n di x  2 ,  Ta ble  2 )  will  be  ta b ulate d  b y  treat me nt  gr o u p. Vital  si g ns  n ot 
meas ure d acc or di n g t o pr ot oc ol were  i de ntifie d d uri n g data re vie w meeti n g.  Meas ures perf or me d 
first i n sta n di n g p ositi o n a n d t he n i n s u pi ne p ositi o n will n ot be ta ke n i nt o acc o u nt f or t he a nal ysis 
of ort h ostatic h y p ot e nsi o n.   
 
1 7. 4.  L A B O R A T O R Y D A T A 
 
Cli nicall y n ot e w ort h y a b n or mal la b orat or y v al ues ( C N A L V) ( See A p pe n di x 4) will be i de ntifie d 
a n d descri be d o n a n i n di vi d ual basi s. Fi ve  se parat e i n di vi d ual data listi n gs b y treat me nt gr o u p will 
be pr o vi de d: 
 f or hae m o gl o bi n (i ncl u di n g c orres p o n di n g i n di vi d ual res ults of er yt hr o c ytes a n d hae mat ocrit), 
 f or platelets (i ncl u di n g c orres p o n di n g i n di vi d ual res ults of er yt hr oc ytes a n d le uc oc ytes),  
 
2 5/ 4 0
f or li ver f u n cti o n para meters (i ncl u di n g c orres p o n di n g i n di vi d ual res ults of ga m ma-G T),  


C o nfi de nti al  
F 3 7 3 2 8 0 C A 2 0 1  
 
St atistic al A n al ysis Pl a n  –  V ersi o n  2  -  1 5/ 0 6/ 2 0 1 7  
2 5 /3 9  
 
 f or ne utr o p hils  or  le uc oc yt es  (i ncl u di n g  c orres p o n di n g  i n di vi d ual  res ults  of  bas o p hils,  
e osi n o p hils, l y m p h o c yt es a n d m o n oc yt es)  
 f or ser u m creati ni ne 
 
 
Esti mate d  creati ni ne cleara nce ( ml/ mi n) will be calc ulate d usi n g C oc kr oft a n d Ga ult met h o d as 
 
x
0. 8 1 4
 x 
µ m ol/ L)
(i n 
 
creati ni ne
 
ser u m
 
k g)
(i n 
t 
b o d y wei g h
 x 
years)]
i n 
 ( 
a ge
 - 
[ 1 4 0
 (0. 8 5  f or fe male) 
 
Patie nts wit h esti mate d creati ni ne cleara n ce ( C oc kr oft met h o d) < 3 0 ml/ mi n  will be als o descri be d 
o n  a n  i n di vi d ual  basis . Val ue s  of  esti mate d  creati ni ne  cleara n ce  ( C o c kr oft  met h o d)  will be 
classifie d as f oll o wi n g:  
 
C re ati ni ne cle ar a nce  
c ate g ori es (ml/ mi n ) 
< 1 5   
[ 1 5-3 0[  
 
F or eac h la b orat or y par a meter, val ues a n d c ha n ges fr o m baseli ne will be ta b ulate d b y tr eat me nt 
gr o u p a n d asses s me nt ti me. 
F or  all  bi oc he mistr y  p ara meters,  scatter  pl ots  hi g hli g hti n g  i n di vi d ual  res ults  will  dis pla y  t he  
baseli ne a n d last val u e of t he la b orat or y m eas ure me nts f or eac h patie nt b y l ocati n g t he p oi nt 
defi ne d b y t he bas eli ne v al ue o n t he a bscissa a n d res pecti vel y last  val ue i n t he or di nate.  
F or  all  hae m at ol o g y  para meters,  scatter  pl ots  hi g hli g hti n g  i n di vi d ual  res ults  will  dis pla y  t h e  
baseli ne a n d w ee k 4, w ee k 1 2 a n d wee k 2 4 of t h e la b orat or y m eas ure me nts f or eac h patie nt b y 
l ocati n g t he p oi nt d efi ne d b y the b aseli ne val ue o n t he a bs cissa a n d res pecti vel y w ee k 4, w ee k 1 2 
a n d wee k 2 4 v al ue i n t he or di nate.  
Eac h treat me nt gr o u p will be differ e ntl y i de ntifie d. T he first bisecti n g li ne ( 4 5° li ne), t he li nes of 
l o wer a n d u p per n or mal ra n ge, t h e li nes of P ote ntiall y Cli nicall y Si g nifi ca nt C ha n ge ( P S C) ra n ge 
a n d Cli nicall y n ote w ort h y a b n or mal l a b orat or y val ue  ( C N A L V) ra n ge a d de d o n t he pl ots (see 
A p pe n dices 3 a n d 4). 
 
F or all bl o o d la b orat or y para meters, s hift ta bles will be pr o vi de d t o d e pict t he n u m bers of  patie nt
2 6/ 4 0
s 
wit h p ost -trial dr u g a d mi nistrati o n variati o ns at eac h assess me nt ti me as c o m pare d t o t h e bas eli ne 


C o nfi de nti al  
F 3 7 3 2 8 0 C A 2 0 1  
 
St atistic al A n al ysis Pl a n  –  V ersi o n  2  -  1 5/ 0 6/ 2 0 1 7  
2 6 /3 9  
 
val ues ( meas ur e d o n t he last bl o o d sa m ple c ollecte d bef ore t he first trial dr u g a d mi nistrati o n) b y 
treat me nt gr o u p. A 3 -p oi nt scale (l o w, n or m al, hi g h) will be us e d as defi n e d b y t he n or mal ra n ges 
i n use i n t he la b orat or y i n c har ge of t he ass a ys. 
N ote : zer o la b orat or y val ues wit h o ut cli nical si g nifica nce will ha ve t o be c o nsi dere d as missi n g 
f or statistical a nal ysis. 
 
1 7. 5.  C O A G U L A TI O N P A R A M E T E R S 
F or c o a g ulati o n  para met ers,  val ues  a n d  c h a n ges  fr o m  baseli ne will  be ta b ulate d  b y treat me nt  
gr o u p a n d assess me nt ti me. 
Scatter pl ots hi g hli g hti n g i n di vi d ual res ults f or c oa g ulati o n para meters ( pr ot hr o m bi n ti me/I N R, 
acti vate d p artial t hr o m b o plasti n ti me a n d t hr o m bi n cl otti n g ti me) bef ore a n d after st u d y treat me nt  
a d mi nistrati o n (last val ue) will be pr o d uce d. 
 
1 7. 6.  E C G 
I n di vi d ual ta b ulat e d data f or E C G a b n or m alities will be dis pla ye d. 
 
1 7. 7.  P H Y SI C A L E X A MI N A TI O N  
 
D escri pti ve statisti cs o ver ti me of b o d y wei g ht  v al ues a n d c ha n ges fr o m b aseli ne will be ta b ul ate d 
b y trea t me nt gr o u p a n d assess me nt ti me. 
 
T he res ults o n gl o bal p h ysical e x a mi nati o n will ne ver be ta b ul ate d beca use it ’s o nl y used t o detect 
p ote ntial A E. T he y will be o nl y list e d i n a p pe n di x 1 6 of t he I C H re p ort. 
2 7/ 4 0
 


C o nfi de nti al  
F 3 7 3 2 8 0 C A 2 0 1  
 
St atistic al A n al ysis Pl a n  –  V ersi o n  2  -  1 5/ 0 6/ 2 0 1 7  
2 7 /3 9  
 
1 7. 8.  C O N C O MI T A N T M E DI C A TI O N S 
C o nc o mita nt me dicati o n s will be ta b ulate d b y treat me nt gr o u p  a n d acc or di n g t o t he first st u d y 
dr u g i nta ke  a n d V 9 ( Ta k e n at least o nce bef ore  first st u d y dr u g a d mi nistrati o n , ta ke n at least o nce 
after first -st u d y dr u g a d mi nistrati o n a n d n ot starte d at V 9, starte d  at V 9) wit hi n a descri pti ve 
pers pecti ve. T he y will b e classifi e d b y t h era p e utic area acc or di n g t o t he W H O -D R U G dicti o nar y 
usi n g t he "a n at o mical t hera pe utic c h e mical" classificati o n o n t he  safet y s et. 
N ote : a c o n c o mita nt me dicati o n w hic h be gi ns b ef ore first st u d y dr u g a d mi nistrati o n a n d is o n-
g oi n g after first st u d y dr u g a d mi nistrati o n, is c o u nte d i n b ot h peri o ds “ Ta ke n at least o nce bef ore  
first st u d y dr u g a d mi nistrati o n” a n d  “ta ke n at least o nce after first -st u d y dr u g a d mi nistrati o n a n d 
n ot starte d at V 9”.  
 
