ESCORT-HU : European Sickle Cell Disease Cohort - Hydroxyurea
Conditions: Sickle Cell Disease
Sponsor: Theravia

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ESCORT-HU 
 
Protocol final version dated February 28, 2008 
Amended version (amendment 1) dated June 18, 
2008 
Amended version (amendment 2) dated October 20, 2017 
 
Confidential 
 
 
 
 
 
 
 
 
 
Sponsor: 
Addmedica 
37 rue de Caumartin  
75009 PARIS  
FRANCE 
Phone: +33 (0)1 72 69 01 86 
Fax:     +33 (0)1 73 72 94 13 
CRO:  
Keyrus Biopharma 
18/20 rue Clement Bayard 
92300 Levallois-Perret  
FRANCE 
Phone: +33 (0)1 41 34 28 28   
Fax:     +33 (0)1 41 34 28 29   

Study protocol
CONFIDENTIAL
ESCORT-HU
Final Version amended (amendment 2) dated October 20, 2017 
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Protocol Synopsis 
 
Name of Sponsor : 
Addmedica 
Name of finished product : 
Siklos® 
Name of active ingredients : 
Hydroxycarbamide 
Title of study 
ESCORT-HU : European Sickle Cell Disease Cohort - Hydroxyurea. 
Investigators 
Physicians experienced in the management of sickle cell disease (SCD); 
treating physicians. 
Study centres 
France, United-Kingdom, Greece. Other European countries will be 
encouraged to participate as soon as Siklos® becomes available in their 
country. 
Trial duration 
Up to 8 years recruitment, to get at least 2 
years follow-up. 
Total expected duration : 10 years 
Non-interventional 
follow-
up cohort study. 
Objectives 
In the context of the Risk Management Plan (RMP), as requested from 
Addmedica by the EMA, to collect information about long-term safety of 
Siklos®    (hydroxycarbamide)   when   used   in patients with Sickle Cell 
Disease, assessed on : 
 
Frequency of : 
 myelosuppression 
(requiring 
permanent 
or 
 
temporary 
discontinuation of therapy) secondary to hydroxycarbamide-induced 
myelotoxicity 
 malignancies, skin ulceration and impaired postnatal development 
(growth). 
 amenorrhea, fertility impairment 
 
Safety in nominated sub-populations : 
 young patients (children, adolescents until end of puberty) 
 elderly patients 
 patients with underlying SCD-related hepatic or renal impairment 
 pregnancy and its outcome, particularly for congenital malformations
 concomitant use of hydroxycarbamide and specific therapies : 
o HIV drugs especially Nucleoside Analogue Reverse 
Transcriptase Inhibitors (NRTI) 
o other myelosuppressive agents 
o radiation therapy 
o concomitant use of live vaccines 
Other points of concern are : 
 
Overall mortality and survival time. 
 
Occurrence of SCD events, in particular : 
 painful crises 
 acute chest syndrome 
 stroke 
 acute splenic sequestration 
 infections 

Study protocol
CONFIDENTIAL
ESCORT-HU
Final Version amended (amendment 2) dated October 20, 2017 
Page 3/38
 
 
 
Name of Sponsor : 
Addmedica 
Name of finished product : 
Siklos® 
Name of active ingredients : 
Hydroxycarbamide 
Methodology 
Multicentre, prospective, non-interventional cohort study in patients with 
SCD treated with Siklos® and followed-up for up to ten years. 
All patients prescribed Siklos® within 8 years of its commercialisation until 
reaching at least 2000 patients will be enrolled in this cohort.  
The follow-up of these patients will be strictly observational and will fit within 
their usual clinical monitoring without any controlled treatment, specific 
exam or modification of their follow-up, in compliance with the SPC of this 
orphan product. Patients’ data could be collected retrospectively especially 
when the patient started Siklos before being enrolled in the study.  
Patients will be evaluated at inclusion, then every 1 to 4 months, according 
to normal monitoring of the disease and to the recommendations of Siklos® 
specification for use. A minimum of a yearly follow-up will be requested. 
Patients will be informed by their initiating physician about the study and 
enrolled in case they agree to participate. Solely physicians experienced in 
the care of SCD (reference centres) are legitimated to initiate a Siklos®
treatment; follow-up is authorised by both initiating and  treating physicians.
Number of subjects 
Around 2000 patients treated with Siklos®. 
The number of subjects is determined taking into account 20% of severe 
SCD on an overall 24 000 estimated number of subjects with the disease in 
Europe, and approximately 50% of these on Siklos®. 
This will allow for an estimation of frequencies of events as low as 0.5% with 
a precision of 0.2%. 
Diagnosis and main 
criteria for recruitment 
 
Male or female ambulatory patients, aged 2 years and more (children, 
adolescents or adults) 
 
With symptomatic sickle cell syndrome 
 
Treated with Siklos® 
 
Having been informed of the study by the initiating physician and 
consenting to participate to the cohort. 
Test product, dose and 
mode of administration 
Siklos®: 15 to 30 mg/kg/day usual dosage and 35 mg/kg/day as Maximum 
Tolerated Dose (MTD). 
Starting dosage: 15 mg/kg/day; to adjust by steps of 5 mg/kg/day 
according to clinical and haematological response. 
Duration of treatment 
Permanent 
Reference product, dose 
and mode of 
administration 
Not applicable 

Study protocol
CONFIDENTIAL
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Name of Sponsor : 
Addmedica 
Name of finished product : 
Siklos® 
Name of active ingredients : 
Hydroxycarbamide 
Criteria for evaluation 
Safety 
The primary safety parameter is the occurrence of adverse events and 
serious adverse events, specifically: 
 
Frequency of malignancies 
 
Frequency of skin ulceration (broken out by severity) 
 
Frequency of myelosuppression requiring temporary or permanent 
discontinuation of Siklos®. 
The secondary safety parameters are: 
 
Effects of Siklos® on growth development : specific examinations 
(scintigraphy, radiography, …) if the difference with the normal growth   is 
upper than 2 standard deviations 
 
Outcome of pregnancies: rates of miscarriage, stillbirths, APGAR score 
at birth, congenital malformations 
 
Any occurrence of an unforeseen safety pattern. 
 
A special focus will be given to specific population, e.g., elderly patients, 
patients with renal or hepatic impairment, HIV patients, patients receiving 
live vaccine, patients treated with other myelopsuppressive products or  with 
radiotherapy, … 
Siklos® effects : 
 
Overall mortality and survival rates 
 
Frequency of SCD events : 
 painful crises 
 acute chest syndrome 
 stroke 
 acute splenic sequestration 
 infections 
 
Hospitalisations due to SCD events 
 
Frequency of blood transfusions. 

