FranceLEVO - Zimino® Registry: a French Registry Evaluating the Use of Levosimendan (Zimino®)
Conditions: Acute Heart Failure
Sponsor: Arcothova

 
Zimino® - levosimendan - Study protocol V1_08.11.2019 
 
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STUDY PROTOCOL 
 
 
FRANCE ZIMINO® REGISTRY:  
A FRENCH REGISTRY EVALUATING THE USE OF ZIMINO® 
 
 
Short study title:  
France-LEVO 
Study design: 
Real-life, multicentre registry study 
 
Coordinating Investigator 
 
Pr Bernard Cholley, MD, PHD 
CO-Coordinating Investigator: 
Pr Alexandre Mebazaa, MD, PhD 
Sponsor:  
ARCOTHOVA,  
SAR II – Hôpital Haut-Lévèque 
Avenue Magellan 
33600 Pessac, France 
 
 
 
Version: 
V1 
Date:  
08 November 2019 
 
 
 
Property of Arcothova 
Confidential 
The information provided in this document is strictly confidential and is available for review to investigators, health 
authorities and ethics committees. Unauthorised copying or use of this information is prohibited. 

 
Zimino® - levosimendan - Study protocol V1_08.11.2019 
 
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Information 
 
Title 
France Zimino® registry: A French registry evaluating 
the use of Zimino 
Protocol version  
Final Version - V1_08.11.2019 
Date of protocol 
08 November 2019 
Active substance 
Levosimendan 
Medicinal product 
Zimino 
Product reference 
Not applicable 
Procedure number 
2019-A02903-54 
Marketing authorisation 
holder (MAH) 
Orion Corporation, Finland 
Research question and 
objectives 
To provide real-life follow-up data on patients who 
have been treated with Zimino® according to local 
routine clinical practice in France.  
Country of study 
France 
Sponsor 
ARCOTHOVA  
(Anesthésistes-Réanimateurs Cœur Thorax Vaisseaux) 
 
Marketing authorisation holder 
 
MAH 
Orion Corporation, Finland 
 
 

 
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1. TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................................. 1 
1. 
TABLE OF CONTENTS.......................................................................................................... 3 
2. 
LIST OF ABBREVIATIONS .................................................................................................... 5 
3. 
RESPONSIBLE PARTIES ....................................................................................................... 6 
4. 
ABSTRACT ......................................................................................................................... 7 
5. 
AMENDMENTS AND UPDATES ........................................................................................... 10 
6. 
MILESTONES .................................................................................................................... 10 
7. 
RATIONALE AND BACKGROUND ....................................................................................... 10 
7.1 
Background ................................................................................................................ 10 
7.2 
Rationale .................................................................................................................... 10 
8. 
RESEARCH QUESTION AND OBJECTIVES ............................................................................ 10 
9. 
RESEARCH METHODS ....................................................................................................... 11 
9.1 
Study design ............................................................................................................... 11 
9.2 
Setting ........................................................................................................................ 12 
9.2.1 
Hospitals ................................................................................................................ 12 
9.2.2 
Study population ................................................................................................... 12 
9.2.2.1 
Inclusion criteria ............................................................................................... 12 
9.2.2.2 
Exclusion criteria .............................................................................................. 12 
9.2.2.3 
Removal of patients from assessments ............................................................. 12 
9.2.3 
Medicinal product ................................................................................................. 12 
9.2.4 
Study procedures ................................................................................................... 12 
9.3 
Variables to be collected ............................................................................................ 13 
9.3.1 
Demographic and baseline characteristics ............................................................ 13 
9.3.2 
Zimino® treatment ................................................................................................ 14 
9.3.3 
Concomitant inotropes .......................................................................................... 14 
9.3.4 
Chronic atrial fibrillation ....................................................................................... 15 
9.3.5 
Pre-existing dialysis .............................................................................................. 15 
9.3.6 
Pre-existing mechanical assistance ....................................................................... 15 
9.3.7 
Tolerance ............................................................................................................... 15 
9.3.8 
Serious adverse events after the start of Zimino® (regardless of causal 
relationship to Zimino®) ....................................................................................... 16 
9.3.9 
Mortality ................................................................................................................ 16 
9.3.10 
Length of ICU/CCU and hospital stay .................................................................. 16 

