Clinical trial NCT03806452
Conditions: Sickle Cell Disease
Keywords: albuminuria hydroxycarbamide
Sponsor: Theravia
Start date: 2019-05-28; Completion date: 2024-05-30
Enrollment: 86 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this phase IIb, international, multicentre, double-blind, randomised, placebo-controlled study is to determine the effect of hydroxycarbamide on albuminuria after 6 months of treatment in SCD adult patients.

Detailed description:

Arms: arm 1: Hydroxycarbamide will be supplied as 100 mg or 1000 mg film-coated tablets. The posology will be based on the patient's body weight (bw). Hydroxycarbamide will be prescribed at a dose of 15 mg/kg bw/day and will be adminitered for 6 months.

Hydroxycarbamide will be administered for 12 months for patients qualified as responders willing to continue to participate in the trial. arm 2: Placebo will be supplied as 100 mg or 1000 mg film-coated tablets. The posology will be based on the patient's body weight (bw). Placebo will be prescribed at a dose of 15 mg/kg bw/day and will be adminitered for 6 months.

Hydroxycarbamide will be administered for 12 months for patients qualified as responders willing to continue to participate in the trial.
Interventions: intervention 1: Hydroxycarbamide intervention 2: Placebo Oral Tablet
Intervention descriptions: intervention 1: Hydroxycarbamide tablets of 100 and 1000 mg intervention 2: Placebo tablets of 100 and 1000 mg to mimic hydroxycarbamide tablets

Protocol documents:
Prot_SAP_000.pdf: 
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STUDY PROTOCOL 
Multicentre randomized double-blind placebo-controlled study to 
evaluate the effect on albuminuria of 6 months treatment with 
hydroxycarbamide (Siklos®) or a placebo in adults with sickle cell 
disease: 
SIKAMIC (SIklos on Kidney function and AlbuMInuria Clinical 
trial) 
 
 
 
Protocol number 
SIK-FR-17-1 
EUDRACT number 
2018-002899-41 
Protocol date 
 22 December 2022 
Protocol version 
Protocol Amendment 7 Version 1.0 
Investigational product 
name 
Siklos® (hydroxycarbamide) 
100 mg or 1000 mg film-coated tablets 
Indication 
Sickle Cell Disease 
Sponsor 
ADDMEDICA S.A.S. 
16 rue Montrosier 
92200 Neuilly-sur-Seine, France 
Tel.: +33 (0)1 72 69 01 86 
http://www.addmedica.com 
Sponsor Signatory 
Laura THOMAS-BOURGNEUF, Clinical Operations 
Manager 
 
 
Coordinating Investigator 
Professor Pablo BARTOLUCCI 
Centre de Référence des Syndromes Drépanocytaires 
Majeurs, Hôpital Henri-Mondor, APHP, Université 
Paris-Est Créteil 
51, avenue du Mal-de-Lattre-de-Tassigny  
94010 Créteil Cedex, France  
 
 
 
CONFIDENTIAL: This document is property of ADDMEDICA S.A.S. and contains 
confidential information. It may not be forwarded to third parties without explicit written prior 
consent from ADDMEDICA S.A.S. Reproductions, either in part or in whole, may not be 
published or copied in any manner, without the explicit written consent of ADDMEDICA 
S.A.S. 
 


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STUDY ADMINISTRATIVE STRUCTURE 
Role/Responsibility 
Company/Organisation 
Name(s) 
Sponsor 
ADDMEDICA S.A.S. 
16, rue Montrosier 
92200 Neuilly-sur-Seine, France 
Tel.: +33 (0) 172 690 186 
http://www.addmedica.com 
 
Sponsor Signatory 
ADDMEDICA S.A.S. 
16, rue Montrosier 
92200 Neuilly-sur-Seine, France 
Tel.: +33 (0) 172 690 186 
http://www.addmedica.com 
Laura THOMAS-BOURGNEUF 
Tel.: +33 (0) 172 690 186 
Fax.: +33 (0) 173 729 413 
laura.thomas-
bourgneuf@addmedica.com 
Project Management & 
Monitoring 
ICTA PM  
11 rue du Bocage 
21121 FONTAINE LES DIJON 
 FRANCE 
Tel : +33 (0) 380 534 000 
www.icta.fr 
Marion DAVID 
Tel : +33 (0) 380 534 000 
marion.david@icta.fr 
 
IMP labelling and 
packaging 
Creapharm 
Allée des Landais CS10034  
51726 Reims Cedex - France   
Mobile : +33 (0) 620 569 360 
 
Pharmacovigilance 
ADDMEDICA 
pv@addmedica.com  
16, rue Montrosier 
92200 Neuilly-sur-Seine, France 
Tel:   +33 (0) 172 690 186 
http://www.addmedica.com  
 
 
 
Data Management 
ICTA PM 
11 rue du Bocage 
21121 Fontaine les Dijon, France 
Tel: +33 (0) 380 534 000 
http://www.icta.fr/ 
 
Marie-Céline TRIPONNEY 
Tel : +33 (0) 380 534 000 
marie-celine.triponneyt@icta.fr 
 
Biostatistics 
ICTA PM 
11 rue du Bocage 
21121 Fontaine les Dijon, France 
Tel: +33 (0) 380 534 000 
http://www.icta.fr/ 
 
Edwige YON 
Tel : +33 (0) 380 534 000 
edwige.yon@icta.fr 
 
 
Medical Writing 
ICTA PM 
11 rue du Bocage 
21121 Fontaine les Dijon, France 
Tel: +33 (0)3 80 53 40 00 
http://www.icta.fr/ 
Maria 
GACKIERE 
KATSOGIANNOU  
Tel : +33 (0) 380 534 070 
Maria.GACKIERE@icta.fr 
 