1 8.  C H A N G E S SI N C E P R O T O C O L R E D A C TI O N  
 
T he f oll o wi n g m o dificati o ns were ma d e t o statistical a nal yses c o m pare d t o t h ose e n visa ge d i n t he 
Versi o n 9 of t he pr ot o c ol date d Dece m ber 6 t h, 2 0 1 6: 
- pre dicti ve pr o ba bilit y of s uccess a n d c o n diti o nal p o wer f or pri mar y efficac y criteri o n will be 
a d de d  
- s u b gr o u ps a nal yses f or pri mar y criteri o n will be a d de d  
- R O C  c ur ves f or pri mar y criteri o n e x pl orat or y a n al yses acc or di n g t o D H A will be a d de d  
- t he sec on d ar y criteria a nal yses re peate d o n t he P P set  will n ot be perf or m e d 
-t he sec o n d ar y criteria w ere e xte n de d t o t he fl utter detecti o n as t he pri mar y efficac y criteri o n 
- V S  para meters  i n  sta n di n g p ositi o ns will n ot  be a nal ys e d ( o nl y pr o vi de d i n i n di vi d ual da ta 
list n gs) 
- Fr e q ue ncies o n t he E C G cli nical i nter pretati o n will n ot be prese nte d ( n ot c ollecte d) - A n al ysis of 
T E A Es o cc ure n ces b y M e d D R A S O C, P T, s eri o us ness a n d Treat me nt Gr o u p will be a d de d as per 
E u dra C T re q uir e me nt  
 
N ote : t he F ull A nal ysis Set defi ni ti o n was clarifi e d wit h t he defi niti o n of s uccessf ul car di o versi o n 
as eit her s p o nta ne o us car di o versi o n bef ore V 3 or s uccessf ul E C V p erf or m e d at V 3. 
 
1 9.  D A T A P R O C E S SI N G  
 
Versi o n 9. 4 of S A S S oft ware f or wi n d o ws will be use d t o perf or m t he statistical pr oce d ures. 
 
2 0.  A P P E N DI X    
 
2 8/ 4 0
A p pe n di x 1:  C o n ve nti o ns relate d t o refere n ce d ates a n d a n al ysis st u d y da y varia bles  


C o nfi de nti al  
F 3 7 3 2 8 0 C A 2 0 1  
 
St atistic al A n al ysis Pl a n  –  V ersi o n  2  -  1 5/ 0 6/ 2 0 1 7  
2 8 /3 9  
 
A p pe n di x 2:  C ar di o vasc ular s afet y 
A p pe n di x 3:  L ist of Pre d efi ne d P ote ntiall y Cli nicall y Si g nifica nt C ha n ge f or La b orat or y 
Val ues ( ¤) 
A p pe n di x 4:  Defi niti o n of cli nicall y n ote w ort h y a b n or mal la b orat or y val ues ( C N A L V)  
2 9/ 4 0
A p pe n di x 5:  Ta bles, fi g ures a n d listi n gs 


C o nfi de nti al  
F 3 7 3 2 8 0 C A 2 0 1  
 
St atistic al A n al ysis Pl a n  –  V ersi o n  2  -  1 5/ 0 6/ 2 0 1 7  
2 9 /3 9  
 
 
A p pe n di x 1  
C O N V E N TI O N S R E L A T E D T O R E F E R E N C E D A T E S A N D  
A N A L Y SI S S T U D Y D A Y V A RI A B L E S  
p a ge 1/ 1  
 
 
Refere n ce d ates ar e us uall y e q ui val e nt t o:  
•  F or t he Refer e nce  Start Date: t he date of first st u d y dr u g i nta k e f or treate d p atie nts, t he 
date of r a n d o misati o n f or ra n d o mise d a n d n o n treate d patie nts a n d t he date of i nf or me d 
c o nse nt date i n ot her cas e (f or listi n gs of i n di vi d ual data) 
•  F or t he Refer e nce E n d D ate: t he date of l ast i nta ke of st u d y treat me nt. 
 
S o me a nal ysis ma y r e q uire t he c o m p utati o n of d urati o n fr o m a refere nce da y t o a p ost- refere n ce 
da y. D urati o n will be defi ne d as f oll o wi n g: 
 D urati o n (i n da ys) = Dat e - Refere n ce dat e + 1 da y  
 D urati o n (i n mi n utes) = ( Da te/ti me) – ( Refere n ce date/ti me) 
3 0/ 4 0
 


C o nfi de nti al  
F 3 7 3 2 8 0 C A 2 0 1  
 
St atistic al A n al ysis Pl a n  –  V ersi o n  2  -  1 5/ 0 6/ 2 0 1 7  
3 0 /3 9  
 
 
A p pe n di x 2  
C A R DI O V A S C U L A R S A F E T Y  
p a ge 1/ 1  
 
 
T a ble 1: Pre defi ne d Li mits f or P ot e nti all y Cli nic all y Si g nific a nt C h a n ges ( P S C) a n d P S C 
Le a di n g t o Cli nic all y Si g nific a nt V al ues ( P S C V)  
P ar a meter  
P S C  
P S C V  
S B P  
I ncre ase ≥ 2 0 m m H g  
Decre ase ≥ 2 0 m m H g  
S B P ≥ 1 6 0 m m H g a n d i ncre ase ≥ 2 0 m m H g  
S B P ≤ 9 0 m m H g a n d decre ase ≥ 2 0 m m H g  
D B P  
I ncre ase ≥ 1 0 m m H g  
Decre ase ≥ 1 0 m m H g  
D B P ≥ 1 0 0 m m H g a n d i ncrease ≥ 1 0 m m H g  
D B P ≤ 5 0 m m H g a n d decre ase ≥ 1 0 m m H g  
H R  
I ncrease ≥ 2 0 b p m  
Decre ase ≥ 2 0 b p m  
H R ≥ 1 2 0 b p m a n d i ncrease ≥ 2 0 b p m  
H R ≤ 5 0 b p m a n d decre ase ≥ 2 0 b p m  
 
 
 
T a ble 2: Defi niti o n of ort h ost atic h y p ote nsi o n 
Ort h ost atic H y p ote nsi o n *  
S B P Decrease ≥ 2 0 m m H g  
or  
D B P Decrease ≥ 1 0 m m H g bet wee n s u pi ne a n d sta n di n g p ositi o ns  
T he C o nse ns us C o m mi ttee of t he A merica n A ut o n o mic S oci et y a n d t he A merica n Aca de m y of Ne ur ol o g y. 
C o nse ns us state me nt o n t he defi niti o n of ort h ostatic h y p ote nsi o n, p ure a ut o n o mic fail ure a n d m ulti ple s yste m 
atr o p h y. Ne ur ol o g y 1 9 9 6; 4 6: 1 4 7 0 -3.  
3 1/ 4 0
 


C o nfi de nti al  
F 3 7 3 2 8 0 C A 2 0 1  
 
St atistic al A n al ysis Pl a n  –  V ersi o n  2  -  1 5/ 0 6/ 2 0 1 7  
3 1 /3 9  
 
  
A p pe n di x 3  
LI S T O F P R E D E FI N E D  P O T E N TI A L L Y C LI NI C A L L Y  
SI G NI FI C A N T C H A N G E F O R L A B O R A T O R Y V A L U E S ( ¤) 
p a ge 1/ 1  
 
 
P A R A M E T E R S  
U NI T  
P S C  
 
 
 