 
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9.3.11 
Re-hospitalisations up to 30 (±15) and 90 (±15) days after hospital 
discharge ................................................................................................................ 17 
9.4 
Data sources ............................................................................................................... 17 
9.5 
Study size ................................................................................................................... 17 
9.6 
Data management ....................................................................................................... 17 
9.7 
Data analysis .............................................................................................................. 17 
9.7.1 
Statistical hypotheses ............................................................................................ 18 
9.7.2 
Analysis populations ............................................................................................. 18 
9.7.3 
Statistical analyses ................................................................................................. 18 
9.8 
Quality control ........................................................................................................... 18 
9.8.1 
Training ................................................................................................................. 18 
9.8.2 
Investigators .......................................................................................................... 18 
9.8.3 
Case report forms .................................................................................................. 19 
9.8.4 
Monitoring ............................................................................................................. 19 
9.9 
Limitations of the research methods .......................................................................... 19 
9.10 
Other aspects .............................................................................................................. 19 
9.10.1 
Protocol amendments ............................................................................................ 19 
9.10.2 
Insurance and remuneration .................................................................................. 19 
9.10.3 
Completion of the study ........................................................................................ 19 
9.10.4 
Retention of records .............................................................................................. 20 
10. 
PROTECTION OF HUMAN SUBJECTS ................................................................................... 20 
10.1 
Ethical and regulatory compliance ............................................................................. 20 
10.2 
Patient information and informed consent ................................................................. 20 
10.3 
Data protection ........................................................................................................... 21 
11. 
MANAGEMENT AND REPORTING OF ADVERSE EVENTS / ADVERSE REACTIONS.................. 21 
12. 
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS ............................... 21 
13. 
REFERENCES .................................................................................................................... 21 
ANNEX 1. 
LIST OF STAND-ALONE DOCUMENTS .................................................................. 22 
Sponsor signature ..................................................................................................................... 22 
Investigator signature ............................................................................................................... 22 

 
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2. LIST OF ABBREVIATIONS 
 
ANSM 
CRF/eCRF 
EEC 
Agence Nationale de Sécurité du Médicaments et des Produits de Santé  
Case report form/electronic Case Report Form 
External Electrical Cardioversion  
EC 
Ethics Committee 
EDC 
Electronic Data Capture 
GCP 
Good Clinical Practice 
GPP 
Good Pharmacoepidemiology Practices  
IABP 
Intra-Aortic Aalloon Pump 
ICU/CCU 
Intensive Care Unit /Coronary Care Unit 
MACE 
Major Adverse Cardiovascular Event 
SAE 
SAPS 
SAS® 
SOFA 
Serious Adverse Event 
Simplified Acute Physiology Score 
Statistical Analysis System 
Sequential Organ Failure Assessment 
VA ECMO 
Veno-Arterial ExtraCorporeal Membrane Oxygenation 
VV ECMO 
Veno-Venous ExtraEorporeal Membrane Oxygenation 
 
 
 

 
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3. RESPONSIBLE PARTIES 
 
Sponsor 
ARCOTHOVA (Anesthésie-Réanimation Coeur-Thorax-Vaisseaux)  
SAR II – Hôpital Haut-Leveque  
Avenue Magellan  
33604 Pessac  
Email: arcothova@chu-bordeaux.fr  
Tel.: +33 6 52 54 44 58  
Dr Sophie Provenchere, President ARCOTHOVA 
The sponsor is responsible for the design and conduct of the study. The sponsor will ensure 
adequate monitoring of the study. 
 
Coordinating investigator  
Pr Bernard Cholley, MD, PH 
Service d'Anesthésie-Réanimation 
Chef du Pôle Anesthésie-Réanimation 
Rééducation-Traumatologie (ARRT) 
Hôpital Européen Georges Pompidou  
20-40 rue LEBLANC  
75908 PARIS CEDEX 15  
Tel : 01 56 09 25 15 / Fax : 01 56 09 30 60 
Mail: bernard.cholley@aphp.fr  
 
Scientific committee  
Pr Bernard Cholley – HEGP-APHP  
Pr Julien Amour-Pitié Salpétrière-APHP  
Pr Jean-Luc Fellahi-Hospices Civils de Lyon  
Pr Dan Longrois-Hôpital Bichat-APHP  
Pr Bruno Levy-CHU Nancy  
Pr Alexandre Mebazaa-Hôpital Lariboisière-APHP  
Pr Alexandre Ouattara-CHU Bordeaux  
 
Sponsor and Scientif committee signatures are provided in Annex 1. 
 
Investigators 
In this protocol ‘investigator’ refers to physician who is responsible for all treatment decisions 
and the conduct of the study at a study centre. 
Signatures of the investigators will be collected in Annex 2. 