Study protocol
CONFIDENTIAL
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Final Version amended (amendment 2) dated October 20, 2017 
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Name of Sponsor : 
Addmedica 
Name of finished product : 
Siklos® 
Name of active ingredients : 
Hydroxycarbamide 
Data collection 
Data will be collected through electronic media. The list of data is not limited 
to the foreseen ones listed below and may be increased according to interest 
or emergent patterns. 
Baseline data will include : 
 
Demographic characteristics (date of birth, gender, height, weight), 
occupation 
 
SCD history : 
 Type of expressed Hb : HbSS, HbSC, HbSβ0 or HbSβ+ 
 Neonatal screening of the disease 
 Date (or year) of first appearance of SCD symptoms 
 Date (or year) of SCD diagnosis 
 History of SCD manifestations : 
o history of growth delay 
o infections 
o number and type of vaso-occlusive complications : acute chest 
syndrome, priapism, stroke, hepatopathy, acute splenic 
sequestration, skin ulceration, other 
o number of hospitalisation in relation with SCD 
 
Presence or absence of skin ulceration 
 
Any history of malignancy (type, location, date, resolution) 
 
Classical clinical examination (cardiovascular, respiratory, digestive …) 
 
In males whether sperm had been examined 
 
In females obstetric history, especially amenorrhea (if applicable) 
 
Treatment history data : 
 Blood transfusions 
 History of treatment by hydroxycarbamide (other than Siklos®) will  
be also documented : start, end dates, last dose 
 
Siklos® treatment initiation : date of start treatment, dose 
 
Live vaccines 
 
Other relevant concomitant conditions and associated treatment 
 
Biological data : current haemoglobin, MCV, HbF, ferritin, white cell count 
and differential, platelets, urinalysis (protein), liver function tests, blood 
urea and creatinine. 
Baseline data will be collected as far as possible for all symptomatic SCD 
patients screened to enter the cohort. 

Study protocol
CONFIDENTIAL
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Final Version amended (amendment 2) dated October 20, 2017 
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Name of Sponsor : 
Addmedica 
Name of finished product : 
Siklos® 
Name of active ingredients : 
Hydroxycarbamide 
Follow-up data are not limited to those listed below : 
 
Demographic data : height, weight 
 
Growth, school, occupation 
 
Presence or absence of skin ulceration 
 
Malignancy (type, location, date, resolution) 
 
Pregnancy 
 
Other concomitant pathologies/adverse events not related to sickle cell 
disease, with description, seriousness, start and end date, outcome, 
severity, relation with previous pathology, ancillary examination, 
treatments, relationship to Siklos® 
 
Events related to sickle cell disease with description, start and end date, 
severity, outcome, new transcranial Doppler (if any) 
 
Classical clinical examination 
 
Biological data: at least blood count, liver function tests, blood urea and 
creatinine 
 
Follow-up of Siklos® treatment 
 
Concomitant medication, in particular : 
 HIV drugs (NRTI) 
 Myelosuppressive agents 
 Radiotherapy 
 Live vaccines 
 
Infections 
 
Number and type of SCD events : 
 Painful crisis 
 Acute chest syndrome 
 Priapism 
 Stroke 
 Hepatopathy 
 Acute splenic sequestration 
 Other 
 
Number of hospitalisation in relation with SCD 
 
Treatment discontinuation or withdrawal, and reasons. 
Statistics 
All statistical analyses will be performed at the 5% significance. 
Parameters will be summarized using mean, median, standard deviation, 
range for continuous data and counts or percentages for categorical data. 
Descriptive statistics will be used to : 
 
Report the prevalence of primary and secondary parameters. 
 
Describe the global population and the sub-populations. 
Appropriate multivariate analysis will be used to describe the determinants 
of the observed events. 
Regular interim reports will be issued in accordance with the PSUR 
schedule (twice a year), in accordance with the RMP. 
The report will present a general description of the population included and 
frequencies of all primary and secondary parameters on the global 
population. 
Sub-population analyses will be performed when the collected data on the 
same parameters will be sufficient. 

Study protocol
CONFIDENTIAL
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Glossary of abbreviations and definition of terms 
 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
CI 
Confidence Interval 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
EC 
Ethics Committee 
EMA 
European Medicines Agency 
Hb 
Haemoglobin 
IRB 
Independent Review Board 
MedDRA 
Medical dictionary for Regulatory Activities 
NA 
Not Applicable 
PSUR 
Periodic Safety Update Reports 
RMP 
Risk Management Plan 
SAE 
Serious Adverse Event 
SCD 
Sickle Cell Disease 
SD 
Standard Deviation 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedures 

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Investigators and study administrative structure 
 
Sponsor 
 
Addmedica 
37 rue de 
Caumartin  
F-75009 PARIS 
Medical Director 
Sponsor’s representative 
Dr Corinne Duguet 
Phone : +33 (0)1 72 69 01 86 
Fax : 
+33 (0)1 73 72 94 13 
email : corinne.duguet @addmedica.com 
 
Steering Committee 
A Steering Committee will comprise medical experts involved in the cohort follow-up, the 
sponsor, and an independent epidemiologist. The Steering Committee will oversee the 
conduct and reporting of the cohort follow-up, assuring expert clinical guidance and a 
high standard of scientific quality, reviewing all SAEs and clinical endpoints reported by 
the sites (i.e., initial diagnoses, laboratory values, results of procedures) to determine the 
occurrence of clinical issues, and proposing any necessary protocol amendments to be 
submitted to health authorities. 
The number of representative of each country will be linked to the prevalence of SCD in 
the country. Presently it is foreseen to have 4 representatives for United-Kingdom and 
France and 2 for Greece 
The Steering Committee Charter will define the responsibilities of the 
committee.  
Members of the committee will be determined according to their skills, number 
of patients included in their center, availabilities for meeting and interest in 
participating. 
 
 
European Clinical Board Committee (ECBC) 
A least one of the physicians specialised in SCD of each country in Europe is recruited to 
participate to the ECBC, the missions of which are the following ones: 
 To animate the cohort follow-up in each country and ensure its development 
 To propose and decide on development of the action to set up. 
The European Clinical Board Committee charter will define the responsibilities of the 
committee. 

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Contract research organisations 
 
Pharmacovigilance 
For Drug Consulting 
6 Rue Rouget de Lisle 
92240 Malakoff 
Qualified 
Person 
for
Dr Corinne Duguet 
  Pharmacovigilance 
 
Phone : +33 (0)1 72 69 01 86
 Fax : 
+33 (0)1 73 72 94 13 
 email : corinne.duguet@addmedica.com 
 
 
Trial management (data 
collection and on-site 
quality control) 
 
 
Peter Holmes Clinical (November 2007 to September 
2014) 
65 rue Paul Eluard 
93200 Saint Denis 
FRANCE 
Keyrus Biopharma (since March 2015) 
18/20 rue Clement Bayard 
92300 Levallois-Perret  
FRANCE 
Outsourced CRAs 
 
Caroline Dumas 
Reseaulution society 
34 bis rue Parmentier 
92800 Puteaux 
FRANCE 
 
Hervé Perrier (Freelance CRA) 
 
Sophie Armand (Freelance CRA) 
 
Database host 
Arone 
4, rue Leroux 
94100 SAINT-MAUR DES FOSSES 
FRANCE 
 
Statistics 
Inferential 
35, rue Godot de Mauroy   
75009 Paris 
FRANCE 
 
 

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Table of contents 
PROTOCOL SYNOPSIS 
2 
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS 
7 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
8 
Sponsor 
8 
Steering Committee 
8 
European Clinical Board Committee (ECBC) 
9 
Contract research organisations 
10 
TABLE OF CONTENTS 
11 
1 
INTRODUCTION AND STUDY RATIONALE 
13 
2 
OBJECTIVES 
15 
3 
INVESTIGATIONAL PLAN 
16 
4 
COHORT POPULATION 
17 
4.1 
Number and type of patients 
17 
4.2 
Recruitment criteria 
17 
4.3 
Patients identification 
17 
5 
TREATMENT 
18 
6 
EVALUATION CRITERIA 
19 
6.1 
Safety parameters 
19 
6.2 
Parameters assessing Siklos® effects 
19 
7 
ADVERSE EVENT REPORTING 
20 
7.1 
Definitions 
20 
7.1.1 
Adverse Event 
20 
7.1.2 
Serious Adverse Events 
20 
7.1.3 
Adverse Reaction 
21 
7.1.4 
Unexpected Adverse Reaction 
21 
7.1.5 
Abnormal Test Findings 
21 
7.1.6 
Hospitalisation 
21 
7.1.7 
Exposure In Utero 
22 
7.2 
Reporting Adverse Events 
23 
7.2.1 
Reporting Period 
23 
7.2.2 
Severity Assessment 
24 
7.2.3 
Causality Assessment 
24 
7.2.4 
Serious Adverse Event Reporting Requirements 
24 
8 
DATA COLLECTION 
26 
8.1 
Physician identification 
26 