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Academic Scientific 
Expert 
Professor Vincent Audard 
Centre de Référence Syndrome Néphrotique Idiopathique 
Hôpital Henri-Mondor, APHP, Université Paris-Est Créteil 
51 avenue du Maréchal de Lattre de Tassigny  
94000 Créteil 
 
Independent Data 
Monitoring Committee 
• 
Ms Claire RIGOTHIER, MD, nephrologist, RPPS number : 
10004628623, groupe hospitalier Pellegrin place Amelie Raba Leon 
33076 Bordeaux cedex, France 
• 
Mr Jean-Philippe HAYMANN, MD, nephrologist, RPPS number 
10000562909, HU Est parisien site Tenon, AP-HP, service 
d'explorations fonctionnelles, 4 rue de la Chine, 75970 paris cedex 
20, France 
• 
Ms Françoise DRISS, MD, RPPS number 10000222819, Hôpital 
Bicêtre, service d'hématologie, 78, rue du Général Leclerc, 94275 
Le Kremlin-Bicêtre Cedex, France 
• 
Mr Eric GUEMAS, biostatistician co-founder & CEO at Biossec, 9-
11 rue Anatole de la Forge, 75017 Paris, France 
 
 
 
 
 


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PROTOCOL SPONSOR SIGNATURE PAGE 
Multicentre randomized double-blind placebo-controlled study to 
evaluate the effect on albuminuria of 6 months treatment with 
hydroxycarbamide (Siklos®) or a placebo in adults with sickle cell 
disease : 
SIKAMIC (SIklos on Kidney function and AlbuMInuria Clinical 
trial) 
 
 
 
Protocol number 
SIK-FR-17-1 
EUDRACT number 
 
2018-002899-41 
Protocol date 
22 December 2022 
 
Sponsor 
ADDMEDICA S.A.S. 
16, rue Montrosier 
92200 Neuilly-sur-Seine, France 
 
Sponsor signatory 
Laura THOMAS-BOURGNEUF, Clinical Operations Manager 
 
 
 
 
 
Date  
Signature 
 
 


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PROTOCOL COORDINATING INVESTIGATOR AND 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
Multicentre randomized double-blind placebo-controlled study to 
evaluate the effect on albuminuria of 6 months treatment with 
hydroxycarbamide (Siklos®) or a placebo in adults with sickle cell 
disease : 
SIKAMIC (SIklos on Kidney function and AlbuMInuria Clinical 
trial) 
 
 
 
Protocol Number 
SIK-FR-17-1 
EUDRACT Number 
 
2018-002899-41 
Protocol Date 
22 December 2022 
 
I certify that I will conduct the study in compliance with the protocol, any amendments, 
GCP and all applicable regulatory requirements. 
 
Coordinating Investigator 
Name: Professor Pablo BARTOLUCCI 
Institution:  Centre de Référence des Syndromes Drépanocytaires Majeurs,  
Hôpital Henri-Mondor, APHP, Université Paris-Est Créteil 
51, avenue du Mal-de-Lattre-de-Tassigny  
94010 Créteil Cedex, France  
 
Date  
Signature 
 
 
Principal Investigator 
Name: 
 
Date  
Signature 
 
 


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SYNOPSIS 
Study rationale: 
Sickle cell disease (SCD) is associated with a high frequency of 
chronic kidney disease (CKD), which constitutes an independent risk 
factor for death in this population. In term of epidemiology SCD-
associated nephropathy (SCAN) is a growing matter of concern 
because chronic renal failure affects from 12% to 16% of adult patients 
[1-3]. In elderly patients, renal failure is a major contributor to death 
[4, 5]. Thus, the early diagnosis of SCAN together with the recognition 
of the associated clinical and biologic risk factors are of major interest 
to make it possible to initiate kidney-protective therapy at early stages 
of renal impairment. SCAN is a progressive condition that begins 
during childhood. Acidic, hypertonic and hypoxic intrinsic 
environment of the renal medulla enables HbS polymerisation and 
erythrocyte sickling within the vasa recta – the capillary networks that 
supply blood to the medulla. Erythrocytes sickling leads to occlusion 
of the blood vessels with impairment of blood flow, ischaemia, and 
infarction of the tubular cells. The ischaemic damage results, in turn, 
in release of vasodilating substances such as prostaglandins and nitric 
oxide, which feed back to the glomerulus and tend to increase the 
glomerular filtration rate. Albuminuria is considered to be a relevant 
biomarker for the detection of early glomerular damage in patients with 
sickle cell disease (SCD). A broad spectrum of glomerular diseases has 
been described in SCD patients, with elevated albuminuria, isolated 
glomerular enlargement and focal segmental glomerulosclerosis 
(FSGS) being the most frequent lesions [6]. As observed in diabetic 
nephropathy, prolonged hyperfiltration firstly observed in SCD 
probably contribute to progressive renal damage and development of 
proteinuria. Hyperfiltration and proteinuria are two major causes of 
subsequent glomerulosclerosis and reduction in kidney function [6-8]. 
In this first trial we suggest to evaluate the effect of hydroxycarbamide 
(Siklos®) on albuminuria. 
 