 
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4. ABSTRACT 
Title 
France Zimino® registry: A French registry evaluating the use of levosimendan (Zimino®)  
Protocol version and date 
V1, 08 November 2019 
Rationale and background 
The French National Authority for Health (Haute Autorité de santé) requested a registry study to 
obtain post-market surveillance data to describe baseline clinical profiles, management and 
outcome of patients treated with Zimino®. This study is designed to provide real-life data on the 
use, safety and clinical outcomes of Zimino® in routine clinical practice in France. 
Research question and objectives 
Primary objective: 
• To provide real-life follow-up data on patients who have been treated with Zimino® 
according to local routine clinical practice in France.  
Secondary objectives:  
• To describe the use of concomitant inotropes during hospitalisation. 
• To assess re-hospitalisations 30 and 90 days after hospital discharge.  
• To evaluate tolerance and serious adverse events (SAEs) during hospitalisation.  
• To assess mortality 30 and 90 days after hospital discharge. 
Primary endpoints 
• Indication for Zimino®.  
• Dose and duration of treatment with Zimino®. 
• Length of intensive care unit / coronary care unit (ICU/CCU) stay from the start of Zimino®. 
• Length of hospital stay from the start of Zimino®. 
Secondary endpoints 
• Concomitant inotropes during hospitalisation. 
• Re-hospitalisations 30 and 90 days after hospital discharge. 
• Tolerance, as assessed by hypotension and atrial fibrillation during hospitalisation. 
• SAEs, including major cardiovascular events (MACEs), mechanical assistance, dialysis or 
any other event engaging the vital prognosis during hospitalisation. 
• Mortality during hospitalisation 30 and 90 days after hospital discharge. 
Study design 
This is a real-life, non-interventional, observational, multicentre study in all patients (including 
children) receiving Zimino® in France.  
The patients will be evaluated during the index hospitalisation and on follow-up days 30 (±15) 
and 90 (±15) after hospital discharge. The follow-up can be a phone call or a visit to the hospital. 
Patients who meet the eligibility criteria will be identified consecutively at each hospital. The 
participating hospitals will vary in size and medical activities, depending on their location and 
the population size they serve.  
The physician will determine the patient’s treatment strategy. Drug prescriptions and the 
indications to perform diagnostic or therapeutic procedures will be left completely to the 
discretion of the physicians.  
The estimated enrollment period is 12 months (enrollment of the first patient – enrollment of the 
last patient), or less if the cohort (n=600) is completed earlier, and the maximum total data 
collection period is 15 months. 
 

 
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Population 
Inclusion criteria: 
• Patients receiving Zimino® treatment. 
• Patients or patient’s families not objecting to the patient’s participation in the study. 
Exclusion criteria: None 
Medicinal product, dose and mode of administration 
Zimino® 2.5 mg/ml concentrate for solution for infusion. Dose and duration of treatment will be 
at the discretion of the physicians. 
Variables 
• Demographic characteristics, including age and sex 
• Dates of hospital and ICU/CCU admission and discharge 
• Reason for hospitalisation. 
• Cardiogenic shock (yes/no; if yes, date of the first symptoms) 
• Zimino® prescription, including indication for use, dose and duration (date and hour), bolus 
(yes/no). 
• Concomitant inotropes: drug name, dose, duration (date and hour) 
• Chronic atrial fibrillation (yes/no) 
• Pre-existing amiodarone before the start of Zimino® (yes/no) 
• Pre-existing betablockers before the start of Zimino® (yes/no) and higher dose 
• Pre-existing dialysis before the start of Zimino® (yes/no)  
- 
Start date 
- 
Date of weaning (or death) 
• Pre-existing mechanical assistance before the start of Zimino® 
o Venoarterial extracorporeal membrane oxygenation (VA ECMO) (central or 
peripheral) 
o Veno-venous ECMO (VV ECMO) 
o Impella® 5.0 or Impella® 2.5 or Impella CP 
o Intra-aortic balloon pump (IABP) 
o Berlin Heart EXCOR 
For all the assistances collect : 
- 
Start date of mechanical assistance  
- 
Date of assistance weaning (or death) 
• Tolerance information during the levosimendan infusion ncluding:  
o Hypotension  
- 
Catécholamines (yes/no) if yes : Start date/ stop date 
- 
Zimino® reduced (yes/no) or Interrupted (yes/no) or 
Discontinued (yes/no) 
o New atrial fibrillation 
− Need for amiodarone (yes/no) 
− Need for cardioversion (yes/no) 
• SAEs after the start of Zimino®:  
o MACEs, defined as death of cardiac origin, stroke, myocardial infarction, heart 
rhythm disorder requiring cardioversion or cardiogenic pulmonary oedema  
o Death of other cause 
o Mechanical assistance 
− VA ECMO (central or peripheral)  
− VV ECMO 

 
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− Impella® 5.0 or Impella® 2.5 or Impella CP 
− IABP 
− Berlin Heart EXCOR 
 