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8.2 
Baseline data 
26 
8.3 
Follow up form 
27 
8.4 
Withdrawal form 
28 
8.5 
Pregnancy form 
28 
8.6 
Collection of AEs and SAEs 
29 
8.7 
Data protection 
29 
9 
RECRUITMENT AND FOLLOW-UP 
30 
9.1 
Recruitment of physicians specialised in SCD 
30 
9.2 
Recruitment of patients and follow-up 
30 
9.3 
Study conduction 
30 
9.4 
Flow chart 
31 
10 
MONITORING 
32 
11 
MANAGEMENT AND VALIDATION OF DATA 
32 
12 
ANALYSIS AND REPORTS 
33 
13 
COMMITTEES 
34 
13.1 
European Clinical Board Committees (ECBC) 
34 
13.2 
Steering Committee (SC) 
34 
14 
LEGAL FRAMEWORK AND PATIENT INFORMATION 
35 
14.1 
Legal framework 
35 
14.2 
Description of the patient information sheet 
35 
15 
REFERENCES 
36 
APPENDICES 
37 
Responsibilities of the Marketing Authorisation Holder 
37 

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1 
Introduction and study rationale 
Sickle cell disease (SCD) is an autosomic recessive hereditary disease involving 
the haemoglobin S (HbS). SCD disease is present in HbS homozygote patients 
(HbSS). It is also present in heterozygote patients expressing HbS, HbC, (HbSC) 
and during β-thalassemia (HbS-β-thalassemia patients). SCD severity varies 
depending on the Hb expressed haplotypes (Table 1). 
 
Table 1: Impact of Hb type expressed on SCD severity 
 
HbSS 
HbSC 
HbSβ° 
HbS β+ 
Severe 
Moderate 
Severe 
Moderate 
 
The clinical manifestations of SCD result primarily from haemolytic anaemia and 
effects of repeated intravascular sickling, causing vaso-occlusion and ischemic 
injury. Chronic organ damage in SCD is an insidious process that may affect almost 
every organ system and can lead to considerable morbidity and mortality at an 
early age. Loss of splenic function, sickle nephropathy (proteinuria and renal 
failure), pulmonary hypertension, and brain ischemic lesions are examples of long-
term end-organ damage observed in SCD1,2,3,4. The commonest disorder of SCD 
is painful vaso-occlusive crisis, followed by infection and acute chest syndrome 
(ACS), occurring in up to 40% of patients and commoner in children. ACS is 
characterised by episodes of chest pain, fever, leukocytosis, and uni-or bi-lateral 
pulmonary infiltrates. Other manifestations of SCD include: 
 Stroke (with a high frequency in children in their first decade) 
 Priapism (associated with a risk of future impotence) 
 Infections 
 Aplastic crisis (often caused by parvovirus infection) 
 Acute bone marrow infections 
 Sequestration crises 
 Major organ damage to the heart, lungs, kidney, eyes, and femoral heads. 
 
Splenic sequestration predominantly occurs in children with homozygous HbS and 
is a life-threatening complication. Renal organ damage may lead to end- stage 
renal failure. 
 
Apart in periods of acute syndrome, SCD patients are ambulatory. The main 
causes of hospitalisation and death in patients with SCD are severe recurrent 
infections and subsequent complications such as vaso-occlusive crises. Average 
life-expectancy is 42 years in males and 48 years in females. 
 
Hydroxycarbamide is a cytostatic myelosuppressive drug that, in most individuals, 
reactivates Fœtal Haemoglobin (HbF) synthesis. It has  been marketed since 1968, 
in several EU member states, under different trade marks (Hydrea®, Litalir®, 
Oncocarbide®), for the treatment of haematological cancer and chronic 
myeloproliferative 
disorders, 
as 
polycythaemia 
vera 
and 
essential 
thrombocythaemia. 
 
Considering SCD, hydroxycarbamide is the only product which efficacy has been 
studied in a relatively large placebo-controlled trial. Hydroxycarbamide appears, 
when used as monotherapy, to be the least toxic and most effective therapeutic 
option for SCD: hydroxycarbamide has been demonstrated to decrease the 
frequency of acute painful episodes, the incidence of acute chest syndrome,   the 

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blood transfusion requirement and morbidity and mortality5,6. However, 
hydroxycarbamide therapy is not effective in all patients. Children are usually good 
responders, but it is estimated that 10 to 25% of adult patients are refractory to this 
therapy due to hypoplastic bone marrow, genetic factors, or variations in drug 
metabolism. Furthermore, significant variation of HbF production is observed in 
good responder patients7,8. 
 
In summary, SCD is one of the most common inherited diseases worldwide. It is 
associated with lifelong morbidity and a reduced life expectancy, and any 
evaluation of the safety profile of treatments for SCS must take into account the 
significant morbidity and mortality associated with the disease, independent of 
treatment. 
 
It is estimated that between 400 and 500 patients are chronically treated by 
Hydrea® in France. This represents a significant part of the severe SCD patients. 
 
Although the role of hydroxycarbamide in the prevention of painful crises and in the 
decrease of mortality and morbidity in SCD patients is well-established 5,9,10, long-
term safety data with hydroxycarbamide in this indication is limited, particularly in 
certain sub-populations : 
 Young patients 
 Patients with hepatic or renal impairment 
 During pregnancy or lactation 
 Elderly patients. 
 
The assessment of the leukemogenic potential of hydroxycarbamide is confounded 
by such observations being previously made in patients with underlying 
myeloproliferative diseases (e.g., Essential Thrombocytemia and Polycytemia 
Vera). 
 
Other concerns should be investigated: 
 Concomitant use of hydroxycarbamide and HIV drugs 
 Concomitant use of hydroxycarbamide with myelopsuppressive agents and 
radiation therapy. 
 Concomitant use of live vaccines. 
 
Siklos® is an orphan product. It is the only hydroxycarbamide authorised in SCD 
treatment. It is indicated for the prevention of recurrent painful vaso-occlusive 
crises including acute chest syndrome in both children and adult patients. 
Unanswered questions remain about its long-term safety especially in young 
patients who might be exposed for decades. 
 
In order to answer all these questions, the European Medicine Agency (EMA) 
requested for a European cohort study to be performed. The present study will be 
performed to respond to this EMA demand. It aims to explore and collect 
information about the effects of Siklos® and its long-term safety in SCD patients. 

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2 
Objectives 
This study is driven by the Risk Management Plan required by EMA. 
 
The objective of this cohort study is to collect information about long-term safety of 
Siklos® (hydroxycarbamide) when used in current practice for the prevention or 
treatment of symptomatic complications in patients with Sickle Cell Disease, 
assessed on the frequency of : 
 Myelosuppression (requiring permanent or temporary discontinuation of 
therapy) secondary to hydroxycarbamide-induced myelotoxicity 
 Malignancies, skin ulceration and impaired postnatal development (growth) 
 Amenorrhea, fertility impairment. 
 