Decre ase  
I ncre ase 
M U S C L E  
Creati ne  P h os p h o ki nase  
U / l  
- 
2 3 6  
KI D N E Y  
Creati ni ne  
Urea  
Uric aci d  
P h os p hate  
Calci u m  
µ m ol/l  
m m ol/l  
µ m ol/l  
m m ol/l  
m m ol/l  
- 
- 
- 
0. 3 9  
0. 3 0  
3 5  
3. 2  
1 1 9  
0. 3 9  
0. 3 0  
E L E C T R O L Y T E S  
S o di u m  
P otassi u m  
C hl ori de  
Bicar b o nate  
m m ol/l  
m m ol/l  
m m ol/l  
m m ol/l  
8 
1. 1  
8 
7  
8 
1. 1  
7 
8  
M E T A B O LI S M/  
N U T RI TI O N A L  
Gl uc ose (ra n d o m)  
Al b u mi n  
Pr otei n  
C h ol ester ol 
H D L c h olester ol  
L D L c h olester ol  
Tri gl yceri des  
m m ol/l  
g/l  
g/l  
m m ol/l  
m m ol/l  
m m ol/l  
m m ol/l  
3  
6 
1 1  
- 
0. 9 1  
2. 1 7  
- 
3. 7  
6 
1 0  
1. 9 7  
0. 8 5  
2. 0 4  
2. 9 1  
E R Y T H R O C Y T E S  
Er yt hr oc yte c o u nt  
Hae m o gl o bi n  
Hae mat ocrit  
M C V  
M C H ( Fe)  
M C H C ( Fe)  
T/l  
g/l  
1 
fl 
f m ol 
m m ol/l  
0. 7  
2 0  
0. 0 6  
7 
0. 1 9  
2  
0. 7  
- 
0. 0 6  
7 
0. 1 9  
2 
L E U K O C Y T E S  
Le u k oc yte c o u nt  
G/l  
4. 2  
3. 8  
DI F F E R E N TI A L  
C O U N T  
Ne utr o p hils  
L y m p h oc ytes  
M o n oc ytes  
E osi n o p hils  
B as o p hils  
G/l  
G/l  
G/l  
G/l  
G/l  
3. 4 7  
1. 7 6  
- 
- 
- 
3. 1 9  
1. 6 3  
0. 4 9  
0. 4 1  
0. 1 4  
U RI N E  
S pecific gra vit y  
p H  
- 
- 
0. 0 1 7  
2  
0. 0 1 5  
2  
LI V E R  
T otal bilir u bi n  
A S A T ( S G O T)  
A L A T ( S G P T)  
Ga m ma G T  
Al kali ne p h os p hatase  
µ m ol/l  
U/l  
U/l  
U/l  
U/l  
- 
- 
- 
- 
-- 
1 0  
N x ( 2 3/ 3 6)  
N x ( 2 8/ 4 5)  
N x ( 2 5/ 3 8)  
N x ( 3 0/ 9 5)  
N = u p per li mit of n or m al r a n ge  
 
( ¤) Delt a-li mits fr o m « Ro uti ne L a b or at ory Tests i n Cli nic al Tri als  » W. Lei g h T h o m ps o n, R occ o L. Br u nelle, 
Gre g ory G. E n as, P atrick J. Si m ps o n a n d R a n dy L. W alker Lilly Rese arc h L a b or at ories, Lilly C or p or ate Ce nter, 
I n di a n a p olis, I n di a n a i n « Cli nic al Tri als a n d Tri b ul ati o ns  » 1 9 8 8.
3 2/ 4 0
 


C o nfi de nti al  
F 3 7 3 2 8 0 C A 2 0 1  
 
St atistic al A n al ysis Pl a n  –  V ersi o n  2  -  1 5/ 0 6/ 2 0 1 7  
3 2 /3 9  
 
 
A p pe n di x 4 
D E FI NI TI O N O F C LI NI C A L L Y N O T E W O R T H Y A B N O R M A L  
L A B O R A T O R Y V A L U E S ( C N A L V)  
p a ge 1/ 1  
 
 
 
P A R A M E T E R S  
B aseli ne v al ue  
C N A L V  
H A E M O G L O BI N  
N ot missi n g  
Decrease of at least 2 g/ dl a n d val ue < 1 0 g/ dl  
 
Missi n g  
Val ue < 1 0 g/ dl  
N E U T R O P HI L S  
- 
< 1 5 0 0/ m m 3  
W B C 
(if missi n g val ue f or ne utr o p hils) 
- 
< 3 0 0 0/ m m 3  
P L A T E L E T S  
- 
< 1 0 0 0 0 0/ m m 3  
S E R U M C R E A TI NI N E  
N ot missi n g  
I ncrease of at least 3 0 % as c o m pare d t o baseli ne 
val ue a n d val ue > 1 5 0 µ m ol/l  
 
Missi n g  
Val ue > 1 5 0 µ m ol/l  
LI V E R F U N C TI O N T E S T S  
 
 
 
A L A T  
N or ma l 
A L A T > 2 N  
 
 
≤ 2. 5 N  
I ncrease of at least 1 0 0 % as c o m pare d t o baseli ne 
val ue  
 
 
> 2. 5 N  
val ue > 5 N  
a n d/ or  
A S A T  
N or mal  
A S A T > 2 N  
 
 
≤ 2. 5 N  
I ncrease of at least 1 0 0 % as c o m pare d t o baseli ne 
val ue  
 
 
> 2. 5 N  
val ue > 5 N  
a n d/ or  
Al k ali ne p h os p h at ase ( A P)  
N or mal  
A P > 1. 2 5 N  
 
 
A b n or mal  
A P > 2 N  
a n d/ or  
T ot al bilir u bi n ( T B)  
N or mal  
T B > 1. 5 N  
 
 
A b n or mal  
T B > 2 N  
 
N = u p pe r li mit of n or m al r a n g e  
I nter n ati o n al c o nse ns us Meeti n g. I nter n ati o n al J o ur n al of Cli nic al P h ar m a c ol o g y, T h er a p y a n d T o xic ol o g y, 1 9 9 0; 2 8: 3 1 7-3 2 2  
3 3/ 4 0
St a n d ar dis ati o n of d efi niti o ns a n d criteri a of c a us ality assess me nt of a d verse dr u g re a cti o ns: dr u gs -i n d u ce d liver dis or ders: re p ort 
of a n St a n d ar dis ati o n of d efi niti o ns a n d criteri a of c a us ality assess me nt of a d verse dr u g re a cti o ns: dr u gs -i n d u ce d cyt o p e ni a. 
I nte n ati o n al J o ur n al of Cli nic al P h ar m a c ol o g y, T h er a p y a n d T o xic ol o g y, 1 9 9 1; 2 9: 7 5-8 1  


C o nfi de nti al  
F 3 7 3 2 8 0 C A 2 0 1  
 
St atistic al A n al ysis Pl a n  –  V ersi o n  2  -  1 5/ 0 6/ 2 0 1 7  
3 3 /3 9  
 
A p pe n di x 5 : T A B L E S, FI G U R E S A N D LI S TI N G S   
p a ge 1/ 4  
 
 
S E C TI O N  
Title  
R T F ref ere nce  
1 0. 1  
N u m ber of s cree n e d a n d ra n d o mise d patie nts, a n d reas o ns f or n o n 
ra n d o misati o n [ Scree ne d patie nts set] 
1 0 _ 1a _ra n dtrt. R T F  
1 0. 1  
N u m ber of patie nts wit h st u d y disc o nti n uati o n a n d reas o n f or 
disc o nti n uati o n  [ Ra n d o mise d patie nts set]  
1 0 _ 1 d 1 _ p wst u d y _ o v. R T F  
1 0. 2  
N u m ber of P atie nts wit h Maj or pr ot oc ol D e viati o ns [ Ra n d o mise d Patie nt s 
Set ] 
1 0 _ 2a _ maj _ de v. R T F  
1 0. 2  
N u m ber of P atie nts e xcl u de d fr o m a nal ysis sets a n d reas o ns  [Ra n d o mise d 
Patie nts Set ] 
1 0 _ 2 b _reas _e xcl. R T F  
1 1. 1  
N u m ber of  patie nts i n eac h a nal ysis set  [ Ra n d o mised patie nts Set]  
1 1 _ 1 _aset . R T F 
1 1. 1  
N u m ber of p atie nts b y st u d y visit  [Ra n d o m ised patie nts sets ] 
1 1 _ 1 b _ b y visit. R T F  
1 1. 2  
De m o gr a p hic c haracteristics [ F A S]  
1 1 _ 2a _ de m o. R T F  
1 1. 2  
Disease c haracteristics at baseli ne  [ F A S] 
1 1 _ 2c _ disc har. R T F  
1 1. 3  
Treat me nt C o m plia nce [ F A S]  
1 1 _ 3a. R T F  
1 1. 3  
E xtra p olate d treat me nt c o m plia nce [ F A S]  
1 1 _ 3 b. R T F  
1 1. 4. 1. 1  
Ti me t o first rec urre nce of A F or atrial e mer ge nce - S ur vi val c ur ves a n d 
L o gra n k test [ F A S]  
1 1 _ 4 _ 1 _ 1 _ 1 _ pri ma na _ K M.
gif  
1 1. 4. 1. 1  
Ti me t o first rec urre nce of A F or atrial e mer ge nce - K M s u m mar y 
[ F A S] 
1 1 _ 4 _ 1 _ 1 _ 2 _ pri ma na _ K M .
R T F  
1 1. 4. 1 . 1 
Ti me t o first rec urre nce of A F or atrial e mer ge nce - C o x a nal ysis [ F A S] 1 1 _ 4 _ 1 _ 1 _ 3 _ pri ma na _c o x .
R T F  
1 1. 4. 1. 1  
Ti me t o first rec urre nce of A F or atrial e mer ge nce - S ur vi val c ur ves a n d 
L o gra n k  test [ P P] 
1 1 _ 4 _ 1 _ 2 _ 1 _s u p a na_ K M .gi
f 
1 1. 4. 1. 1  
Ti me t o first rec u rre nce of A F or atrial e mer ge nce - K M s u m mar y [ P P] 1 1 _ 4 _ 1 _ 2 _ 2 _ s u pa na _ K M. R
T F  
1 1. 4. 1. 1  
Ti me t o first rec urre nce of A F or atrial e mer ge nce - C o x a nal ysis [ P P] 
1 1 _ 4 _ 1 _ 2 _ 3 _ s u pa na _c o x. R
T F  
 