- 
Start date of mechanical assistance  
- 
Date of assistance weaning (or death) 
o Dialysis 
- 
Start date 
- 
Date of weaning (or death) 
o Any other event engaging the vital prognosis during hospitalisation, including septic 
shock and digestive haemorrhage 
• Mortality during hospitalisation and up to follow-up days 30 and 90 after hospital discharge. 
• Re-hospitalisations up to follow-up days 30 and 90 after discharge, including number and 
duration of re-hospitalisations, main reason for re-hospitalisation and re-administration of 
Zimino® 
 
Data sources 
Data will be collected from medical records and follow-up interviews and entered into the 
electronic case report forms (eCRFs).  
Data before admission to the hospital and during hospitalisation will be obtained during index 
hospitalisation. The prospective follow-up data will be obtained on days 30 and 90 after discharge 
by calling the patient or patient’s family or during the patient’s visit to the hospital. Follow-up 
data will also be collected from medical records. 
Study size 
600 patients will be included in the registry.  
Data analysis 
The objective of the study is to provide real-life follow-up data in patients who received 
Zimino®. There is no formal hypothesis to be tested. All enrolled patients who have received 
Zimino® will be included in the analysis. All variables will be summarised overall and by 
indication for the use. For categorical variables proportions and 2-sided 95% confidence intervals 
will be presented. If applicable, the potential differences between indications of Zimino® will be 
tested. Additional subgroup analyses may be performed based on the observed data. 
Milestones 
Data collection for the main study is expected to start by January, 2020 and to be completed 
before December 31th, 2020. 
 
 

 
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5. AMENDMENTS AND UPDATES 
A pilot e-CRF study may be conducted before the main study to evaluate the feasibility of the 
methods to establish a Zimino® registry. A protocol amendment may be prepared accordingly. 
6. MILESTONES 
 
Milestone 
Planned date 
First Patient In 
January, 2020 
Last Patient In 
January, 2021 
Last Patient Out 
April, 2021 
Interim report 
NA 
Final Data base lock 
July, 2021 
Final report of study results 
October, 2021 
7. RATIONALE AND BACKGROUND 
7.1 
Background 
The French National Authority for Health (Haute Autorité de Santé) requested a registry study 
to obtain post-market surveillance data to describe baseline clinical profiles, management and 
hospital outcome of patients treated with Zimino®. 
7.2 
Rationale 
There is an increased interest in the use of real-life data to observe how new medicines are used 
in clinical practice. A properly designed registry can provide real-life view of clinical practice, 
patient outcomes, safety and effectiveness. 
This study is designed to provide real-life data on the use, safety and clinical outcomes of 
Zimino® in clinical practice in France.  
8. RESEARCH QUESTION AND OBJECTIVES 
In this real-life, multicentre study, patients treated with Zimino® will be followed for 90 days 
after discharge from the hospital 
The primary objective is to provide real-life follow-up data on patients who have been treated 
with Zimino® in France.  

 
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The secondary objectives are: 
• To describe the use of concomitant inotropes during hospitalisation.  
• To assess re-hospitalisations at 90 days after discharge.  
• To evaluate tolerance and serious adverse events (SAEs) during hospitalisation  
• To assess mortality during hospitalisation and at 30 and 90 days after discharge. 
9. RESEARCH METHODS 
9.1 
Study design 
This is a real-life, multicentre study in patients treated with Zimino® in a real-life setting.  
Each patient will be treated as decided by the physician according to current local clinical 
practice. The decision to prescribe Zimino® to the patient is made by the physician in charge, 
regardless of the possibility to include the patient in the study. The informed consent may be 
obtained at any time during hospital stay, before or after the start of Zimino® .  
The patients will be evaluated during the index hospitalisation and at day-30 and day-90 after 
discharge. The follow-up can be done via a phone call, or a visit to the hospital. The study design 
is presented in .  
Figure 1. 
The estimated enrollment period is 12 months (enrollment of the first patient – enrollment of the last 
patient), or less if the cohort (n=600) is completed earlier, and the maximum total data collection 
period is 15 months.  
Figure 1. 
Study design 
Admission
Hospital and ICU/CCU stay
Discharge
Follow-up at 30 
(±15) days
Follow-up at 90 
(±15) days
• 
Re-hospitalisations
• 
Re-administration of 
Zimino
• 
Mortality
During index hospitalisation
• 
Zimino prescription
• 
Concomitant inotropes
• 
Chronic atrial fibrillation
• 
Pre-existing amiodarone before Zimino
• 
Pre-existing dialysis before Zimino
• 
Pre-existing mechanical assistance 
before Zimino
• 
Tolerance after start of Zimino
• 
SAEs after start of Zimino
• 
Mortality
At discharge
• 
ICU/CCU and 
hospital discharge 
dates
Enrollment and informed consent
At admission
• 
Demographics
• 
Hospital and ICU/CCU 
admission dates
• 
Reason for hospitalisation
• 
Cardiogenic shock
Zimino treatment
ICU = Intensive care unit; CCU = Coronary care unit; 
SAE = Serious adverse event
• 
Re-hospitalisations
• 
Re-administration of 
Zimino
• 
Mortality
 

 
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9.2 
Setting 
9.2.1 
Hospitals 
France-Levo will enroll 600 consecutive patients receiving levosimendan at all French sites 
where Zimino® is prescribed. 
 