Particular attention will be given to special populations or circumstances: 
 Young patients (children and adolescents until end of puberty) 
 Elderly patients 
 Patients with underlying SCD-related hepatic or renal impairment 
 Pregnancy and its outcome, particularly for congenital malformations 
 Concomitant use of hydroxycarbamide and specific therapies : 
 HIV drugs ; especially Nucleoside Analogue Reverse Transcriptase 
Inhibitors (NRTI) 
 other myelosuppressive agents 
 radiation therapy 
 live vaccines 
 
Other points of concern are: 
 Overall mortality and survival time 
 Occurrence of SCD events, in particular : 
 painful crises 
 infectionsacute chest syndrome 
 stroke 
 acute splenic sequestration 

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3 
Investigational plan 
 
This is a multicentre, prospective, non-interventional cohort study in patients with 
SCD treated with Siklos® and followed-up for up to ten years. Patients will be 
initially recruited in France, United-Kingdom and Greece. The other European 
countries will be encouraged to participate as soon as Siklos® becomes available. 
All patients prescribed Siklos® within 8 years of its commercialisation until reaching 
at least 2000 patients will be enrolled in this cohort.  
 
The follow-up of these patients will be strictly observational and will fit within their 
usual clinical monitoring without any controlled treatment, specific exam or 
modification of their follow-up, in compliance with the SPC of this orphan product. 
 
Patients will be evaluated at inclusion, then every 1 to 4 months, according to 
normal monitoring of the disease and to the recommendations of Siklos® 
specification for use. A minimum of a yearly follow-up will be requested. 
 
Patients will be informed by their initiating physician about the study and enrolled 
in case they agree to participate. Solely physicians experienced in the care of SCD 
(reference centres) are legitimated to initiate a Siklos® treatment; follow-up is 
authorised by both initiating and treating physicians. Patients will give their 
agreement for the retrospective collection of their data since Siklos initiation. This 
is justified by the fact that the initiation period is a sensitive period for potential 
adverse events. 
 
A Steering Committee, formed by medical experts from all the countries involved 
in the cohort, sponsor representatives and an independent epidemiologist, will 
oversee the conduct and reporting of the cohort, to assure expert clinical guidance 
and a high standard of scientific quality. 
 
A Clinical Board committee, formed by at least one physician expert in SCD 
management in each participating country, will animate the cohort follow-up in each 
country and ensure its development, and will propose actions to the Steering 
Committee. 
 
CROs are appointed by the sponsor to ensure the study management: enrolment 
of participating physicians, study monitoring, data collection through electronic 
forms (e-CRF), data management, statistics and reporting to the Steering 
Committee. 
 
Analyses of data collected will be conducted at least twice a year, to fit with the 
Risk Management Plan and Periodic Safety Update Reports. 

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4 
Cohort Population 
The cohort is composed of patients suffering from symptomatic SCD and entitled 
to a treatment with Siklos®. 
 
4.1 
Number and type of patients 
 
Around 2000 patients treated with Siklos®. 
 
The number of subjects is determined taking into account 20% of severe SCD on 
an overall 24 000 estimated number of subjects with the disease in Europe, and 
approximately 50% of these on Siklos®. 
 
4.2 
Recruitment criteria 
 
Patients will be enrolled in the study cohort if they satisfy the following criteria 
 Male or female ambulatory patients 
 Aged 2 years and more 
 With symptomatic sickle cell syndrome 
 Treated with Siklos®  
 Having been informed of the study by the initiating physician and consenting  to 
participate to the cohort (for children, the persons having parental authority must 
be informed and give a participation consent) 
 
4.3 
Patients identification 
 
A unique identifying number will be generated automatically based on the position 
of the subject in the cohort, on four digits with a one digit key-control added to the 
four digits number. 
 
Additional information is collected for the physician convenience: 
 Patient's date of birth. 

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5 
Treatment 
The dosage should be based on the patient’s body weight. 
 
The starting dose of Siklos® is 15 mg/kg/day and the usual dose is between 15 and 
30 mg/kg/day. Under exceptional circumstances a maximum dose of 35 mg/kg/day 
might be justified under close haematological monitoring. 
 
Duration: As long as the patient responds to therapy either clinically or 
haematologically (e.g., increase of Haemoglobin F (HbF), Mean Corpuscular 
Volume (MCV), neutrophile count) the dose of Siklos® should be maintained. 
 
In case of non-response (re-occurrence of complications or no decrease in 
complication rate) the daily dose may be increased by steps of 5 mg/kg/day. 
 
In the event a patient does still not respond when treated with the maximum dose 
of hydroxycarbamide (35 mg/kg/day) over three to six months, permanent 
discontinuation of Siklos® should be considered. 
 
The initial prescription of Siklos® must be done by a physician experienced in SCD 
management (initiating physician), normally a hospital physician. Renewing of 
prescription can be done by the treating physician, providing an annual renewal of 
prescription is done by the initiating physician. 

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6 
Evaluation Criteria 
 
6.1 
Safety parameters 
 
The primary safety parameters will be : 
 Frequency of malignancies 
 Frequency of skin ulceration (broken out by severity) 
 Frequency 
of 
myelosuppression 
requiring 
temporary 
or 
permanent 
discontinuation of Siklos®. 
 
The secondary safety parameters will be : 
 Effects of Siklos® on growth development. Specific examinations (scintigraphy, 
radiographies, …) should be done if the difference with normal growth is greater 
than 2 standard deviations 
 Outcome of pregnancies: rates of miscarriage, stillbirths, APGAR score at 
birth, congenital malformations. 
 Frequency of serious adverse events. 
 Any occurrence of unforeseen safety patterns. 
 
Special attention will be given to specific populations or conditions, e.g.: elderly 
patients, patients with renal and hepatic impairment, HIV patients, patients 
receiving live vaccine or other myelosuppressive agents or radiotherapy, … 
 
Definitions for AEs, SAEs and pregnancies, as well as procedures to follow are 
presented in Section 7. It is of utmost importance that all people participating in the 
trial understand these definitions and procedures. It is the investigator's 
responsibility to ensure that this knowledge is acquired. 
 
6.2 
Parameters assessing Siklos® effects 
The effects on Siklos® on SCD will be assessed on the following non limitative 
list : 
 Overall mortality and survival rates 
 Frequency of vaso-occlusive complications : 
 painful crises 
 acute chest syndrome 
 stroke 
 acute splenic sequestration 
 infections 
 Hospitalisations due to SCD events 
 Frequency of blood transfusions 

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7 
Adverse Event Reporting 
 
7.1 
Definitions 
 
7.1.1 
Adverse Event 
 
An adverse event is any untoward medical occurrence in a subject taking Siklos®; 
the event need not necessarily have a causal relationship with the treatment or 
usage. Examples of adverse events include but are not limited to : 
 Abnormal test findings 
 Clinically significant symptoms and signs 
 Changes in physical examination findings 
 Hypersensitivity 
 Progression/worsening of underlying disease. 
 
Additionally, they may include signs or symptoms resulting from : 
 Drug overdose 
 Drug withdrawal 
 Drug abuse 
 Drug misuse 
 Drug interactions 
 Drug dependency 
 Exposure in utero 
 Pregnancy and lactation. 
 
7.1.2 
Serious Adverse Events 
 
A serious adverse event or serious adverse drug reaction is any untoward 
medical occurrence at any dose that : 
 Results in death 
 Is life-threatening (immediate risk of death) 
 Requires inpatient hospitalisation or prolongation of existing hospitalisation 
 Results in persistent or significant disability/incapacity 
 Results in congenital anomaly/birth defect. 
 
Medical and scientific judgement should be exercised in determining whether an 
event is an important medical event. An important medical event may not be 
immediately life-threatening and/or result in death or hospitalisation. However, if it 
is determined that the event may jeopardise the subject and/or may require 
intervention to prevent one of the other outcomes listed in the definition above, the 
important medical event should be reported as serious. 
 