Ti me t o first rec urre nce of A F or atrial e mer ge nce - S ur vi val c ur ves a n d 
L o gra n k t est [F A S  patie nts  wit h a D H A baseli ne < = me dia n of t he D H A at 
baseli ne ] 
1 1 _ 4 _ 1 _ 4 _ 1 _ se nsa na _ D H A
1 _ K M. gif  
 
Ti me t o first rec urre nce of A F or atrial e mer ge nce - K M s u m mar y [ F A S 
patie nts  wit h a D H A baseli ne < = me dia n of t he D H A at baseli ne ] 
1 1 _ 4 _ 1 _ 4 _ 2 _ se nsa na _ D H A
1 _ K M . R T F 
 
Ti me t o first rec urre nce of A F or atrial e mer ge nce - C o x a nal ysis [ F A S 
patie nts  wit h a D H A baseli ne < = me dia n of t he D H A at baseli ne ] 
1 1 _ 4 _ 1 _ 4 _ 3 _ se nsa na _ D H A
1 _c o x . R T F 
 
Ti me t o first rec urre nce of A F or atrial e mer ge nce - S ur vi val c ur ves a n d 
L o gra n k test [F A S  patie nts  wit h a D H A baseli ne > me dia n of t he D H A at 
baseli ne ] 
1 1 _ 4 _ 1 _ 4 _ 4 _se nsa na _ n o n 
D H A 2 _ K M. gif  
 
Ti me t o first rec urre nce of A F or atrial e mer ge nce - K M s u m mar y [ F A S 
patie nts  wit h a D H A baseli ne > me dia n of t he D H A at baseli ne ] 
1 1 _ 4 _ 1 _ 4 _ 5 _ se nsa na _ D H A
2 _ K M . R T F 
 
Ti me t o first rec urre nce of A F or atrial e mer ge nce - C o x a nal ysis [ F A S 
patie nts  wit h a D H A baseli ne > me dia n of t he D H A at baseli ne ] 
1 1 _ 4 _ 1 _ 4 _ 6 _ se nsa na _ D H A
2 _c o x . R T F 
3 4/ 4 0


C o nfi de nti al  
F 3 7 3 2 8 0 C A 2 0 1  
 
St atistic al A n al ysis Pl a n  –  V ersi o n  2  -  1 5/ 0 6/ 2 0 1 7  
3 4 /3 9  
 
S E C TI O N  
Title  
R T F ref ere nce  
 
Ti me t o first rec urre nce of A F or atrial e mer ge nce - S ur vi val c ur ves a n d 
L o gra n k test [F A S patie nts  wit h vasc ular or car diac t hera pe utic pr oce d ures 
t hat will be  i de ntifie d i n t he data re vie w meeti n g re p ort < 3 m o nt hs] 
1 1 _ 4 _ 1 _ 5 _ 1 _se nsa na _s ur g 1
_ K M. gif  
 
Ti me t o first rec urre nce of A F or atrial e mer ge nce - K M s u m m ar y [F A S 
patie nts  wit h 
vasc ular  or  car diac  t hera pe utic  pr oce d ures  t hat  will  be   
i de ntifie d i n t he data re vie w me eti n g re p ort < 3 m o nt hs] 
1 1 _ 4 _ 1 _ 5 _ 2 _ se nsa na_s ur g 1
_ K M . R T F 
 
Ti me t o first rec urre nce of A F or atrial e mer ge nce - C o x a nal ysis [F A S 
patie nts  wit h 
vas c ular  or  car diac  t hera pe utic  pr oce d ures  t hat  will  be   
i de ntifie d i n t he data re vie w me eti n g re p ort < 3 m o nt hs] 
1 1 _ 4 _ 1 _ 5 _ 3 _ se nsa na_s ur g 1
_c o x . R T F 
 
Ti me t o first rec urre nce of A F or atrial e mer ge nce - S ur vi val c ur ves a n d 
L o gra n k  test  [F A S  patie nts  wit h o ut  vasc u lar  or  car diac  t hera pe utic  
pr oce d ures  t hat  will  be   i de ntifie d  i n  t he  data  re vi e w  meeti n g  
re p ort < 3 m o nt hs] 
1 1 _ 4 _ 1 _ 5 _ 4 _se nsa na _s ur g 2
_ K M. gif  
 
Ti me t o first rec urre nce of A F or atrial e mer ge nce - K M s u m mar y [F A S 
patie nts  wit h o ut  vasc ular  or  car diac  t hera pe uti c  pr oce d ures  t hat  will  be   
i de ntifie d i n t he data re vie w me eti n g re p ort < 3 m o nt hs] 
1 1 _ 4 _ 1 _ 5 _ 5 _ se nsa na_s ur g 2
_ K M . R T F 
 
Ti me t o first rec urre nce of A F or atrial e mer ge nce - C o x a nal ysis [F A S 
patie nts  wit h o ut  vasc ular  or  car diac  t hera pe utic  pr oce d ures  t hat  will  be  
i de ntifie d i n t he data re vie w me eti n g re p ort < 3 m o nt hs] 
1 1 _ 4 _ 1 _ 5 _ 6 _ se nsa na_s ur g 2
_c o x . R T F 
1 1. 4. 1. 1  
Pri mar y crit eri o n - Ti me t o first rec urre nce of A F or atrial e mer ge nce 
a n d i nteracti o n treat me nt gr o u p b y c o u ntr y – C o x a nal ysis [ F A S]  
1 1 _ 4 _ 1 _ 5 _ 1 _i nter _c o u n tr y.
R T F  
 
1 1. 4. 1. 1  
Pri mar y crit eri o n - Ti me t o first rec urre nce of A F or atrial e mer ge nce 
a n d i nteracti o n treat me nt gr o u p b y D H A baseli ne  – C o x a nal ysis [ F A S]  
1 1 _ 4 _ 1 _ 6 _ 1 _i nter _ D H A . R
T F  
 
1 1. 4. 1. 1  
Pri mar y crit eri o n - Ti me t o first rec urre nce of A F or atrial e mer ge nce a n d 
ge n der  – C o x a nal ysis [ F A S]  
1 1 _ 4 _ 1 _ 7 _ 1 _ ge n der . R T F 
 
1 1. 4. 1. 1  
Pri mar y crit eri o n - Ti me t o first rec urre nce of A F or atrial e mer ge nce a n d 
a ge – C o x a nal ysis [ F A S]  
1 1 _ 4 _ 1 _ 8 _ 1 _a ge . R T F 
 
1 1. 4. 1. 1  
Pri mar y crit eri o n - Ti me t o first rec urre nce of A F or atrial e mer ge nce a n d 
B S A  – C o x a nal ysis [ F A S]  
1 1 _ 4 _ 1 _ 9 _ 1 _ B S A . R T F 
 
1 1. 4. 1. 1  
Pri mar y crit eri o n - Ti me t o first rec urre nce of A F or atrial e mer ge nce a n d 
d urati o n of c urre nt A F u p t o selecti o n visit  – C o x a nal ysis [ F A S]  
1 1 _ 4 _ 1 _ 1 0 _ 1 _c urre nt . R T F 
 
1 1. 4. 1. 1  
P ri mar y crit eri o n - Ti me t o first rec urre nce of A F or atrial e mer ge nce a n d 
ti me fr o m first d oc u me nte d persiste nt A F u p t o selecti o n visit– C o x 
a nal ysis [ F A S]  
1 1 _ 4 _ 1 _ 1 1 _ 1 _first F A . R T F 
 
1 1. 4. 1. 1  
Pri mar y crit eri o n - Ti me t o first rec urre nce of A F or atrial e mer ge nce a n d 
Ti me fr o m heart f ail ure dia g n osis u p t o selecti o n visit  – C o x a nal ysis [ F A S]  
1 1 _ 4 _ 1 _ 1 2 _ 1 _ heartf ail . R T F 
 