9.2.2 
Study population 
The study will enrol 600 patients in France.  
To ensure that patients are captured in a representative way and to avoid selection bias issues, 
study participation will be proposed to all consecutive patients who have received Zimino® 
during the recruitment period. The hospitals will stop recruitment once data from 600 patients 
have been collected.  
All available information regarding patients receiving Zimino® but not entered into the registry 
will be collected.  
9.2.2.1 
Inclusion criteria 
Patients are eligible to be included in the study if all of the following criteria apply: 
1. Patients receiving Zimino®. 
2. Patients or patient’s families not objecting to the patient’s participation in the study. 
9.2.2.2 
Exclusion criteria 
None. 
9.2.2.3 
Removal of patients from assessments 
Patients are free to discontinue the study at any time without providing a reason. However, the 
investigator should try to identify the reason and document it in the case report form (CRF).  
The study monitor should be notified about premature discontinuations. If the discontinuation is 
due to an SAE, the study monitor should be notified by investigator within 24 hours. 
9.2.3 
Medicinal product 
Current clinical practice use.  
9.2.4 
Study procedures 
The prospective follow-up data will be obtained on days 30 and 90 after discharge by calling the 
patient or a patient’s family member, or during a visit to the hospital if the patient is hospitalized 
or comes for a scheduled consultation. Follow-up data may also be obtained by review of 
medical records. 

 
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For patients who have been transferred to another hospital, follow-up data will be collected by 
contacting the respective hospital according to local practice. For patients who have been 
discharged home or to another care facility, follow-up data will be collected by contacting the 
patient or the patient’s family. Every effort will be made according to local practice to ensure 
that the patient is alive before contacting the patient’s family. 
Table 1 lists study procedures and indicates with an ‘x’ during which visit a particular procedure 
is performed. 
Table 1. 
Schedule of study procedures 
 
During index 
hospitalisation 
During follow-up  
30 (±15) days 
after discharge 
90 (±15) days 
after discharge 
Patient identification 
x 
 
 
Informed consent 
x 
 
 
Inclusion criteria 
x 
 
 
Demographic characteristics 
x 
 
 
Hospital and ICU/CCU admission dates 
x 
 
 
Reason for hospitalisation 
x 
 
 
Cardiogenic shock 
x 
 
 
Zimino® treatment 
x 
 
 
Concomitant inotropes 
x 
 
 
Chronic atrial fibrillation 
x 
 
 
Pre-existing amiodarone 
x 
 
 
Pre-existing dialysis  
x 
 
 
Pre-existing mechanical assistance 
x 
 
 
Tolerance 
x 
 
 
SAEs 
x 
x 
x 
Mortality 
x 
x 
x 
ICU/CCU and hospital discharge dates 
x 
 
 
Re-hospitalisations 
 
x 
x 
ICU = Intensive care unit; CCU = Coronary care unit; SAE = Serious adverse event 
9.3 
Variables to be collected 
Data will be collected for all patients and recorded on the CRFs as follows: 
9.3.1 
Demographic and baseline characteristics 
• Age,  
• Sex 
• Date of admission to the hospital  

 
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• Date of ICU/CCU admission 
• SAPS II score (= IGS2) 
• SOFA score on ICU admission 
• Reason for hospital admission (pop-up menu) [1) medical HF decompensation, 
2)surgical cardiac procedure, 3)other ICU admission (text)] 
• Did the patient have cardiogenic shock (yes/no)?  
o If yes, date of the first symptoms of the cardiogenic shock  
9.3.2 
Zimino® treatment 
• Indication for the use of Zimino® pop-up menu: 1) cardiogenic shock (medical setting 
or post cardiac surgery), 2) Heart failure decompensation (medical, setting), 3) Low 
cardiac output syndrome (post cardiac surgery), 4) heart failure decompensation in a 
patient receiving beta-blockers, 5) ECMO weaning, 6) repetitive use in a patient with 
end-stage heart failure, 7) other (text) 
• SOFA score on the day of ZIMINO® initiation 
• Start of Zimino® treatment (start date and hour) 
• Dose (g/kg/min) and total dose (mg) of Zimino® 
• Was bolus injection of Zimino® administered (yes/no)? 
• End of Zimino® treatment (stop date and hour) 
9.3.3 
Concomitant inotropes 
• Use of other inotropes (yes/no) 
o Dobutamine,  
o Start of dobutamine (date and hour) 
o Maximal dose of dobutamine 
o End of dobutamine (stop date and hour) 
o Noradrenaline 
o Start of noradrenaline (date and hour) 
o Maximal dose of noradrenaline 
o End of noradrenaline (stop date and hour) 
o Adrenaline 
o Start of adrenaline (date and hour) 