Examples of such events are intensive treatment in an emergency room or at home 
for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalisation; or development of drug dependency or drug abuse. 

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7.1.3 
Adverse Reaction 
 
An adverse reaction is defined as a response to a medicinal product which is 
noxious and unintended and which occurs at doses normally used in man for the 
prophylaxis, diagnosis or therapy of disease or for the restoration, correction or 
modification of physiological function. 
 
Response in this context means that a causal relationship between Siklos® and an 
adverse event is at least a reasonable possibility. Adverse reaction also includes 
adverse clinical consequences associated with use of the product outside the 
terms of the Summary of Product Characteristics or other conditions laid down for 
the marketing and use of the product (including prescribed doses higher than those 
recommended, overdoses or abuse). 
 
7.1.4 
Unexpected Adverse Reaction 
 
An unexpected adverse reaction is an adverse reaction which nature, severity or 
outcome is not consistent with the Summary of Product Characteristics (SmPC). 
This includes class-related reactions mentioned in the SmPC but not specifically 
described as occurring with this product. 
 
7.1.5 
Abnormal Test Findings 
 
The criteria for determining whether an abnormal objective test finding should be 
reported as an adverse event are as follows : 
 Test result is associated with accompanying symptoms, and/or 
 Test result requires additional diagnostic testing or medical/surgical 
intervention, and/or 
 Test result leads to a change in Siklos® dosing based on SmPC 
recommendations or discontinuation from ESCORT-HU, significant additional 
concomitant drug treatment, or other therapy, and/or 
 Test result is considered to be an adverse event by the physician or sponsor. 
 
Merely repeating an abnormal test, in the absence of any of the above conditions, 
does not constitute an adverse event. Any abnormal test result that is determined 
to be an error does not require reporting as an adverse event. 
 
7.1.6 
Hospitalisation 
 
Hospitalisation for worsening of a pre-existing condition (e.g., for work-up of 
persistent pre-treatment lab abnormality) or any event related to sickle cell disease 
should be considered as a serious adverse event. 
 
Hospitalisation or prolongation of hospitalisation in the absence of a precipitating, 
clinical adverse event is not in itself a serious adverse event and should not be 
reported. Examples include : 
 Admission for treatment of a preexisting condition (except sickle cell disease) 
not associated with the development of a new adverse event 
 Social admission (e.g., subject has no place to sleep) 
 Administrative admission (e.g., for yearly physical exam) 
 Optional admission not associated with a precipitating clinical adverse event 
(e.g., for elective cosmetic surgery) 

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 Pre-planned treatments or surgical procedures should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject. 
 
Diagnostic and therapeutic non-invasive and invasive procedures, such as 
surgery, should not be reported as adverse events. However, the medical condition 
for which the procedure was performed should be reported if it meets the definition 
of an adverse event. For example, an acute appendicitis that begins during the 
adverse event reporting period should be reported as the adverse event, and the 
resulting appendectomy should be recorded as treatment of the adverse event. 
 
7.1.7 
Exposure In Utero 
 
Amendment 1 : Despite specific recommendations regarding necessity to use 
contraception while taking Siklos (Summary Product Characteristics), despite 
specific recommendations regarding patient desire of pregnancy, indicating that 
Siklos has to be stopped 3 to 6 months before conception, an exposure to Siklos 
in-utero can occurs. According to the needs detailed in the Risk Management Plan 
(mod 1.8 Rev 4 page: 41 and 47) to follow specifically all pregnancies in the frame 
of Escort-HU, the following procedure has to be set up. 
 
An exposure in-utero (EIU) occurs if : 
 A female becomes, or is found to be, pregnant either while receiving or having 
been directly exposed to Siklos® (e.g., environmental exposure), or the female 
becomes, or is found to be, pregnant after discontinuing and/or being directly 
exposed to Siklos® (maternal exposure) 
 A male has been exposed, either due to treatment or environmental, to  Siklos® 
prior to or around the time of conception and/or is exposed during the partner 
pregnancy (paternal exposure). 
 
If any subject or subject’s partner becomes or is found to be pregnant during the 
subject’s treatment with Siklos®, the physician must submit this information to 
Addmedica on an Exposure in Utero Form. In addition, the physician must submit 
information regarding environmental exposure to a Addmedica product in a 
pregnant woman (e.g,. a nurse reports that she is pregnant and has been exposed 
to a cytotoxic product by inhalation or spillage) using the Exposure in Utero Form. 
This must be done irrespective of whether an adverse event has occurred and 
within 24 hours of awareness of the pregnancy. The information submitted should 
include the anticipated date of delivery (see below for information related to 
induced termination of pregnancy). 
 
Follow-up is conducted to obtain pregnancy outcome information on all Exposure 
in Utero reports with an unknown outcome. The physician will follow the pregnancy 
until completion or until pregnancy termination (i.e., induced abortion) and then 
notify Addmedica of the outcome. The physician will provide this information as a 
follow up to the initial Exposure in Utero Form. The reason(s) for an induced 
abortion should be specified. An EIU report is not created when an ectopic 
pregnancy report is received since this pregnancy is not usually viable. Rather, a 
serious adverse event case is created with the event of ectopic pregnancy. 
 
If the pregnancy outcome meets the criteria for immediate classification as a 
serious adverse event i.e., spontaneous abortion (including miscarriage and 
missed abortion), stillbirth, neonatal death, or congenital anomaly (including   that 

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in an aborted foetus, stillbirth or neonatal death), the physician should follow the 
procedures for reporting serious adverse events. 
 
In the case of a live birth, the “normality” of the newborn can be assessed at the 
time of birth (i.e., no minimum follow-up period of a presumably normal infant is 
required before an Exposure in Utero Form can be completed). The “normality” of 
an aborted foetus can be assessed by gross visual inspection, unless pre- abortion 
test findings are suggestive of a congenital anomaly. 
 
All neonatal deaths that occur within 1 month of birth should be reported, without 
regard to causality, as serious adverse events. In addition, any infant death after 1 
month that the physician assesses as possibly related to the in utero exposure to 
the investigational medication should be reported. 
 
All births (normal or not) will be followed on the long term by questioning the mother 
or the father (the subject having taken Siklos®) on follow-up visits. In  case of 
adverse event which is assessed by the physician as related to mother’s or father’s 
administration, it will be managed upon post-MAA pharmacovigilance rules. 
 
7.2 
Reporting Adverse Events 
 
All observed or volunteered adverse events regardless of suspected causal 
relationship to Siklos® will be reported as described in the following sections. 
 
The physician is to report all directly observed adverse events and all adverse 
events spontaneously reported by the subject on the adverse event page(s) of the 
database. In addition, each subject will be questioned about adverse events. 
 
For all adverse events not related to sickle cell disease, the physician must pursue 
and obtain information adequate both to determine the outcome of the adverse 
event and to assess whether it meets the criteria for classification as a serious 
adverse event requiring immediate notification to Addmedica or its designated 
representative. For all adverse events not related to sickle cell disease, sufficient 
information should be obtained by the physician to determine the causality of the 
adverse event. The physician is required to assess causality. For adverse events 
not related to sickle cell disease with a causal relationship to Siklos®, follow-up by 
the physician is required until the event or its sequelae resolve or stabilise at a level 
acceptable to the physician, and Addmedica concurs with that assessment. 
 
Each adverse event not related to sickle cell disease is to be assessed to 
determine if it meets the criteria for serious adverse event. If a serious adverse 
event occurs, expedited reporting will follow local and international regulations, as 
appropriate. 
 