1 1. 4. 1. 1  
Pri mar y crit eri o n - Ti me t o first rec urre nce of A F or atrial e mer ge nce a n d 
N Y H A gr a de  – C o x a nal ysis [ F A S]  
1 1 _ 4 _ 1 _ 1 3 _ 1 _ N Y H A . R T F 
 
1 1. 4. 1. 1  
Pri mar y crit eri o n - Ti me t o first rec urre nce of A F or atrial e mer ge nce a n d 
left atrial area – C o x a nal ysis [ F A S]  
1 1 _ 4 _ 1 _ 1 4 _ 1 _leftatrial . R T F 
 
1 1. 4. 1. 1  
Pri mar y crit eri o n - Ti me t o first rec urre nce of A F or atrial e mer ge nce a n d 
Left ve ntric ular ej ect i o n fracti o n – C o x a nal ysis [ F A S]  
1 1 _ 4 _ 1 _ 1 5 _ 1 _left ve ntri . R T
F  
 
3 5/ 4 0


C o nfi de nti al  
F 3 7 3 2 8 0 C A 2 0 1  
 
St atistic al A n al ysis Pl a n  –  V ersi o n  2  -  1 5/ 0 6/ 2 0 1 7  
3 5 /3 9  
 
S E C TI O N  
Title  
R T F ref ere nce  
1 1. 4. 1. 2  
N u m ber of A F /fl utter e pis o des i n t he first wee k f oll o wi n g V 3 [ F A S] 
1 1 _ 4 _ 1 _ 2 _ 1 _ n b A F . R T F 
1 1. 4. 1. 2  
D urati o n of A F /fl utter e pis o des i n t he first wee k f oll o wi n g V 3 [ F A S] 
1 1 _ 4 _ 1 _ 2 _ 2 _ d ur A F . R T F 
1 1. 4. 1. 2  
Ti me t o first A F rec urre nce /fl utter e mer ge nce  less t ha n 1 0 mi n utes - 
S ur vi val c ur ves a n d L o gra n k test [ F A S]  
1 1 _ 4 _ 1 _ 2 _ 4 _ 1 _ A Fless 1 0 _ K
M. gif  
1 1. 4. 1. 2  
Ti me t o first A F rec urre nce /fl utter e mer ge nce less t ha n 1 0 mi n utes - 
K M s u m mar y [ F A S] 
1 1 _ 4 _ 1 _ 2 _ 4 _ 2 _ A Fless 1 0 _ K
M . R T F 
1 1. 4. 1. 2  
Ti me t o first  A F  rec urre nce/fl utter e mer ge nce less t ha n 1 0 mi n utes - 
C o x a nal ysis [ F A S] 
1 1 _ 4 _ 1 _ 2 _ 4 _ 3 _ A Fless 1 0 _c
o x . R T F 
1 1. 4. 1. 2  
Ti me t o first s y m pt o matic A F / Fl utter - S ur vi val c ur ves a n d L o gra n k test 
[ F A S] 
1 1 _ 4 _ 1 _ 2 _ 4 _ 1 _ s y m pt A F_ K
M. gif  
1 1. 4. 1. 2  
Ti me t o first s y m pt o matic A F / Fl utter - K M s u m mar y [ F A S] 
1 1 _ 4 _ 1 _ 2 _ 4 _ 2 _ s y m pt A F_ K
M . R T F 
1 1. 4. 1. 2  
Ti me t o first s y m pt o matic A F / Fl utter - C o x a nal ysis [ F A S] 
1 1 _ 4 _ 1 _ 2 _ 4 _ 3 _ s y m pt A F_c
o x . R T F 
1 1. 4. 1. 2  
Ma xi m u m E H R A  sc ore– C M H [ F A S] 
1 1 _ 4 _ 1 _ 2 _ 5 _e hra . RT F  
1 1. 4. 1. 2  
Fr e q ue nc y of s y m pt o ms  - –[ F A S] 
1 1 _ 4 _ 1 _ 2 _ 6 _s y m ptfre q . R T
F  
1 1. 4. 1. 2  
Pres u me d arr y ht mia  - –[ F A S] 
1 1 _ 4 _ 1 _ 2 _ 7 _ arr h y. R T F 
1 1. 4. 1. 2  
N u m ber of s y m pt o matic A F  rec urre nce/ Fl utter e mer ge nce  - [ F A S] 
1 1 _ 4 _ 1 _ 2 _ 8 _ n b _s y m ptrec u.
R T F  
1 1. 4. 1. 2  
N u m ber of h os pital izati o ns- [ F A S] 
1 1 _ 4 _ 1 _ 2 _ 9 _ 1 _ n b _ h os pit . R
T F  
1 1. 4. 1. 2  
D urati o n of h os pitalizati o ns - [ F A S] 
1 1 _ 4 _ 1 _ 2 _ 9 _ 2 _ d ur _ h os pit.
R T F  
1 1. 4. 1. 2  
Car di o versi o n assess me nt - [ F A S] 
1 1 _ 4 _ 1 _ 2 _ 1 0 _car di o v _asse
ss.R T F  
1 1. 4. 1. 2  
Ec h ocar di o gra p hic para meters val ues a n d c ha n ges o ver ti m e- [ F A S] 
1 1 _ 4 _ 1 _ 2 _ 1 1 _ec h o para m _a
ssess.R T F  
1 1. 4. 1. 2  
Val ues a n d c ha n ges fr o m baseli ne f or re d bl o o d cell c o nce ntrati o n of D H A 
[ F A S] 
1 1 _ 4 _ 1 _ 2 _ 1 2 _ D H A. R T F  
1 2. 1  
T otal e xte nt of e x p os ure t o t he st u d y dr u g [ Saf et y Set ] 
1 2 _ 1 _a _ e x p os . R T F 
1 2. 2. 1  
S u m mar y of a d verse  e ve nts [ Saf et y Set]  
1 2 _ 2 _ 1 _ae _ o ver vie w. R T F  
1 2. 2. 2  
N u m ber  of p atie nts wit h at least o ne  treat me nt-e mer ge nt a d vers e e ve nt b y 
Me d D R A pri mar y s yste m or ga n class a n d p ref erre d ter m [ Saf et y S et ] 
1 2 _ 2 _ 2a _teae _s oc pt. R T F  
1 2. 2. 2  
N u m ber of patie nts wit h at least o ne relate d  treat me nt -e mer ge nt a d verse 
e ve nt b y Me d D R A pri mar y s yst e m or ga n class a n d pref erre d ter m [ Saf et y 
Set ] 
1 2 _ 2 _ 2 b _relteae _s oc pt. R T F  
1 2. 3. 1. 1  
Listi n g of d eat hs  [Saf et y Set ] 
1 2 _ 3 _ 1 _ 1 _ d eat hs _list.rtf  
1 2. 3. 1. 2  
Listi n g of seri o us a d verse e v e nts  [Saf e t y Set] 
1 2 _ 3 _ 1 _ 2 _sae _list.rtf  
1 2. 3. 1. 3  
Listi n g of a d verse e ve nts lea di n g t o defi niti ve st u d y treat me nt 
disc o nti n uati o n  [Saf et y Set ] 
1 2 _ 3 _ 1 _ 3 _ae defst o ptrt _list.
rtf 
1 2. 4. 2. 2  
He mat ol o g y: N u m ber of patie nts wit h  variati o n s o ver ti me [ Safet y Set] 
1 2 _ 4 _ 2 _ 2 _ 1 H e m. R T F 
3 6/ 4 0


C o nfi de nti al  
F 3 7 3 2 8 0 C A 2 0 1  
 
St atistic al A n al ysis Pl a n  –  V ersi o n  2  -  1 5/ 0 6/ 2 0 1 7  
3 6 /3 9  
 