 
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o Maximal dose of adrenaline 
o End of adrenaline (stop date and hour) 
o Milrinone 
o Start of milrinone (date and hour) 
o Maximal dose of milrinone 
o End of milrinone (stop date and hour) 
 
9.3.4 
Chronic atrial fibrillation 
• Chronic atrial fibrillation (yes/no) 
• Pre-existing treatment with amiodarone before the start of Zimino® (yes/no) 
9.3.5 
Pre-existing dialysis 
o Pre-existing dialysis before the start of Zimino® (yes/no). If yes,  
− Date of weaning (or death) 
9.3.6 
Pre-existing mechanical assistance  
• Pre-existing mechanical assistance before the start of Zimino® (yes/no). If yes,  
o Date of insertion 
o Type of mechanical assistance 
− Venoarterial extracorporeal membrane oxygenation (VA ECMO) (central 
or peripheral) 
− Veno-venous ECMO (VV ECMO) 
− Impella® 5.0, Impella® 2.5) or Impella CP 
− Intra-aortic balloon pump (IABP) 
− Berlin Heart EXCOR 
o Date of weaning (or death) 
9.3.7 
Tolerance  
• Hypotension during and after the start of Zimino® (yes/no).  
o If yes, was noradrenaline started or its dose increased? (yes/no). 
o Duration of hypotension (minutes, hours) 

 
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• New atrial fibrillation after the start of Zimino® (yes/no)? If yes,  
o Was amiodarone given? (yes/no). 
o Was beta-blocker given ? (yes/no) 
o Was cardioversion performed? 
o Persistent AF? (yes or no) 
o If transient, duration of AF (min, hours, days) 
 
9.3.8 
Serious adverse events during and after the start of Zimino® (regardless of 
causal relationship to Zimino) 
SAEs will be collected regardless of causal relationship of the event to Zimino® treatment: 
• MACE defined as death of cardiac origin, stroke, myocardial infarction, heart rhythm 
disorder requiring external electrical cardioversion (EEC) or cardiogenic pulmonary 
oedema  
• Death of non cardiac origin 
• Mechanical assistance : Start date and date of weaning 
• Dialysis : Start date and date of weaning 
• Any other event engaging the vital prognosis, including septic shock and digestive 
haemorrhage 
• Date of start event, end of event or ongoing 
For all the variables above, duration of the event will also be recorded. 
9.3.9 
Mortality 
Time of death and cause of death will be recorded up to follow-up day 90. 
9.3.10 
Length of ICU/CCU and hospital stay 
• Date of ICU/CCU discharge. 
• Hospital-free days at day-30 and day-90 
• Date of hospital discharge 
 
The length and clinical aspects of the hospital and CCU/ICU stay before starting Zimino® are 
expected to vary widely among patients. Therefore, all length of stay endpoints are primarily 
measured from the time of starting Zimino® treatment. 

 
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9.3.11 
Re-hospitalisations up to 30 (±15) and 90 (±15) days after hospital discharge 
• Was the patient re-admitted to the hospital (yes or no) 
• If yes: date of admission 
• If yes: date of discharge 
• Main reason for re-hospitalisation 
• Re-administration of Zimino® (yes/no) 
9.4 
Data sources 
Data will be collected from medical records and follow-up interviews and entered into the 
eCRFs.  
9.5 
Study size 
The study will enrol 600 patients in France.  
This sample size will allow to describe a proportion of 50% (most conservative hypothesis) with 
a precision to at least 4.5% with an estimation of non available data fom 10 to 20%. 
 
Hypothesis 
Proportion 
α 
accuracy 
N  
% Non available data 
N total 
Scenario 1 
50,00% 
5% 
4,5% 
475 
10% 
523 
Scenario 2 
50,00% 
5% 
4,5% 
475 
15% 
547 
Scenario 3 
50,00% 
5% 
4,5% 
475 
20% 
570 
 
9.6 
Data management 
Data to be collected according to the study protocol (and amendments, if any) will be recorded 
into an electronic data capture (EDC) system using eCRFs at the site. 
Investigators and other relevant site personnel will be trained to use the EDC system. After 
completion of training, they are provided with user names and authorised access to enter and 
correct data on the eCRFs. 
Individual data fields in the EDC system may be locked on an ongoing basis during the study. 
The fields may be unlocked if further updates are needed. When all data have been entered and 
all queries resolved, the whole database will be locked.  
9.7 
Data analysis 
Statistical analyses, tables and patient data listings will be performed with SAS® for Windows 
9.4 or later (SAS Institute Inc., Cary, NC, USA). Statistical analysis will be performed by or 
under the supervision of the sponsor. 