Rational for controlled trial versus placebo 
As yet, there is no definitively proven treatment that slows the 
progression of glomerular damage in SCD patients. Few therapeutic 
options are available for the treatment of SCAN. Some authors 
recommend the use of usual renal protective measures, including renin–
angiotensin-system inhibitors (RAS inhibitors) (angiotensin-converting 
enzyme (ACE) inhibitor and angiotensin II-receptor blocker (ARB)) to 
reduce the degree of proteinuria and to slow the decline in renal 
function, although there are no published guidelines in this population 
on when to introduce this form of therapy [9, 10] . 
Regardless of underlying renal disease, proteinuria has been known for 
many years to be associated with rapid progression of chronic kidney 
disease, and reducing this proteinuria with RAS inhibitors is a key 
factor to delay glomerular filtration rate (GFR) deterioration in patients 
with either diabetic or non-diabetic proteinuric renal disease [11]. 
Several studies in SCD patients have reported possible clinical benefit 
of these drugs on renal function but generally with small series and short 
follow-up time. Falk et al (1992) [1] first showed in 10 SCD patients 
that 2 weeks of enalapril led to a 57% decrease in proteinuria that 
rebounded after treatment discontinuation. Other authors also found 
that proteinuria was reduced by 43.3–76.3% in 5 out of 7 SCD patients 
treated with fosinopril (10 mg daily) for 6 months [12]. These results 


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are supported by a 6-month placebo-controlled study on 22 SCD 
patients, which indicated that captopril significantly reduces 
microalbuminuria and diastolic blood pressure [13]. A recent phase 2 
open label study including 32 participants found that administration of 
an angiotensin-II-receptor-1 blocker during 6 months significantly 
decreased albuminuria (albumin-to-creatinine ratio) level [14]. In a 
prospective multicentric non-randomized trial including 42 SCD 
patients, Haymann et al showed that ACE inhibitors appears safe and 
effective in decreasing albuminuria [15]. Nevertheless, to date, no 
randomized, prospective clinical trials with adequate sample size have 
clearly demonstrated the potential benefit of RAS inhibitors, and their 
tolerance among SCD patients. 
 
Hydroxycarbamide is one of the cornerstone treatments for the 
management of SCD patients and its efficacy is generally attributed to 
its ability to boost the levels of fetal Hb (HbF) [16]. Hydroxycarbamide 
is known to decrease the frequency of acute pain episodes and acute 
chest syndrome (ACS), the need for red blood cell transfusions, and the 
number of hospitalisations. Siklos® is approved since 2007 in the 
European Union (EU) for the prevention of recurrent painful VOC, 
including acute ACS, in adult, adolescent and children older than 2 
years old suffering from SCD and since 2017 in the United States of 
America (USA) to reduce the frequency of painful crises and the need 
for blood transfusions in pediatric patients from 2 years of age and older 
with sickle cell anemia with recurrent moderate to severe painful crises. 
Several observational studies conducted in adult SCD patients have 
shown that hydroxycarbamide has possible protective renal effects and 
may be considered as a promising therapeutic option [17, 18]. 
 
Rational for the choice of endpoints: 
Proteinuria begins as microalbuminuria, and progresses to overt 
macroalbuminuria and nephrotic syndrome, which reflects the 
worsening of glomerular damage. Microalbuminuria is most often the 
first clinical indicator of glomerular damage in SCD [8]. According to 
KDIGO (Kidney Disease: Improving Global Outcomes) Guideline 
2013, microalbuminuria also known as moderately increased 
albuminuria refers to a situation where urine albumin-to-creatinine ratio 
(ACR) ranges from 3−30 mg/mmol [19]. Macroalbuminuria also 
known as severely increased albuminuria refers to a situation where 
ACR ranges from 30 to 300 mg/mmol. 
The GFR is usually reported as primary endpoint in renal disease 
however due to the changes of GFR at the beginning of the renal 
impairment with hyperfiltration, the ACR ratio will be more accurate as 
primary endpoint. In this study, eGFR will be analysed as a secondary 
endpoint. Arlet et al (2012) showed that glomerular hyperfiltration, is a 
frequent finding observed, which is frequently associated with 
microalbuminuria or macroalbuminuria [20]. In the study of Arlet et al 
in non-Afro-American SCD patients, the best method for estimating 
eGFR from serum creatinine seems to be the CKD-EPI equation 
without adjustment for ethnicity. This equation is particularly accurate 
to estimate high GFR values, including glomerular hyperfiltration, and 
thus should be recommended to screen SCD adult patients at high risk 
for SCD nephropathy. 
 
 
 


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Choice of targeted population 
Renal impairment is common to any clinical phenotypes of SCD 
however, hemolytic phenotype seems more exposed [21]. Because 
severe patients with vaso-occlusive phenotype have less renal injuries 
and are already treated with hydroxycarbamide (HC), they will be 
excluded from the study.  
Clinical guidelines recommend the prescription of renin angiotensin 
system inhibitors (RAS inhibitors) (either ACE inhibitors or 
angiotensin 
receptor 
blockers 
[ARBs]) 
only 
in 
case 
of 
macroalbuminuria with ACR ≥ 100 mg/mmol. Hence patients with 
ACR ≥ 100 mg/mmol will be excluded from the study.   
Variations in GFR in SCD at early stages of kidney injury are not fully 
understood, although the occurrence of hyperfiltration with an 
increased GFR and concomitant microalbuminuria is likely the first 
sign of renal impairment. A recent study presented at the last American 
Society of Hematology meeting by Biemond et al. demonstrated a clear 
correlation between the long-term subclinical renal function 
deterioration and microalbuminuria in 167 SC patients [22]. However, 
as clinical relevance of a decrease in GFR in hyperfiltrating patients is 
not ascertained in the current state of knowledge, patients with renal 
hyperfiltration will not be included in the study. 
 