S E C TI O N  
Title  
R T F ref ere nce  
1 2. 4. 2. 2  
Bi oc he mistr y: N u m ber of patie nts wit h variati o ns  o ver ti me [ Saf et y Set]  
1 2 _ 4 _ 2 _ 2 _ 1 Bi oc h. R T F  
1 2. 4. 2. 3  
C N A L V: Pati ents wit h hae m o gl o bi n  <  1 0  g/ d L  a n d decrease d fr o m 
baseli ne > = 2 g/ d L (if baseli ne was meas ure d)  [Saf et y Set ] 
1 2 _ 4 _ 2 _ 3a _ he m o g. R T F  
1 2. 4. 2. 3  
C N A L V: Pati ents wit h ne utr o p hils <  1. 5 G/ L or W B C < 3 G/ L (if 
ne utr o p hils missi n g) [ Saf et y Set ] 
1 2 _ 4 _ 2 _ 3 b _ ne utr. R T F  
1 2. 4. 2. 3  
C N A L V: Pati ents wit h platelets  <  1 0 0  G/ L [ Saf et y Set ] 
1 2 _ 4 _ 2 _ 3c _ plat. R T F  
1 2. 4. 2. 3  
C N A L V: Pati ents wit h A L A T > 2 N  or A S A T > 2 N or A L P > 1. 2 5 N or T B 
> 1. 5 N, a n d n or mal baseli ne val ue, or G G T > 3 N (if baseli ne < 3 N)   
[Saf et y Set ] 
1 2 _ 4 _ 2 _ 3 d _li ver. R T F  
1 2. 4. 2. 3  
C N A L V: Patie nts wit h creati ni ne > 1 5 0 µ m ol/ L a n d i ncrease b y 3 0 % fr o m 
baseli ne val ue (if a n y) [ Saf et y S et ] 
1 2 _ 4 _ 2 _ 3e _ creat. R T F 
1 2. 4. 2. 3  
Patie nts wit h esti mate d creati ni ne cleara nce < 3 0 ml/ mi n   [ Saf et y S et] 
1 2 _ 4 _ 2 _ 3f _ clear. R T F  
1 2. 5. 1  
S B P C ha n ges o ver Ti me [ Saf et y S et ] 
1 2 _ 5 _ 1 _ 1 _fi g C H _ S B P. gif  
1 2. 5. 1  
D B P C ha n ges o ver Ti me [ Saf et y S et ] 
1 2 _ 5 _ 1 _ 1 _fi g C H _ D B P . gif 
1 2. 5. 1  
H R  C ha n ges o ver Ti me [ Saf et y Set ] 
1 2 _ 5 _ 1 _ 1 _fi g C H _ H R. gif  
1 2. 5. 1  
S u pi ne V S  meas ure me nts : I nci de nce of p ost -baseli ne P S Cs a n d P S C Vs 
[Saf et y Set ] 
1 2 _ 5 _ 1 _ 2 _ S C V S . R T F 
1 2. 5. 1  
S u pi ne B P  meas ure me nts : I nci de nce of p ost -baseli ne P S Cs a n d P S C Vs 
[Saf et y Set ] 
1 2 _ 5 _ 1 _ 2 _ S C B P. R T F  
1 2. 5. 1  
S u pi ne H R meas ure me nts : I nci de nce of p ost -baseli ne P S Cs a n d P S C Vs 
[Saf et y Set ] 
1 2 _ 5 _ 1 _ 2 _ S C H R. R T F  
1 2. 5. 1  
B P meas ure me nts : N u m ber of patie nts wit h at least o ne p ost -baseli ne 
ort h ostatic h y p ote nsi o n [ Saf et y Set]  
1 2 _ 5 _ 1 _ 2 _ Ort h o B P. R T F  
1 2. 5. 3  
P atie nts wit h E C G a b n or malities (I n vesti gat or’s e val uati o n) [ Saf et y Set]  
1 2 _ 5 _ 3 _ 1 _ 2 _ec g _a b n . R T F 
1 4. 1  
N u m ber of  p atie nts  per c o u ntr y a n d ce ntre [ Ra n d o mise d patie nts]  
 
1 4 _ 1a _aset perce nter _all . R T
F  
1 4. 1  
N u m ber of patie nts wit h mi n or de viati o ns [ Ra n d o mise d Pa tie nts Set] 
1 4 _ 1 b _ mi n or _ de v . R T F 
1 4. 1  
De m o gr a p hic c haracteristics [ Saf et y Set]  
1 4 _ 1 c_ de m o Saf. R T F  
1 4. 1  
De m o gr a p hic c haracteristics [ P P]  
1 4 _ 1c _ de m o P P. R T F  
1 4. 1  
Disease c haracteristics at baseli ne [ P P]  
1 4 _ 1c _ disc har P P. R T F  
1 4. 1  
N u m ber  ( %) of p atie nts wit h at  least o ne me dical or s ur gical hist or y b y  
Me d D R A pri mar y s yste m or ga n class a n d pref err e d ter m  [ Saf et y S et ] 
1 4 _ 1 d _ me d hist _s oc pt _saf . R
T F  
1 4. 1  
N u m ber  ( %) of p atie nts wit h at least o ne c o nc o mita nt d isease at ti me of 
selecti o n b y  Me d D R A pri mar y s yste m or ga n  class a n d pref err e d ter m 
[Saf et y Set ] 
1 4 _ 1 e_c diseasesel _s oc pt _sa
f. R T F 
1 4. 1  
N u m ber  ( %) of p atie nts wit h at least o ne me dicati o n  ta ke n bef ore first st u d y 
dr u g a d mi nistrati o n , b y W H O-Dr u g A T C 1 a n d  A T C 2 [ Saf et y Set ] 
1 4 _ 1 f_ p me d _atc _saf .R T F  
1 4. 1  
N u m ber  ( %) of p atie nts wit h at least o ne me dicati o n  bef ore first st u d y 
treat me nt a d mi nistrati o n li n ke d t o t he st u d y pat h ol o g y, b y W H O-Dr u g 
A T C 1a n d A T C 2 [ Saf et y Set ] 
1 4 _ 1 g _ p me d _li n k _atc _saf.
R T F  
1 4. 3. 1  
N u m ber  of p atie nts wit h at least o ne A E occ urre d bef ore first 
a d mi nistrati o n b y Me d D R A pri mar y s yste m or ga n class a n d p ref erre d ter m 
[Saf et y Set ] 
1 4 _ 3 _ 1 _ ae _s oc pt. R T F  
1 4. 3. 1  
N u m ber  of p atie nts wit h at least o ne  treat me nt-e mer ge nt a d vers e e ve nt b y 
Me d D R A pri mar y s yste m or ga n class, p ref erre d ter m a n d ma xi m u m 
i nte nsit y [Saf et y Set ] 
1 4 _ 3 _ 1 a _teae _s o c pt ma xi. R T
F  
3 7/ 4 0


C o nfi de nti al  
F 3 7 3 2 8 0 C A 2 0 1  
 
St atistic al A n al ysis Pl a n  –  V ersi o n  2  -  1 5/ 0 6/ 2 0 1 7  
3 7 /3 9  
 