 
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9.7.1 
Statistical hypotheses 
No specific statistical hypothesis that would be evaluated in a confirmatory manner is specified 
in this study or against any historical control. Instead, the emphasis is on estimation and 
exploratory analyses.  
No inferential statistics will be performed. 
9.7.2 
Analysis populations 
All enrolled patients who have received Zimino® will be included in the analysis. All available 
data will be analysed. 
9.7.3 
Statistical analyses 
The variables will be evaluated by frequency tables and summary statistics, as applicable. 
Variables will be summarised also by indication for the use, if feasible. For categorical variables, 
proportions and 2-sided 95% confidence intervals will be presented.  
For the primary objective, all clinical and sociodemographic characteristics (age, sex, clinical 
scores) use of Zinimo treatment (indication, dose, duration, routes) will be described at each 
available time point.  
For secondary objectives, use of concomitant inotropes during the hospitalisation (percentage of 
patient, duration etc…) will be described, as well as rate of patient rehospitalised at 90 days after 
discharge. 
For safety and tolerance analysis, description of hypothension, new atrial fibrillation will be 
done as well as all SAEs occurred during and after Zimino® treatment. 
Rate of mortality will be calculated and described. 
If applicable, the potential differences between indications of Zimino® will be tested in an 
exploratory way, as no statistical hypothesis have been done. Additional subgroup analyses may 
be performed based on the observed data. 
9.8 
Quality control 
9.8.1 
Training 
Training will be arranged for the investigators and other relevant site personnel. This training 
will include a review of the protocol and completion of the CRFs. The investigators will ensure 
that appropriate training relevant to the study is given to the medical, nursing and other personnel 
involved in the study. The investigators will also ensure that any information relevant to the 
conduct of the study is forwarded to other relevant site personnel. 
9.8.2 
Investigators 
A curriculum vitae must be obtained from all investigators who sign the protocol. 

 
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9.8.3 
Case report forms 
Electronic queries about missing, misleading, incomplete or illogical data will appear in the EDC 
system. An audit trail within the system will track all changes/corrections made. The investigator 
has to confirm the content of the eCRFs with an electronic signature. 
9.8.4 
Monitoring 
The study monitor will monitor the study by performing monitoring visits remotely and on-site 
as agreed by the investigator and the sponsor. The study monitor will ensure that the study is 
conducted according to the principles of good clinical practice (GCP) and national regulations 
and that the protocol is followed in all aspects. Each recruiting site will be monitored at least 
once. It will be verified that the clinical facilities remain appropriate, and that the CRFs 
correspond with source data. 
9.9 
Limitations of the research methods 
Potential limitations of this study are because of its non-interventional design. However, the 
non-interventional design of the study is a preferred way to collect real-world data. 
One limitation of this study is that there is no control group with which to compare the outcomes. 
In a severely ill population, serious adverse events are likely to take place, without causal 
relationship to levosimendan treatment.  
Selection bias is avoided by requesting a systematic, consecutive recruitment procedure and 
using a screening log to collect data on the number of patiens who were not included in the study 
and the reason for this. Interviewer bias is avoided by using questionnaires similar to routine 
standard care and training the physicians and nurses before the study start. 
Other limitations, such as amount of missing data, are expected to be similar to other multicentre, 
non-interventional studies. 
9.10 Other aspects 
9.10.1 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by the sponsor and scientific committee. 
9.10.2 
Insurance and remuneration 
Not applicable. 
9.10.3 
Completion of the study 
The sponsor reserves the right to prematurely close the site or terminate the study for valid 
scientific or administrative reasons. 
Sites will be closed upon study completion. A site is considered closed when all required 
documentation has been collected and closure procedures have been performed. 

 
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9.10.4 
Retention of records 
Recommendations in the Guidelines for Good Pharmacoepidemiology Practices (GPP) issued 
by the International Society for Pharmacoepidemiology (ISPE GPP) will be followed for the 
retention of records. 
10. PROTECTION OF HUMAN SUBJECTS 
10.1 Ethical and regulatory compliance 
The study protocol, synopsis in French and description of procedure for obtaining a non-
opposition statement will be submitted to the applicable ECs for favourable opinion. 
The study protocol will be submitted to French National Agency for Medicines and Health 
Products Safety (ANSM) for information. 
 