 
7.2.1 
Reporting Period 
 
Serious adverse events require immediate notification to Addmedica or its 
designated representative, beginning from the time that the subject provides oral 
informed consent to participate in a cohort follow-up called ESCORT-HU, i.e., 

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prior to receiving Siklos®, through and including 28 calendar days after the last 
administration of Siklos®. Any serious adverse event occurring any time after the 
reporting period must be promptly reported if a causal relationship to Siklos® is 
suspected. 
 
Adverse events (serious and non-serious) should be recorded in the database from 
the time the subject has taken at least one dose of Siklos® through 28 calendar 
days after the last administration of Siklos®. 
 
7.2.2 
Severity Assessment 
 
If required on the adverse event case report forms, the physician will use the 
adjectives MILD, MODERATE, or SEVERE to describe the maximum intensity of 
the adverse event. For purposes of consistency, these intensity grades are defined 
as follows : 
MILD 
Does not interfere with subject's usual function. 
MODERATE 
Interferes to some extent with subject's usual function. 
SEVERE 
Interferes significantly with subject's usual function. 
 
Note the distinction between the severity and the seriousness of an adverse event. 
A severe event is not necessarily a serious event. For example, a headache may 
be severe (interferes significantly with subject's usual function) but would not be 
classified as serious unless it met one of the criteria for serious adverse events, 
listed above. 
 
7.2.3 
Causality Assessment 
 
The physician’s assessment of causality must be provided for all adverse events 
not related to sickle cell disease (serious and non-serious). A physician’s causality 
assessment is the determination of whether there exists a reasonable possibility 
that Siklos® caused or contributed to an adverse event. If the physician’s final 
determination of causality is unknown and the physician does not know whether or 
not Siklos® caused the event, then the event will be handled as “related Siklos®” 
for reporting purposes. If the physician's causality assessment is "unknown but not 
related to Siklos®", this should be clearly documented on study records. 
 
7.2.4 
Serious Adverse Event Reporting Requirements 
 
If a serious adverse event occurs, Addmedica is to be notified within 24 hours of 
awareness of the event by the physician. In particular, if the serious adverse event 
is fatal or life-threatening, notification to Addmedica must be made immediately, 
irrespective of the extent of available adverse event information. This timeframe 
also applies to additional new information (follow-up) on previously forwarded 
serious adverse event reports as well as to the initial and follow-up reporting of 
Exposure in Utero cases. 
 
In the rare event that the physician does not become aware of the occurrence of a 
serious adverse event immediately (e.g., if an outpatient subject initially seeks 
treatment elsewhere), the physician is to report the event within 24 hours after 
learning of it and document the time of his/her first awareness of the adverse event. 

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For all serious adverse events, the physician is obligated to pursue and provide 
information to Addmedica in accordance with the timeframes for reporting specified 
above. In addition, a physician may be requested by Addmedica to obtain specific 
additional follow-up information in an expedited fashion. This information may be 
more detailed than that captured on the adverse event case report form. In general, 
this will include a description of the adverse event in sufficient detail to allow for a 
complete medical assessment of the case and independent determination of 
possible causality. Information on other possible causes of the event, such as 
concomitant medications and illnesses must be provided. In the case of a subject 
death, a summary of available autopsy findings must be submitted as soon as 
possible to Addmedica or its designated representative. 

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8 
Data collection 
Data will be collected electronically in a database created and monitored by 
CROs. 
 
During this study, patients can be followed-up by both the initiating and the treating 
physicians. Only the former is allowed to initiate Siklos® treatment and by the same 
way to enroll new patients in the study. Familial physician is allowed to access to 
data recorded by initiating physician and to record new data collected during the 
patient follow up visits. 
 
8.1 
Physician identification 
 
Physicians (treating physicians or specialised physicians initiating Siklos® 
treatment) will be identified using the following informations : 
 Username 
 First name 
 Last name 
 Hospital Centre 
 Address 
 City 
 ZIP/Postal code 
 Country 
 Phone 
 E-Mail 
 Title 
 National physician number 
 Speciality 
 Current functions 
 
8.2 
Baseline data 
 
Demographic characteristics : date of birth, gender, height, weight. 
School, occupation. 
History of SCD : 
 Type of expressed Hb: HbSS, HbSC, HbSβ° or HbS β+. This data is assessed 
routinely in SCD and is necessary to determine its severity 
 Whether the diagnosis was made as neonatal screening 
 Date (or year) of first appearance of SCD symptoms 
 Date (or year) of SCD diagnosis 

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 History of SCD manifestations : 
 history of growth delay 
 infections during the elapsed year 
 number and type of vaso-occlusive complications during the elapsed year : 
 painful crisis 
 acute chest syndrome 
 priapism 
 stroke 
 hepatopathy 
 acute splenic sequestration 
 other 
 Number of hospitalisation in relation with 
SCD. Presence or absence of skin 
ulceration. 
Any history of malignancy (type, location, date, resolution). 
In males whether sperm had been examined. 
In females obstetric history (if applicable). 
 
Treatment history data : 
 Blood transfusions 
 History of treatment by hydroxycarbamide (other than Siklos®) will be also 
documented: start, end dates, last dose. 
 
Siklos® treatment initiation: date of treatment start, dosage. If the patient is not 
prescribed Siklos®, reason. 
 
Other relevant concomitant conditions and associated treatment. 
Clinical examination. 
Biological data, as performed routinely in the disease management, with at least 
Haemoglobin, MCV, HbF, ferritin, white cell count and differential, platelets, 
urinalysis (protein), liver function tests, blood urea and creatinine. 
 
8.3 
Follow up form 
 
Demographic data : height, weight. 
Growth, school, occupation. 
Presence or absence of skin ulceration 
Malignancy (type, location, date, resolution). 
Pregnancy (see below). 
Other concomitant pathologies/adverse events with description, seriousness, start 
and end date, outcome, severity, relation with a pre-existing condition, ancillary 
examination, and relationship to Siklos® 

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Concomitant treatments, in particular : 
 HIV drugs (NRTI) 
 Myelosuppressive agents 
 Radiotherapy 
 Live vaccines 
Infections. 
Number and type of vaso-occlusive complications : 
 Painful crisis 
 Acute chest syndrome 
 Priapism 
 Stroke 
 Hepatopathy 
 Acute splenic sequestration 
 Other 
 
Number of hospitalisation in relation with SCD. 
Number of transfusions. 
Clinical examination. 
 
Biological data : at least blood count, liver function tests, blood urea and 
creatinine. 
 
Siklos® information: changes in dosage, temporary discontinuations, withdrawal  
of treatment and reasons. 
 
8.4 
Withdrawal form 
 Date of last information available. 
 Reasons for discontinuation. 
 
8.5 
Pregnancy form 
 
If any subject is found to be pregnant during the treatment follow-up, the evaluation 
of the risk-benefit ratio will be made on an individual basis outweighing the 
respective risk of continuing Siklos® therapy against the switch to a blood 
transfusion programme. Siklos® should normally be stopped. 
 
The pregnancy should be reported immediately using the pregnancy notification 
form available in the database. 
 
All pregnancies will be followed up to final outcome, using the pregnancy follow- 
up form. The outcome, including any premature termination, miscarriage or foetal 
death will be reported. 
 
The follow-up of children born from a parent receiving Siklos® is a 
Pharmacovigilance concern. Such children will be followed-up for at least one year. 

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8.6 
Collection of AEs and SAEs 
 
Adverse events, serious or not, will be collected in a specific form available in the 
database. These effects will be reported according to the ADDMEDICA 
Pharmacovigilance SOPs. 
 