Rational for the duration of study 
A retrospective study of Bartolucci et al. suggested that  
HU administered for 6 consecutive months without concomitant use of 
RAS inhibitors could significantly decrease urine albumin/creatinine 
ratio (ACR) [17]. This timepoint has been chosen in the SIKAMIC trial 
to assess the efficacy of hydroxycarbamide (Siklos®) in achieving at 
least a 30% decrease of ACR. Only patients qualified as responders 
after 6 months of treatment will be offered to continue to receive the 
study treatment and their follow-up will be extended to 6 additional 
months. 
 
The purpose of this phase IIb, international (France and Africa), 
multicentre, double-blind, randomised, placebo-controlled study is to 
determine the effect of hydroxycarbamide on albuminuria after 6 
months of treatment in SCD adult patients. A 6 months study will allow 
to better document the natural history of the SCAN and to assess the 
response to Siklos® in this population. 
Objectives: 
Primary objective 
The primary objective of this trial is to demonstrate the effect of 6-
month treatment with hydroxycarbamide (Siklos®) against placebo in 
achieving at least a 30% decrease of the albuminuria (albumin to 
creatinine ratio; ACR) baseline value in adult sickle cell patients.  
Secondary objectives 
• 
To compare the estimated GFR (eGFR) according to CKD-
EPI formula* between hydroxycarbamide (Siklos®) and 
placebo group at 6 months.   
• 
To compare the proportion of patients in hydroxycarbamide 
versus placebo group with an improvement in the 
albmuminuria stage, i.e. a shift from grade A3 to grade A2 
albuminuria (macro- to microalbuminuria), from grade A2 to 
grade A1 albuminuria (micro- to normoalbuminuria) or from 
grade 
A3 
to 
grade 
A1 
albuminuria 
(macro- 
to 


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normoalbuminuria), according to the KDIGO staging system 
at 6 months. 
• 
To compare the proportion of patients in hydroxycarbamide 
versus placebo group with a renal disease progression 
supported by an increase in albuminuria at 6 months, as 
compared to baseline. 
• 
To identify some clinical and biological markers potentially 
associated with response to treatment. 
• 
To describe the evolution of ACR from inclusion to month 6.  
• 
To describe the evolution of eGFR from inclusion to month 6. 
• 
To describe the evolution of ACR of responder patients from 
inclusion to month 12.  
• 
To describe the evolution of eGFR of responder patients from 
inclusion to month 12. 
• 
To evaluate the safety of hydroxycarbamide throughout the 
entire study period. 
• 
To evaluate the impact of the study treatment on SCD-related 
events throughout the entire study period. 
Optional exploratory objective 
• 
To identify any biomarker predictive of SCN (BIOBANK). 
 
*eGFR (millilitres per minute per 1.73 m2) = 141 × min (Scr/k,1)α × max(Scr/k,1)-1.209 × 
0.993Age × 1.018 (for women), where Scr is serum creatinine, k is 0.7 for women and 0.9 
for men, α is -0.329 for women and -0.411 for men, min indicates the minimum of Scr/k 
or 1, and max indicates the maximum of Scr/k or 1.  
Study design/assessments: 
Study design: Phase-IIb, prospective, two-armed, parallel-design, 
international, multicentric, randomized, double blind, placebo-
controlled trial in adult patients with HbSS or HbSβ0 SCD and ACR 
between 3 to 100 mg/mmol. The patients will be recruited in France and 
in Africa. After having given written informed consent (ICF), they will 
be 
examined 
to 
determine 
their 
eligibility 
according 
to 
inclusion/exclusion criteria. The eligible patients will be randomised to 
receive in a 1:1 ratio: 
• Hydroxycarbamide (Siklos®) (hydroxycarbamide group) 
• Placebo (placebo group) 
Randomization will be stratified according to ACR baseline value:  
• 
]3-30 mg/mmol] microalbuminuria  
• 
or ]30-100 mg/mmol[ macroalbuminuria.  
Treatment will be administered for 6 consecutive months. Patients 
qualified as ‘responders’ after 6 months of treatment will be offered to 
continue the study treatment and their follow-up will be extended to 6 
additional months. 
Study assessments:  
Study assessments will be performed from screening to end-of-study 
visit (V4 – Month 6 for non-responders, V6 -Month 12 for responders 
willing to continue the study) or early termination visit in case of 
deterioration of renal function. Patients will attend a total of 4 to 6 visits 
at the clinic centre. An overview of the study visits and procedures is 
presented hereafter and in the flowchart. 
Assessment of renal function: 
• For ACR calculation, urine albumin and urine creatinine will be 
assessed on first-morning urine samples collected on 3 consecutive 


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days at V2 (inclusion) and V4 (Month 6). This assessment will also 
be performed at V6 (Month 12), for patients qualified as 
‘responders’ willing to continue the study. Patients will receive a 
prescription for urine analysis at V1 (screening), V3 and V5 (for 
responder patients willing to continue). They will be asked to collect 
at home first morning urine samples (between 6.30 and 8.30 a.m.) 
in polyethylene containers on 3 consecutive days. Urine samples 
will be stored at room temperature  and the patient will be asked to 
bring the sample to a local lab of his/her choice or to the 
investigator’s site every day or the 3 samples on the third day at the 
most convenient for the patient 
• Intermediate analysis of urine albumin and urine creatinine to 
evaluate ACR will be assessed on one first-morning urine sample at 
V3 (Month 3) and at V5 (Month 9, for responder patients willing to 
continue) in order to identify an effect before 6 months of the 
treatment and to check the sustainability of the effect after 6 months 
for responder patients (dynamics of the response). 
• eGFR will be assessed at V1 (screening), V3 (Month 3) and V4 
(Month 6). Additional eGFR measurements will be performed atV5 
(Month 9) and V6 (Month 12) for patients qualified as ‘responders’ 
willing to continue the study. The CKD-EPI method of calculation 
will be used. eGFR calculation will be automated in the eCRF, 
based on serum creatinine level, age and sex. 
Assessment of vital signs and adverse events:  
• Physical examination and blood pressure measurements will be 
performed at each visit.  
• SCD-related adverse events will be recorded at each visit.  
Assessment of haematological and biochemical parameters: 
• Blood samples for haematology will be collected at V1 (screening), 
Month 1, V3 (Month 3) and V4 (Month 6). Additional blood 
samples will be collected at V5 (Month 9) and V6 (Month 12) for 
patients qualified as ‘responders’ willing to continue the study. 
Blood samples for creatinine, and haemolysis markers will be 
collected at V1 (screening), V3 (Month 3) and V4 (Month 6).  
Additional blood samples will be collected at V5 (Month 9) and V6 
(Month 12) for patients qualified as ‘responders’ willing to continue 
the study.  
 