The study complies with the MR004 reference methodology and does not require the opinion 
of the Expert Committee for Research, Studies and Evaluations in the field of Health 
(CEREES) or specific authorization of the CNIL. Studies in accordance with MR004 are not to 
be submitted to a Committee for the Protection of Persons (CPP). 
In accordance with French law, the documents in this study were registered in the National 
Register of Reference Methodology Studies of the National Institute of Health Data (INDS) 
prior to its implementation. 
The study will be conducted in accordance with the ethical principles that are consistent with 
the Declaration of Helsinki, ICH GCP and the applicable legislation on non-interventional 
studies. The investigators will perform the study in accordance with the local regulations and 
guidelines governing medical practice and ethics. 
The study will be conducted in accordance with the guidelines for the GPP (ISPE GPP) and the 
European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) 
Guide on Methodological Standards in Pharmacoepidemiology (EMA/95098/2010 Rev. 5). 
10.2 Patient information and informed consent 
Patient information will be given and verbal consent will be obtained in accordance with the 
French legislation, the Decree No. 2016-1537 of 16 November 2016 on research involving 
human subjects.  
The investigator will ensure that each patient or patient’s family is fully informed about the 
objectives and procedures of the study. The investigator will also explain any possible risks with 
participating in the study and answer all questions regarding the study. After this, the patient or 
patient’s family will be given sufficient time to make a decision regarding participation in the 
study. 
Patients or their family will be informed of the patients’ right to discontinue the study at any 
time without their medical care or legal rights being affected. They will also be informed that 
representatives of the sponsor may inspect relevant parts of the patients’ medical records and 
study data. 

 
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The investigator must obtain consent before data collection begins. The consent can be given 
verbally by the patient or the patient’s family that they do not object to participating in the study. 
The investigator should confirm the receipt of verbal consent by entering the date of the consent 
on the patient’s CRF. 
10.3 Data protection 
Data protection and privacy regulations will be respected for the collection, transmission, 
processing and storage of patient information. 
Information collected during the course of the study will be stored in a database and handled 
confidentially and according to The General Data Protection Regulation (GDPR) (EU) 2016/679 
and local law. 
The patients can be identified in the CRFs only by subject number, age and sex. 
In compliance with all applicable regulations and laws, it is required that the investigator and 
institution permit authorised representatives of the study sponsor, regulatory agency(s) and the 
EC direct access to review the patient’s original medical records for verification of study-related 
procedures and data. Direct access includes examining, analysing and verifying any records and 
reports that are important to the evaluation of the study. The investigator is obligated to inform 
and obtain the informed consent of the patient to permit named representatives to have access to 
his/her study-related records without violating the confidentiality of the patient. 
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS / ADVERSE REACTIONS 
The sponsor performs safety related reporting according to local national reporting requirements. 
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS 
This study will be registered in one of the acceptable registries before the enrolment of the first 
patient. 
The study report will be prepared by or under the supervision of the sponsor. The final report 
will be approved by the appropriate representatives of the sponsor and the investigators. 
The sponsor wishes to collaborate with the investigators to publish the results as timely as 
possible, without compromising accuracy or industrial property rights of the MAH. The 
preparation, submission and authorship for publications containing the study results shall be in 
accordance with a process determined by mutual written agreement between the sponsor and 
participating investigators and in accordance with International Committee of Medical Journal 
Editors (ICMJE) recommendations, available at http://www.icmje.org. 
13. REFERENCES 
EMA/95098/2010 Rev. 5 European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance (ENCePP) Guide on Methodological Standards in 
Pharmacoepidemiology (Revision 5). European Medicines Agency. Accessed April 
2018. Retrieved from 

 
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http://www.encepp.eu/standards_and_guidances/documents/ENCePPGuideofMethStan
dardsinPE_Rev5.pdf.  
GDPR Regulation (EU) 2016/679 of the European Parliament and of the Council of 27 April 
2016 on the protection of natural persons with regard to the processing of personal data 
and on the free movement of such data, and repealing Directive 95/46/EC (General 
Data Protection Regulation). Accessed April 2018. Retrieved from 
http://data.europa.eu/eli/reg/2016/679/oj  
ISPE GPP Guideline for Good Pharmacoepidemiology Practices (GPP) issued by International 
Society for Pharmacoepidemiology. Revision 3, June 2015. Accessed April 2018. 
Retrieved from https://www.pharmacoepi.org/resources/policies/guidelines-08027/.  
 
ANNEX 1. 
LIST OF STAND-ALONE DOCUMENTS 
 
No. 
Document 
reference 
no. 
Date 
Title 
1 
V_1 
08/11/2019 
Sponsor and scientific committee signature 
2 
V_1 
08/11/2019 
Investigator signature 
 
3 
V_1 
08/11/2019 
Information consent form