For all the AEs not related to sickle cell disease recorded, will be collected 
information about: 
 Description, serious or not 
 Start date 
 Outcome 
 End date (if applicable) 
 Severity 
 Relation with previous pathology 
 Ancillary Examination 
 Corrective treatment 
 Relationship to Siklos® (suspected / not suspected) 
 
For all the events related to sickle cell disease recorded, will be collected information 
about: 
 Start date 
 Outcome 
 End date (if applicable) 
 Severity 
 New Transcranial Doppler done or  not 
 
 
8.7 
Data protection 
 
Data encryption 
 
In order to respect patient anonymity, in the database, all personal data allowing 
patient identification will be encrypted. 
 
Rights of access 
 
Physician selected to perform the study and the CRO personal implicated in the 
study conduction are allowed to access to this database. Addmedica and 
competent authorities are allowed to access to data recorded in case of audit. For 
each authorised person, a login and a password will be created. All these persons 
have a duty of confidentiality to the patients and will do their best to meet this duty. 
 
NB: In the database all passwords (used by users or administrators) will be 
encrypted. 

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9 
Recruitment and follow-up 
 
9.1 
Recruitment of physicians specialised in SCD 
 
In each country an exhaustive list of all treatment centres specialized in SCD or 
haemoglobinopaties care (haematologists, paediatricians, internist…) will be 
established in collaboration with the Steering Committee (SC) and the European 
Clinical Board Committee (ECBC) (See section 7). 
 
Furthermore, with the physicians profile defined in each country the study sponsor 
will consider availability of any specific physicians database. 
 
A mailing will be sent to the full list of identified physicians to inform, propose and 
motivate them to participate in this study. In case of agreement, the CRO will 
contact each of them to explain the study and to set up a secure access to the 
database. 
 
9.2 
Recruitment of patients and follow-up 
 
Patients fulfilling all the inclusion criteria will be informed by their initiating physician 
about the study and enrolled in case they agree to participate. It is noteworthy that 
solely the physicians specialised in the care of SCD are legitimated to initiate a 
Siklos® treatment. However, the follow-up is authorised by both initiating and 
treating physicians. 
 
9.3 
Study conduction 
 
For each patient initiated by SIKLOS®, the initiating physician will fill the information 
on the current treating physician in the database. In case of this physician is 
unknown in the study database, the CRO will contact him to propose to participate 
in the study. 
 
A Family Doctor Pack (treating physician pack) written in local language will be 
sent to the treating physician for treatment information and follow-up purpose 
(monitoring of blood count, dosage adjustment, pregnancy, AEs). The details of 
the cohort study will be included in this pack. The treating doctors will be invited to 
complete an electronic form at each visit (intermediate visit form) so that any 
adverse effects can be followed up in a timely manner. 
 
Patients will be followed-up according to normal local medical practice. Each 
treating physician will be included in the database and a reminder will be send 
regularly (4 months) in case of non follow-up data capture for a patient. 
 
Once a year, a follow-up should be mandatory. 
 
Furthermore a patient card will be provided to the patient so that, in case of events 
(hospitalisations, intercurrent events, adverse events…) any physician would be 
able to contact the CRO. 
 
If no forms are received for a year, the patient will be considered as having been 
withdrawn  from  the  study.  In  this  case,  a  specific  withdrawal  form  will    be 

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completed if it is possible, patients who discontinue Siklos® will continue to be 
monitored until the end of the study (10 years). 
 
9.4 
Flow chart 
 
The cohort follow-up is illustrated in the flow chart presented below. 
The forms will be completed electronically in the database. 
 
 
Addmedica 
 
Initiating Physician Pack 
Treatment guide 
Cohort follow up Study 
Patient Packs 
Family doctor Packs 
 
 
 
 
 
Treated 
Patient 
Patient 
Pack 
New Patient 
Electronic
Electronic
Initiating Physician 
Treatment guide 
Cohort follow up Study 
Family doctor Pack 
Treatment guide 
Cohort follow up Study 
Patient Pack 
Family doctor 
Treatment guide 
Cohort follow up Study 

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10 
Monitoring 
Quality control visits will be performed to verify data entered in the Case Report 
Form against patient medical files. 
 
11 
Management and validation of data 
The CRO (Arone) is responsible for management of collected data (construction of 
a Database) and their validation. 
Data will be collected on Electronic Case report Form. 
It is the responsibility of the participating physicians : 
 To  obtain  subject  data  and  collect  them  in  a  prospective  
manner  by questioning the patient; some data could be 
collected retrospectively in patients when enrolment in posterior 
to initiation of treatment by Siklos 
 To ensure that all data collected are recorded directly, accurately and legibly 
 To perform the requested measurements. 
 
100% of at least 5% of visits will be controlled.  
The first on-site quality control visit will be triggered after the inclusion of the fifth 
patient at a site (i.e.  patient visits available in eCRF with at least the first year of 
follow-up for one of the patient that means 3 visits). After the first on-site visit, only 
the biggest recruiting sites will be visited yearly (defined with the sponsor, based 
on the number of patients included). 
 
Qualified designated personnel will perform this quality control in each country. 
 
All study related material will be archived securely according to relevant internal 
procedures. 
 
A detailed archiving procedure will ensure that access to confidential information 
is limited and that the confidentiality of information about study subjects is 
protected. 
 
The archives should be maintained for at least five years after final report or first 
publication of study results, whichever come first. 

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p(1  p)
N 
p(1  p)
N 
 
 
12 
Analysis and Reports 
All statistical analyses will be performed at the 5% significance. 
 
Parameters will be summarised using mean, median, standard deviation, range 
for continuous data and counts or percentages for categorical data. 
 
Descriptive statistics will be used to: 
 Report the prevalence of primary and secondary parameters 
 Describe the global population and the sub-populations. 
 
Appropriate multivariate analysis will be used to describe the determinants of the 
observed events. 
 
Regular interim reports will be issued in accordance with the PSUR schedule. 
 
The report will present a general description of the population included and 
frequencies of all primary and secondary parameters on the global population. 
 
Sub-population analyses will be performed when the collected data on the same 
parameters will be sufficient. 
 
The following formula is used to calculate the confidence interval of a given 
frequency estimate p. 
 

 p  z1 / 2 


; p  z1 / 2 



with z1-/2  the 1–/2-quantile of the standard normal distribution (=1.96), =5% the 
 
significance level and N the sample size. The quantity 
seen as the precision of the estimate p. 
z1 / 2 
can be 
The expected sample size of N=2,000 patients will allow the following precision 
on frequency estimates p: 
Frequency 
Precision 
95% confidence 
  
p 
interval 
 
0,05 
0.0096 
[0.0404 ; 0.0596]
0,01 
0.0044 
[0.0056 ; 0.0144]
0,005 
0.0031 
[0.0019 ; 0.0081]
p(1 p)
N

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13 
Committees 
 
13.1 
European Clinical Board Committees (ECBC) 
 
In each European country involved in this study, a clinical board committee 
including physicians will take place. The missions of these committees are the 
following : 
 To animate the cohort follow-up in each country and ensure its development 
 To propose and decide on development of the action to set up. 
 
A European Clinical Board Committee charter will define more precisely the 
responsibilities of these committees. 
 
13.2 
Steering Committee (SC) 
 
A Steering Committee will comprise the physician heading each of the European 
committees previously described, the sponsor, and an independent statistician. 
The Steering Committee will oversee the conduct and reporting of the cohort 
follow-up, assuring expert clinical guidance and a high standard of scientific quality, 
reviewing all SAEs and clinical endpoints reported by the sites (i.e., initial 
diagnoses, laboratory values, results of procedures) to determine the occurrence 
of clinical issues and proposing any necessary protocol amendments to be 
submitted to the competent authorities. 
 