 


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FLOW CHART OF STUDY VISITS AND ASSESSMENTS 
 
 
 
 
Pre-treatment 
phase 
Treatment phase 
 
Screenin
g 
 
Inclusion 
(Random
isation) 
Follow-
up visit 
Follow-
up or 
End of 
study 
visit1 
Follow-
up Visit2  
Follow-
up Visit2 
 
End of 
study/  
Early 
termination 
Visit number 
V1 
V2 
V3 
V4 
V5 
V6 
 
Schedule (month/day) 
D-30 - 
D0 
D0 
M3 
D90±14 
M6 
D182±14 
M9 
D273±14 
M12 
D365±14 
 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
Randomisation 
 
X 
 
 
 
 
 
Demographic information 
X 
 
 
 
 
 
 
Medical and surgical history 
X 
 
 
 
 
 
 
Previous medication(s)3 
X 
 
 
 
 
 
 
Concomitant medication(s) (CM) 
X 
X 
X 
X 
X 
X 
X 
Physical examination and blood pressure 
X 
X 
X 
X 
X 
X 
X 
Semen cryopreservation4  
X 
 
 
 
 
 
 
Haematology5 
Blood sampling 
Results 
Prescription6 
Biobank blood sample7 
 
X 
 
 
X 
 
 
X 
X 
 
 
X 
X 
 
 
 
X 
X 
 
X 
 
X 
X 
 
 
 
X 
X 
 
X 
 
X 
X 
 
X 
Biochemistry8 
Blood sampling    
Results 
 
X 
 
 
 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
Screening for HIV, HBV, HCV 
Blood sampling 
Results 
 
X 
 
 
 
X 
 
 
 
 
 
Pregnancy test9 for women 
Blood sampling 
Result 
 
X 
 
 
 
X 
 
 
 
 
 
Check of contraceptive use 
X 
X 
X 
X 
X 
X 
X 
Urine analysis : 
 
 
 
 
 
 
 
prescription and a collection kit for urine 
analysis 
X10 
 
X10 
 
X10 
 
 
ECBU and  Hematuria during 3 
consecutive days 
X10 
 
 
X10 
 
X10 
X10 
Urine albumine and urine creatinine for 
ACR during 3 consecutive days 
X10 
 
 
X10 
 
X10 
X10 
Results 
 
X11 
 
X12 
 
X12 
X 


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ACR: Albumin-to-Creatinine Ratio; AE: Adverse Event; CM: Concomitant Medication; D: Day; HBV: 
Hepatitis B Virus; HCV: Hepatitis C Virus; HIV: Human Immunodeficiency Virus; M: Month; SCD: 
Sickle Cell Disease; V: Visit. 
1For unresponsive patients or responsive patients unwilling to continue the study, this visit will be the End of 
study visit. 
2Additional visits only for patients qualified as responders and willing to continue the study. 
3Previous blood transfusions and previous administration of hydroxycarbamide will be reported. 
4Not required if semen cryopreservation was already performed in the past. If semen volume or viable sperm 
cell amount is insufficient for cryopreservation of the collected sample, a spermogram will be performed and 
conserved in CECOS during the whole duration of the study. A control spermogram could be performed in 
patients at least 6 months and at most 9 months after the last dose of treatment. 
5The following assessments will be performed: WBC and differential counts, platelets, MCV, MCHC, MCH, 
Hb, HbF, free Hb, %DRBCs, reticulocytes, endogenous EPO, and ferritin 
6At V2, prescription will be given for hematology assessment in local lab 1 month after treatment initiation. 
7Optional exploratory biobank: blood and urine samples for patients from French sites only. 
8The following assessments will be performed: LDH, AST, ALT, BUN, conjugated and total bilirubin and 
blood creatinine for glomerular filtration rate (GFR) calculation. The CKD-EPI formula will be used for 
eGFR calculation. In addition, fasting glycemia and glycated haemoglobin (HbA1c) may be assessed before 
V2 upon investigator decision.  
eGFR (millilitres per minute per 1.73 m2) = 141 × min (Scr/k,1)α × max(Scr/k,1)-1.209 × 0.993Age × 1.018 (for 
women), where Scr is serum creatinine, k is 0.7 for women and 0.9 for men, α is -0.329 for women and -
0.411 for men, min indicates the minimum of Scr/k or 1, and max indicates the maximum of Scr/k or 1. eGRF 
calculation will be automated in the eCRF, based on serum creatinine level, age and sex. 
9Pregnancy tests will be performed on blood. 
10At V1 and V3 for all patients, and at V5 for patients qualified as responders and willing to continue the 
study: patients will receive a prescription and a collection kit for urine analysis. First morning urine samples 
will be collected between 6. 30 and 8. 30 a.m. during 3 consecutive days before V2 and V4 for all patients, 
and before V6 for patients qualified as responders willing to continue the study. Assessments of hematuria, 
CBEU, urine albumin and urine creatinine for ACR evaluation will be performed at a local lab or at 
investigator’s site. 
11At V2, ACR result will be reported in the CRF and used for randomization. 
12In case of ACR≥100 mg/mmol, a local assessment of ACR will be performed one month later to confirm 
ACR result. Patients will receive a prescription and a collection kit for local ACR assessment on first morning 
urine samples collected during 3 consecutive days. 
13This study is double-blinded. 
14Only for patients qualified as responders and willing to continue the study.  
Intermediate local analysis of urine 
albumin and urine creatinine for ACR on 
one day 
 