S E C TI O N  
Title  
R T F ref ere nce  
1 4. 3. 1  
N u m ber  of p atie nts wit h at least o ne  treat me nt-e mer ge nt a d vers e e ve nt b y 
Me d D R A pri mar y s yste m or ga n class, p ref erre d ter m a n d m ost se vere 
relati o ns hi p t o st u d y dr u g [Saf et y S et ] 
1 4 _ 3 _ 1 b _teae _s o c pt ma xr. R T
F  
1 4. 3. 1 
N u m ber of patie nts wit h at least o ne n o n seri o us T E A E,  a n d t he n u m ber of 
ass ociate d occ urre nces , b y Me d D R A pri mar y s yste m or ga n class a n d 
pref erre d ter m [ Saf et y Set ] 
1 4 _ 3 _ 1c _ nsaeteae _s oc pt. R T
F  
1 4. 3. 1 
N u m ber of patie nts wit h at least o ne T E A E, a n d t he n u m b er of occ urre nces 
of T E A Es b y Me d D R A S O C, Pref erre d Ter m, seri o us ness a n d Treat me nt 
Gr o u p  [ Saf et y Set] 
1 4 _ 3 _ 1e _teae _ occ u _s oc pt. R
T F  
1 4. 3. 1 
N u m ber of patie nts wit h at least o ne relate d T E A E, a n d t he n u m ber of 
occ urre nces of relate d T E A Es b y Me d D R A S O C, Pref erre d Ter m, 
seri o us ness a n d Treat me nt Gr o u p [ Saf et y Set] 
1 4 _ 3 _ 1f _ relteae _ occ u _s oc pt
. R T F 
1 4. 3. 4  
He mat ol o g y Val ues a n d c ha n ges o ver ti me [ Saf et y Set ] 
1 4 _ 3 _ 4 _ 1 a _ 1 He m. R T F  
1 4. 3. 4  
Bi oc he mistr y Val ues a n d c ha n ges o ver ti me [ Saf et y Set ] 
1 4 _ 3 _ 4 _ 1 a _ 2 Bi o c h. R T F  
1 4. 3. 4  
C oa g ulati o n  Val ues a n d c ha n ges o ver ti me [ Saf et y Set ] 
1 4 _ 3 _ 4 _ 1 a _ 3 C o a g. R T F  
1 4. 3. 4  
He mat ol o g y C ha n ges of val ues relati ve t o n or mal ra n ges o ver ti me [Saf et y 
Set ] 
1 4 _ 3 _ 4 _ 1 c _ 1 He m. R T F  
1 4. 3. 4  
Bi o he mistr y C ha n ges of val ues relati ve t o n or mal ra n ges o ver ti me [Saf et y 
Set ] 
1 4 _ 3 _ 4 _ 1 c _ 2 Bi o c h. R T F  
1 4. 3. 4  
La b scatter pl ot: hae mat ocrit ( Wee k 4) [Saf et y Set ] 
1 4 _ 3 _ 4 _ 2 he ma _ w 4 . gif 
1 4. 3. 4  
La b scatter pl ot: hae m o gl o bi n  ( Wee k 4)  [Saf et y Set ] 
1 4 _ 3 _ 4 _ 2 he m o g _ w 4 . gif 
1 4. 3. 4  
La b scatter pl ot: R B C c o u nt  ( Wee k 4)  [Saf et y Set ] 
1 4 _ 3 _ 4 _ 2 R B C _ w 4 . gif 
1 4. 3. 4  
La b scatter pl ot: W B C c o u nt  ( Wee k 4)  [Saf et y Set ] 
1 4 _ 3 _ 4 _ 2 W B C _ w 4 . gif 
1 4. 3. 4  
La b scatter pl ot: retic ul oc ytes ( Wee k 4) [Saf et y Set ] 
1 4 _ 3 _ 4 _ 2 retic_ w 4 . gif 
1 4. 3. 4  
La b scatter pl ot:  Platelets  ( Wee k 4)  [Saf et y Set ] 
1 4 _ 3 _ 4 _ 2 plat _ w 4 . gif 
1 4. 3. 4  
La b scatter pl ot: hae mat ocrit ( Wee k 1 2) [Saf et y Set ] 
1 4 _ 3 _ 4 _ 2 he ma _ w 1 2 . gif 
1 4. 3. 4  
La b scatter pl ot: hae m o gl o bi n  ( Wee k 1 2)  [Saf et y Set ] 
1 4 _ 3 _ 4 _ 2 he m o g _ w 1 2 . gif 
1 4. 3. 4  
La b scatter pl ot: R B C c o u nt  ( Wee k 1 2)  [Saf et y Set ] 
1 4 _ 3 _ 4 _ 2 R B C _ w 1 2 . gif 
1 4. 3. 4  
La b scatter pl ot: W B C c o u nt  ( Wee k 1 2)  [Saf et y Set ] 
1 4 _ 3 _ 4 _ 2 W B C _ w 1 2 . gif 
1 4. 3. 4  
La b scatter pl ot: retic ul oc ytes ( Wee k 1 2) [Saf et y Set ] 
1 4 _ 3 _ 4 _ 2 retic _ w 1 2. gif 
1 4. 3. 4  
La b scatter pl ot:  Platelets  ( Wee k 1 2)  [Saf et y Set ] 
1 4 _ 3 _ 4 _ 2 plat _ w 1 2. gif  
1 4. 3. 4  
La b scatte r pl ot: hae mat ocrit ( Wee k 2 4) [Saf et y Set ] 
1 4 _ 3 _ 4 _ 2 he ma _ w 2 4 . gif 
1 4. 3. 4  
La b scatter pl ot: hae m o gl o bi n  ( Wee k 2 4)  [Saf et y Set ] 
1 4 _ 3 _ 4 _ 2 he m o g _ w 2 4 . gif 
1 4. 3. 4  
La b scatter pl ot: R B C c o u nt  ( Wee k 2 4)  [Saf et y Set ] 
1 4 _ 3 _ 4 _ 2 R B C _ w 2 4 . gif 
1 4. 3. 4  
La b scatter pl ot: W B C c o u nt  ( Wee k 2 4)  [Saf et y Set ] 
1 4 _ 3 _ 4 _ 2 W B C _ w 2 4 . gif 
1 4. 3. 4  
La b scatter pl ot: retic ul oc ytes ( Wee k 2 4) [Saf et y Set ] 
1 4 _ 3 _ 4 _ 2 retic _ w 2 4. gif 
1 4. 3. 4  
La b scatter pl ot:  Platelets  ( Wee k 2 4)  [Saf et y Set ] 
1 4 _ 3 _ 4 _ 2 plat _ w 2 4. gif  
1 4. 3. 4  
La b scatter pl ot: A S A T  (last val ue) [Saf et y Set ] 
1 4 _ 3 _ 4 _ 2 A S T. gif  
1 4. 3. 4  
La b scatter pl ot: A L A T  (l ast val ue)  [Saf et y Set ] 
1 4 _ 3 _ 4 _ 2 A L T. gif  
3 8/ 4 0


C o nfi de nti al  
F 3 7 3 2 8 0 C A 2 0 1  
 
St atistic al A n al ysis Pl a n  –  V ersi o n  2  -  1 5/ 0 6/ 2 0 1 7  
3 8 /3 9  
 
S E C TI O N  
Title  
R T F ref ere nce  
1 4. 3. 4  
La b scatter pl ot: Al kali ne p h os p hatase  (last val ue)  [Saf et y Set ] 
1 4 _ 3 _ 4 _ 2 Al kali n e _ p h os gif  
1 4. 3. 4  
La b scatter pl ot: C o nj u gate d bilir u ni n  (last val ue)  [Saf et y Set ] 
1 4 _ 3 _ 4 _ 2 C o nj u gate d _ Bili. gif  
1 4. 3. 4  
La b scatter pl ot: T otal bilir u ni n (last val ue) [ Saf et y Set ] 
1 4 _ 3 _ 4 _ 2 T otal _ Bili. gif  
1 4. 3. 4  
La b scatter pl ot: Ga m ma G T (last val ue) [ Saf et y Set ] 
1 4 _ 3 _ 4 _ 2 G G T. gif  
1 4. 3. 4  
La b scatter pl ot: T otal C h olester ol (last val ue)  [ Saf et y Set ] 
1 4 _ 3 _ 4 _ 2 T otal _ C h ol. gif  
1 4. 3. 4  
La b scatter pl ot: H D L C h olester ol (last val ue)  [ Saf et y Set ] 
1 4 _ 3 _ 4 _ 2 H D L _ C h ol. gif  
1 4. 3. 4  
La b scatter pl ot: L D L C h olester ol (last val ue)  [ Saf et y Set ] 
1 4 _ 3 _ 4 _ 2 L D L _ C h ol. gif  
1 4. 3. 4  
La b scat ter pl ot: S o di u m  (last val ue) [ Saf et y Set] 
1 4 _ 3 _ 4 _ 2 S o d . gif 
1 4. 3. 4  
La b scatter pl ot: P otassi u m  (last val ue) [ Saf et y Set] 
1 4 _ 3 _ 4 _ 2 P ota . gif 
1 4. 3. 4  
La b scatter pl ot: Bicar b o nate  (last val ue) [ Saf et y Set] 
1 4 _ 3 _ 4 _ 2 Bicar . gif 
1 4. 3. 4  
La b scatter pl ot: C hl ori de  (last val ue) [Saf et y Set ] 
1 4 _ 3 _ 4 _ 2 C hl o. gif  
1 4. 3. 4  
La b scatter pl ot: Al b u mi n  (last val ue) [Saf et y Set ] 
1 4 _ 3 _ 4 _ 2 Al b u . gif 
1 4. 3. 4  
La b scatter pl ot: C reati ni ne (last val ue) [ Saf et y Set] 
1 4 _ 3 _ 4 _ 2 C reat. gif 
1 4. 3. 4  
La b scatter pl ot: Fasti n g gl uc ose  (last val ue) [ Saf et y Set] 
1 4 _ 3 _ 4 _ 2 Gl u c . gif 
1 4. 3. 4  
La b scatter pl ot: Tri gl yceri des  (last val ue) [ Saf et y Set] 
1 4 _ 3 _ 4 _ 2 Tri g . gif 
1 4. 3. 4  
La b scatter pl ot: Fi bri n o ge n (last val ue) [ Saf et y Set ] 
1 4 _ 3 _ 4 _ 2 Fi bri . gif 
1 4. 3. 4  
La b scatter pl ot: pr ot hr o m bi n ti me/I N R  (last val ue) [Sa f et y Set] 
1 4 _ 3 _ 4 _ 2 c o a g 1. gif  
1 4. 3. 4  
La b scatter pl ot: Acti vate d partial t hr o m b o plasti n ti me  (last val ue) [Saf et y 
Set ] 
1 4 _ 3 _ 4 _ 2 c o a g 2. gif  
1 4. 3. 4  
La b scatter pl ot: T hr o m bi n cl otti n g ti me  (last val ue) [ Saf et y Set] 
1 4 _ 3 _ 4 _ 2 c o a g 3 . gif 
1 4. 3. 5  
S u pi ne S yst olic Bl o o d Press ure Meas ure me nts O ver Ti me [ Saf et y S et ] 
1 4 _ 3 _ 5 _ 1 _s b p. GI F  
1 4. 3. 5  
S u pi ne Diast olic B l o o d P ress ure Meas ure me nts O ver Ti me [ Saf et y Set ] 
1 4 _ 3 _ 5 _ 1 _ d b p. GI F  
1 4. 3. 5  
S u pi ne B l o o d P ress ure Meas ure me nts O ver Ti me [ Saf et y Set ] 
1 4 _ 3 _ 5 _ 1 _ B P. R T F  
1 4. 3. 5  
S u pi ne H eart Rate  Meas ure me nts O ver Ti me [ Saf et y Set ] 
1 4 _ 3 _ 5 _ 1 _ hr. GI F  
1 4. 3. 5  
S u pi ne Heart Rate  Meas ure me nts O ver Ti me [ Saf et y Set ] 
1 4 _ 3 _ 5 _ 1 _ hr. R T F  
1 4. 3. 5  
N u m ber of patie nts wit h Pre defi ne d P ote ntiall y Cli nicall y Si g nifica nt 
C ha n ge ( P S C) a n d wit h P S C Le a di n g t o  Cli nicall y Si g nifica nt Val ue 
( P S C V)  i n s u pi ne S yst olic Bl o o d Press ure  [Saf et y Set ] 
1 4 _ 3 _ 5 _ 1 b _ P S C _ P S C V _s b p .
R T F  
1 4. 3. 5  
N u m ber ( %) of patie nts wit h Pre defi ne d P ote ntiall y Cli nicall y Si g nifica nt 
C ha n ge ( P S C) a n d wit h P S C Le a di n g t o Cli nicall y Si g nifica nt Va l ue 
( P S C V)  i n s u pi ne Dia st olic Bl o o d Press ure  [Saf et y Set ] 
1 4 _ 3 _ 5 _ 1 b _  P S C _ P S C V  
_ d b p. R T F  
1 4. 3. 5  
N u m ber ( %) of patie nts wit h Pre defi ne d P ote ntiall y Cli nicall y Si g nifica nt 
C ha n ge ( P S C) a n d wit h P S C Le a di n g t o Cli nicall y Si g nifica nt Val ue 
( P S C V)  i n s u pi ne H eart Rate  [Saf et y Set ] 
1 4 _ 3 _ 5 _ 1 b _  P S C _ P S C V  
_ hr . R T F 
1 4. 3. 5  
B o d y wei g ht val ues a n d c ha n ges fr o m baseli ne o ver ti me [ Saf et y S et]  
1 4 _ 3 _ 5 _ 2 _ 1 _ b o d y w . R T F 
1 4. 3. 5  
N u m ber  ( %) of p atie nts wit h at least o ne co nc o mita nt me dicati o n , b y 
W H O -Dr u g A T C 1 a n d  A T C 2 [ Saf et y S et] 
1 4 _ 3 _ 5 _ 5 _ 1 _ c me d _ atc. R T F  
1 6. 1. 7  
1 6. 1. 7: Ra n d o misati o n  
1 6 _ 1 _ 7. R T F  
1 6. 2. 1  
1 6. 2. 1: Disc o nti n ue d patie nts  
1 6 _ 2 _ 1. R T F  
3 9/ 4 0