Members of the committee will be determined according to their skills, 
number of patients included in their center, availabilities for meeting 
and interest in participating. 

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14 
Legal framework and patient information 
 
14.1 
Legal framework 
 
As previously described, this study will be conducted to respond to EMA demand. 
It will consist in data collection and will not involve any change in the usual patient 
follow-up. Thus, patients must agree to participate (either orally, or by writing 
according to local regulations). Anyway, patients (or their legal guardians) will be 
informed orally about the study by their physician and will be given a written 
information sheet. All measures will be taken to guarantee the anonymity and the 
confidentiality of personal data. 
 
Authorisations to perform the study will be requested from each local authority as 
required in accordance with the local regulation. 
 
14.2 
Description of the patient information sheet 
 
Oral information will include objectives of the study, nature, addresses and duration 
of preservation right of the data, the conditions of access rights and of rectification 
as well as the right to opt out. These information will also be provided as a written 
note to every patient (or persons having parental authority) before  the transmission 
of any data. Date of its delivery will be reported in the data collection forms. 

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15 
References 
 
 
 
 
1 
Pearson HA et al. Functional asplenia in sickle-cell anemia. N Engl J Med. 1969; 
281:923-926. 
2 
Wigfall DR et al. Prevalence and clinical correlates of glomerulopathy in children with 
sickle cell disease. J Pediatr. 2000; 136:749-753. 
3 
Powars D et al. Sickle cell chronic lung disease: prior morbidity and the risk of 
pulmonary failure. Medicine (Baltimore). 1988; 67:66-76. 
4 
Pegelow CH et al. Longitudinal changes in brain magnetic resonance imaging  
findings in children with sickle cell disease. Blood. 2002; 99:3014-3018. 
5 
Charache S et al. Effect of hydroxyurea on the frequency of painful crisis in sickle cell 
anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N 
Engl J Med. 1995; 332:1317-1322. 
6 
Lı ´gia Barbosa Braga et al. Hemoglobin, 29 (3):171-180. (2005) 
7 
De Montalembert et al. J Pediatr Hematol Oncol. 1997; 19 (4):313-8 
8 
Maier-Redelsperger et al. Blood. 1998; 91 (12):4472-9 
9 
Platt OS et al. Mortality in sickle cell disease: life expectancy and risk fac-tors for  
early death. N Engl J Med. 1994; 330:1639-1644. 
10 Thomas AN et al. Causes of death in sickle cell disease in Jamaica. Br Med J (Clin 
Res Ed). 1982; 285:633-635. 

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Appendices 
 
Responsibilities of the Marketing Authorisation Holder 
 
In the context of the European Risk Management Plan, the Agency (EMA) requests 
to Addmedica to initiate a cohort follow-up. This cohort follow-up, a post- 
authorisation safety study, was carried out in accordance with the terms of 
marketing authorisation, and should be conducted with the aim of identifying or 
qualifying a safety hazard relating to Siklos®. 
 
Addmedica is the Marketing Authorisation Holder (MAH) of Silkos®. AnticipSanté 
is responsible on behalf of the MAH, for managing and reporting 
pharmacovigilance activities to the concerned Competent Authorities  (EMA, local 
health authority). Peter Holmes Clinical is responsible for providing and maintaining 
the electronic case report form, including serious adverse events forms. 
 
The legal framework for pharmacovigilance of medicinal products for human use 
in the European Union (EU) is given in Regulation (EC) No 726/20041 and 
Directive 2001/83/EC2 on the Community code relating to medicinal products for 
human use, as last amended by Directive 2004/24/EC3 and by Directive 
2004/27/EC4 (hereafter referred to simply as Directive 2001/83/EC). It should be 
noted that although Chapter 3 of Regulation (EC) No 726/2004 and Title IX of 
Directive 2001/83/EC contain the majority of pharmacovigilance provisions in the 
legislation, other measures directly relevant to the conduct of pharmacovigilance 
are found in other Chapters and Titles of those legislative texts. 
 
The requirements explained in these guidelines are based on the ICH guidelines, 
where these exist, but may be further specified or contain additional requests in 
line with the legislation of the EU. 
 
Responsibilities for the Conduct of Post-Authorisation Safety Studies 
 
The Marketing Authorisation Holder who initiates, manages and/or finances the 
cohort follow-up is responsible for its conduct and should meet the 
pharmacovigilance obligations concerning PASS. The study should be  supervised 
by a designated monitor(s) or monitoring organisation and the names of the 
monitors should be recorded in the study documents. In case the  Marketing 
Authorisation Holder does not directly conduct the study, detailed and clear 
contractual agreements for meeting pharmacovigilance obligations should be 
documented. 
 
The QPPV at EU level and/or, where applicable, the nominated person responsible 
for pharmacovigilance at national level, should be involved in the review of 
protocols for all post-authorisation safety studies, in order to ensure compliance 
with pharmacovigilance requirements. 
 
Reports from Organised Data Collection Systems 
 
Reporting requirements for cases derived from organised data collection systems 
(which include clinical trials, post-authorisation studies, registries, post- 
authorisation named-patient use programmes, other patient support and disease 
management  programmes,  surveys  of  Patients  or  Healthcare  Providers, and 

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information gathering on efficacy or patient compliance) differ depending on 
whether they are derived from interventional or non-interventional studies. 
 
Post-authorisation studies that are non-interventional are not covered by the 
provisions of Directive 2001/20/EC but by Directive 2001/83/EC and Regulation 
(EC) No. 726/2004 (see Annex 1.1 for the definition of a non-interventional trial). 
Serious adverse reactions arising from such studies should be reported on an 
expedited basis according to the same criteria and timelines as adverse reactions 
reported spontaneously by Healthcare Professionals (see Chapter I.4, Section 1); 
this includes any suspected transmission via a medicinal product of an infectious 
agent. For an overview on the expedited reporting requirements in Member States, 
see Annexes 6.1.1, 6.1.2 and 6.1.3. All adverse reactions, i.e. also non- serious 
ones, should be included in the final study report. For reporting of adverse 
reactions in the Periodic Safety Update Reports (PSURs), see   Chapter 
I.6. For further information on post-authorisation safety studies see Chapter I.7. 
 
Reporting of Adverse Reactions 
 
For non-interventional post-authorisation safety studies, conducted inside and 
outside the EU, the usual regulatory requirements for reporting of adverse 
reactions should be fulfilled. 
 
This means that : 
 Reports of all serious adverse reactions arising from such studies within the EU 
should be reported on an expedited basis (i.e. within 15 days), to the Competent 
Authority of the Member State on whose territory the incident occurred, and in 
addition, for products authorised through the mutual recognition or 
decentralised procedures and for products which have been the subject of a 
referral procedure, to the Reference Member State. These reports should also 
be included in the PSURs 
 Reports of all unexpected serious adverse reactions arising from such studies 
outside the EU should be reported on an expedited basis to the Agency and to 
all Member States where the medicinal product is authorised. These reports 
should also be included in the PSURs 
 Reports on expected serious occurring outside the EU should be reported in 6 
on PSURs; all adverse reactions/events including those which are considered 
non-serious, should be summarized in the final study report in frequency tables. 
 
Marketing Authorisation Holders should ensure that they are notified by the 
physician of serious adverse reactions and, if specified in the study protocol, of 
events (those not suspected by the physician or the Marketing Authorisation Holder 
to be adverse reactions).