 
 X 
 
 X 
 
 
Biobank blood and urine sample7 
X 
 
 
X 
 
X 
X 
Dispensation of study treatment13 
 
X 
X 
X14 
X14 
 
 
Compliance to study treatment 
 
 
X 
X 
X 
X 
X 
Assessment of AEs 
 
X 
X 
X 
X 
X 
X 
Diary cards (reporting of drug 
intake/AE/CM/SCD events) 
 
 
 
 
 
 
 
- Dispensing 
 
X 
X 
X 
X 
 
 
- Collection/review 
 
 
X 
X 
X 
X 
X 
Study duration: 
Each patient will be enrolled in the study for a duration of 6 months, 
during which he/she will be taking the placebo or the study treatment 
(i.e. hydroxycarbamide (Siklos®) on a daily basis). Patients qualified 
as responders (patient achieving at least a 30% decrease of the ACR 


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baseline at 6 months )willing to continue the study will continue the 
study for 6 additional months (total duration of 12 months) 
Duration of inclusion period: 49 months 
Total duration of the study: 61 months 
Patient withdrawal decision can araise from the patient himself, the 
investigator or the IDMC. Patients have the right to withdraw their 
consent at any time and irrespective of the reason. The Investigator has 
also the right to withdraw patients from the study for the following 
reasons (including but not limited to):  
- 
Patients transfused more than twice during the study, 
- 
Patients’ inadequate cooperation and compliance with the 
protocol, 
- 
Any life-threatening AE assessed by the Investigator to be 
related to study procedure or administration of study 
treatment, 
- 
Patients experiencing at least 3 VOC or 1 ACS during the 
study, 
- 
Patients with an increase in ACR requiring, upon 
investigator’s judgement, a treatment with ACE or ARA2, 
- 
Development 
of 
an 
intercurrent 
illness 
requiring 
hospitalisation or surgery, 
- 
Loss to follow-up. 
The IDMC stopping rules are defined in the IDMC charter. 
Investigational product – Siklos 
(hydroxycarbamide): 
Formulation: Hydroxycarbamide (Siklos®) will be supplied as 
100 mg or 1000 mg film-coated tablets. Excipients are sodium stearyl 
fumarate, silicified microcrystalline cellulose and basic butylated 
methacrylate copolymer. 
Administration: The posology will be based on the patient’s body 
weight (bw). Hydroxycarbamide (Siklos®) will be prescribed at a dose 
of 15 mg/kg bw/day. The tablet(s) will be taken orally once daily, 
preferably in the morning before breakfast. 
In case of toxicity at 15 mg/kg bw/day, hydroxycarbamide (Siklos®) 
will be temporarily interrupted and/or decreased to 12.5 mg/kg bw/day 
or 10 mg/kg bw/day before excluding the patient for safety issue.  
Storage: below 30°C. 
Reference product (placebo): 
Formulation: Placebo tablets (each containing sodium stearyl 
fumarate, sodium starch glycolate (type A), silicified microcrystalline 
cellulose and basic butylated methacrylate copolymer) will be 
formulated to be identical in appearance to Siklos®. 
Administration: The tablet will be taken orally once daily, preferably 
in the morning before breakfast. 
In case of toxicity at 15 mg/kg bw/day, placebo will be temporarily 
interrupted 
and/or 
decreased 
to 
12.5 mg/kg bw/day 
or 
10 mg/kg bw/day before excluding the patient for safety issue.  
Storage: below 30°C. 
Number of patients: 
96 patients (48 patients for each study group) in approximately 30 
centres in France (32 patients) and 4 centres in Africa (64 patients).  


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Study population: 
Adult men and women with HbSS or HbSβ0 SCD and a value of 
albuminuria ACR over 3 mg/mmol and inferior to 100 mg/mmol 
confirmed by 3 positive urine samples taken one day apart. 
Main inclusion criteria: 
Inclusion criteria 
Patients must meet all the following inclusion criteria to participate in 
the study:  
1. Signed and dated Informed Consent Form (ICF) by a legally 
competent patient. 
2. Patients above 18 years. 
3. Patients with HbSS or HbSβ0 SCD.  
4. Patients with a value of albuminuria, assessed by ACR, over 3 
mg/mmol and inferior to 100 mg/mmol confirmed by 3 
positive urine samples taken one day apart. 
5. Female patients of childbearing potential or postmenopausal 
female with last period < 12 months before screening agreeing 
to use a highly effective form of contraception (oral, injected 
or implanted hormonal contraception, intrauterine device, 
diaphragm, condom, abstinence) during the trial and for 3 
months after hydroxycarbamide discontinuation. 
6. Male patients with partners of childbearing potential agreeing 
to use a highly effective contraception during the trial and for 
3 months after hydroxycarbamide discontinuation. Men with 
pregnant or lactating women should be advised to use a barrier 
method of contraception (condom) to prevent the foetus or 
breastfed infant from exposure to hydroxycarbamide. 
7. Patients who are covered by insurance scheme according to 
local regulatory requierements  
Main exclusion criteria: 
Exclusion criteria 
1. Patients who had severe VOC requiring hospitalisation or 
ACS within the last 4 weeks preceding screening visit. 
2. Patients treated with hydroxycarbamide for any reason within 
the previous 6 months. 
3. Patients who have had chronic blood transfusion or transfusion 
in the last 3 months. 
4. Patients with a history of hypertension (systolic blood pressure 
≥ 140 or diastolic blood pressure ≥ 90 mmHg) treated with 
antihypertensive agent belonging to pharmacological class of 
RAS inhibitor. 
5. Patients who have symptoms suggestive of urinary tract 
infection or patients with gross haematuria. 
6. Patients with a concomitant primary kidney disease. 
7. Patients with any systemic condition that could result in a 
glomerulopathy not related to SCD (e.g. diabetes mellitus, 
active hepatitis B or C infections, HIV infection, systemic 
lupus erythematosus, inflammatory arthropathies). 
8. Patient with a stage 3, 4 or 5 chronic kidney disease (eGFR 
< 60 mL/min per 1.73 m2). 