C o nfi de nti al  
F 3 7 3 2 8 0 C A 2 0 1  
 
St atistic al A n al ysis Pl a n  –  V ersi o n  2  -  1 5/ 0 6/ 2 0 1 7  
3 9 /3 9  
 
S E C TI O N  
Title  
R T F ref ere nce  
1 6. 2. 2  
1 6. 2. 2: Pr ot oc ol de viati o ns  f or ra n d o mise d patie nts 
1 6 _ 2 _ 2. R T F  
1 6. 2. 3  
1 6. 2. 3: Reas o ns f or e xcl usi o n fr o m a nal ysis sets  
1 6 _ 2 _ 3. R T F  
1 6. 2. 4. 1  
1 6. 2. 4. 1: De m o gra p hic data  
1 6 _ 2 _ 4 _ 1. R T F  
1 6. 2. 4. 2  
1 6. 2. 4. 2: Disease c haracteristics  
1 6 _ 2 _ 4 _ 2. R T F  
1 6. 2. 4. 3  
1 6. 2. 4. 3: Me dical a n d S ur gical Hist or y b y patie nt  
1 6 _ 2 _ 4 _ 3. R T F  
1 6. 2. 4. 4  
1 6. 2. 4. 4: C o nc o mita nt Diseases b y patie nt  
1 6 _ 2 _ 4 _ 4. R T F  
1 6. 2. 4. 5  
1 6. 2. 4. 5. 1  Pri or me dicati o ns b y Patie nt  
1 6 _ 2 _ 4 _ 5 _ 1. R T F  
1 6. 2. 4. 5  
1 6. 2. 4. 5. 2  Pri or me dicati o ns b y A T C classificati o n  
1 6 _ 2 _ 4 _ 5 _ 2. R T F  
1 6. 2. 4. 6  
1 6. 2. 4. 6 I ncl usi o n a n d n o n-i ncl usi o n criteria  
1 6 _ 2 _ 4 _ 6 . R T F 
1 6. 2. 5. 1  
1 6. 2. 5. 1: Dates of Visit  
1 6 _ 2 _ 5 _ 1. R T F  
1 6. 2. 5. 2  
1 6. 2. 5. 2: Gl o bal C o m plia nce  
1 6 _ 2 _ 5 _ 2. R T F  
1 6. 2. 5. 3  
1 6. 2. 5. 3 E x p os ure f or ra n d o mise d patie nts  
1 6 _ 2 _ 5 _ 3. R T F  
1 6. 2. 6. 1  
1 6. 2. 6. 1: Ti me t o first rec urre nc e of A F or atrial fl utter  
1 6 _ 2 _ 6 _ 1. R T F  
1 6. 2. 6. 2 
1 6. 2. 6. 2 : H olter meas ure me nts  
1 6 _ 2 _ 6 _ 2 . R T F 
1 6. 2. 6. 3  
1 6. 2 . 6. 3: T T T E M me as ure me nts   
1 6 _ 2 _ 6 _ 3 . R T F 
1 6. 2. 6. 4 
1 6. 2. 6. 4 : D H A meas ure me nts 
1 6 _ 2 _ 6 _ 4 . R T F 
1 6. 2. 7. 1  
1 6. 2. 7. 1: A d verse E ve nts Re p orte d Ter m, Pref erre d Ter m a n d Dates  
1 6 _ 2 _ 7 _ 1. R T F  
1 6. 2. 7. 2  
1 6. 2. 7. 2: A d verse E ve nts b y Patie nt  
1 6 _ 2 _ 7 _ 2. R T F  
1 6. 2. 7. 3  
1 6. 2. 7 . 3: A d verse E ve nts b y S O C, P T, L L T  
1 6 _ 2 _ 7 _ 3. R T F  
1 6. 2. 8. 1  
1 6. 2. 8. 1: Listi n g of i n di vi d ual la b orat or y meas ure me nts  
1 6 _ 2 _ 8 _ 1. R T F  
1 6. 2. 8. 2  
1 6. 2. 8. 2 : Listi n g of i n di vi d ual c oa g ulati o n para meters meas ure me nts  
1 6 _ 2 _ 8 _ 2 . R T F 
1 6. 2. 9. 1  
1 6. 2. 9. 1: Listi n g of vital si g ns meas ure me nts 
1 6 _ 2 _ 9 _ 1. R T F  
1 6. 2. 9. 2  
1 6. 2. 9. 2 : E C G meas ure me nts  
1 6 _ 2 _ 9 _ 2 . R T F 
1 6. 2. 9. 3 
1 6. 2. 9. 3 : P h ysical e xa mi nati o n 
1 6 _ 2 _ 9 _ 3 . R T F 
1 6. 2. 1 0. 1  
1 6. 2. 1 0. 1: C o nc o mita nt  me dicati o ns b y Patie nt  
1 6 _ 2 _ 1 0 _ 1. R T F  
1 6. 2. 1 0. 2  
1 6. 2. 1 0. 2: C o nc o mita nt  me dicati o ns b y A T C classificati o n  
1 6 _ 2 _ 1 0 _ 2. R T F  
 
 
  
 
 
 
 
 
 
 
 
4 0/ 4 0