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9. Patients with eGFR ≥ 140 ml/min/1,73m² due to the lack of 
information 
regarding 
the 
magnitude, 
direction 
and 
significance of the trends in eGFR evolution that could be 
expected in this population  
10. Patients requiring long-term treatment with drugs potentially 
nephrotoxic (see non-exhaustive list). 
11. Patients requiring ACE inhibitors or ARBs within the 
3 months before inclusion regardless of the indication. 
12. Patients requiring long-term treatment with non-steroid anti-
inflammatory drugs. 
13. Patients who have a treatment which can modify the kidney 
function (see non-exhaustive list) in the last 3 months. 
14. Patients known to be infected with HIV. 
15. Female patients who are pregnant or lactating. 
16. Unreliable patients including non-compliant patients, patients 
with known alcoholism or drug abuse or with a history of a 
serious psychiatric disorder as well as patients unwilling to 
give informed consent or to abide by the requirements of the 
protocol. 
17. Simultaneous participation in other clinical trials on an 
investigational medicinal product or previous participation 
within 30 days before inclusion. 
18. Persons in detention by judicial or administrative decision. 
19. Patients with chronic conditions that upon investigator 
judgment may lead to a limited life expectancy. 
Evaluation criteria: 
Primary endpoint - Efficacy 
• 
The primary endpoint of this study is the proportion of patients 
in the hydroxycarbamide and placebo groups achieving at least 
a 30% decrease in ACR baseline value at 6 months after 
treatment initiation. Patients who do not achieve a 30% 
decrease of the ACR baseline value at month 6 will be 
considered non-responders. Requirement for therapeutic 
change from HU to ACE or ARB inhibitors will be considered 
as a failure.  
Secondary endpoints - Efficacy 
• 
The absolute mean change from baseline in eGFR in the 
hydroxycarbamide and placebo groups at 6 months after 
treatment initiation. 
• 
The absolute mean change from baseline in ACR in the 
hydroxycarbamide and placebo groups at 6 months after 
treatment initiation. 
• 
The proportion of patients with an improvement in the 
albmuminuria stage according to the KDIGO staging system: 
- 
Proportion of patients with a shift from grade A3 to 
grade A2 albuminuria (macro- to microalbuminuria) 
at 6 months 


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- 
Proportion of patients with a shift from grade A2 to 
grade A1 albuminuria (micro- to normoalbuminuria) 
at 6 months  
- 
Proportion of patients with a shift from grade A3 to 
grade A1 albuminuria (macro- to normoalbuminuria) 
at 6 months. 
• 
The proportion of patients progressing from microalbuminuria 
to macroalbuminuria in the hydroxycarbamide and placebo 
groups at 6 months after treatment initiation. 
• 
Evolution curve of ACR of the hydroxycarbamide and placebo 
groups from treatment initiation to month 6. 
• 
Evolution curve of eGFR of the hydroxycarbamide and 
placebo groups from treatment initiation to month 6. 
• 
Evolution curve of ACR of responder patients willing to 
continue the study after 6 months, from treatment initiation to 
month 12. 
• 
Evolution curve of eGFR of responder patients willing to 
continue the study after 6 months, from treatment initiation to 
month 12. 
• 
The identification of clinical and biological markers associated 
with response to treatment. 
 
Secondary endpoints – Safety 
• 
The incidence of treatment-emergent AEs and SAEs at each 
timepoint. 
• 
The baseline values and the absolute mean changes from 
baseline in clinical parameters (BMI, diastolic and systolic 
blood pressure, heart rate) in the hydroxycarbamide and 
placebo groups at 6 months after treatment initiation.This 
analysis will also be performed at 12 months for responder 
patients willing to continue the study after month 6. 
• 
The baseline values and the absolute mean changes from 
baseline in haematological parameters (WBC, platelets, MCV, 
MCHC, MCH, Hb, free Hb, HbF, %DRBCs, endogenous 
EPO, and ferritin) in the hydroxycarbamide and placebo 
groups at 6 months after treatment initiation. This analysis will 
also be performed at 12 months for responder patients willing 
to continue the study after month 6. 
• 
The baseline values and the absolute mean changes from 
baseline in haemolysis markers (LDH, AST, ALT, BUN, 
conjugated and total bilirubin, reticulocytes) in the 
hydroxycarbamide and placebo groups at 6 months after 
treatment initiation. This analysis will also be performed at 12 


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months for responder patients willing to continue the study 
after month 6. 
• 
The rate of SCD-related clinical events (such as VOC 
including ACS requiring hospitalisation for at least 48 hours, 
number and duration [days] of hospitalisations, absence of 
blood transfusions and any sickle cell complications 
(priapism, 
cholelithiasis, 
retinopathy…)) 
in 
the 
hydroxycarbamide and placebo groups at 6 months after 
treatment initiation. This analysis will also be performed at 12 
months for responder patients willing to continue the study 
after month 6. 
 
Optional exploratory endpoint 
• 
Biomarkers predictive of SCN may be identified (BIOBANK) 
only for patients included in French sites. 
 
Statistical methods: 
Sample size: 
According to the primary endpoint, a responder is defined as a patient 
achieving at least a 30% decrease of the ACR baseline at 6 months. 
Assuming a 1:1 treatment allocation ratio, the sample size of 86 
evaluable patients will achieve 80% power to detect an absolute 
difference of 25% in responder rates (35% in the Hydroxycarbamide 
group and 10% in the Placebo group) using a Chi-2 test with the normal 
approximation method.  
The 2-sided significance level is set at 5%.  
Assuming that around 10% of randomised patients will not be 
evaluable for the primary outcome measures, 96 patients (48 in each 
group) should be randomised in this study.  
 
Analysis populations: 
The modified Intent-To-Treat (mITT) population, defined as all 
randomised patients who received at least one dose of the study 
medication and at least one ACR assessment post-baseline of the 
primary efficacy measure will be used for the primary efficacy analyses. 
The Per-Protocol (PP) efficacy population, defined as all patients from 
the mITT population without any major protocol deviation, will be used 
for sensitivity efficacy analyses. 
The safety (SAF) population, defined as all patients who received at 
least one dose of the study medication, will be used for safety analyses. 
 
Statistical analyses  
Eligible patients will be randomised in a 1:1 ratio to either 
Hydroxycarbamide or Placebo. The randomisation will be stratified by 
baseline ACR (≤30 mg/mmol and >30 mg/mmol). 
 
Efficacy analysis: 
Primary endpoint 


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The responder rate (ie. percentage of patients achieving at least a 30% 
decrease of the ACR baseline value at 6 months) will be provided in 
each group with its 95% confidence interval.  
Patients requiring a therapeutic change from HC to ACE or ARB 
inhibitors will be considered as non-responder. Patients with no ACR 
measure at 6 months will be considered as non-responder. A sensitivity 
analysis will be done with a Last Observation Carried Forward (LOCF) 
imputation for patients with no ACR measure at 6 months and without 
therapeutic change. 
Both treatment groups will be compared using a Cochran-Mantel-
Haenszel method with the stratification variable (ACR baseline ≤30 vs 
>30 mg/mmol) as adjusted factor. Hypothesis testing will be performed 
at the two-sided 5% significance level. The 95% confidence interval of 
the difference between the groups will also be provided. The mITT 
population will be the main population of analysis for this criterion. 
 
Secondary endpoints 
Each secondary efficacy criterion will be summarised at each time point 
using descriptive statistics. 
If the primary endpoint is statistically significant, then the secondary 
endpoint, absolute mean change from baseline in eGFR, will be tested 
at the 5% significance level. An Analysis of Covariance (ANCOVA) 
with treatment group and baseline eGFR as fixed effects will be 
performed.  For patients with missing value, a Multiple Imputation 
method will be used. Details to implement this approach will be 
provided in the Statistical Analysis Plan (SAP). All other secondary 
endpoint testing will be considered as exploratory. 
 
Safety analysis 
This analysis will be performed on the SAF population. 
Only Treatment-Emergent Adverse Events (TEAEs), defined as any AE 
with an onset date on or after the first dose of study treatment or any 
ongoing event that worsens after the date of the first dose of study 
treatment, will be analysed. Other Adverse Events will be listed. 
The incidence of overall TEAEs, Drug-Related TEAEs, SAEs, Grade 
3-4 of TEAEs and TEAEs leading to dose reduction or treatment 
discontinuation will be provided in each treatment group and overall 
during the first 6 month-period. 
Incidence of SCD-related events (i.e VOC, ACS, hospitalisations, 
blood transfusions) will also be described. 
TEAEs will be summarized by System Organ Class (SOC) and 
Preferred Terms (PT), according to treatment groups, and compared 
using a Chi-2 (or a Fisher Exact test, if the Chi-2 conditions of 
application are not met) at two-sided 5% significance level. 
The incidence of overall TEAEs, Drug-Related TEAEs, SAEs, Grade 
3-4 of TEAEs, and TEAEs leading to dose reduction or treatment 
discontinuation will also be provided from month 6 to month 12 in each 
treatment group and overall for patients qualified as responders willing 
to continue the study. 
The Medical Dictionary for Regulatory Activities (MedDRA) will be 
used for the classification of AEs. This will permit to describe the 
incidence of above AEs by System Organ Class and Preferred Term. 


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Other safety endpoints such as vital signs and laboratory data will be 
descriptively summarised. 
 
 


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TABLE OF CONTENTS 
STUDY ADMINISTRATIVE STRUCTURE .................................................................................... 2 
PROTOCOL SPONSOR SIGNATURE PAGE ................................................................................. 4 
PROTOCOL COORDINATING INVESTIGATOR AND PRINCIPAL INVESTIGATOR 
SIGNATURE PAGE .......................................................................................................... 5 
SYNOPSIS .......................................................................................................................................... 6 
TABLE OF CONTENTS ..................................................................................................................20 
LIST OF TABLES ............................................................................................................................23 
LIST OF FIGURES...........................................................................................................................23 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................................24 
TRADEMARKS ................................................................................................................................26 
1. 
INTRODUCTION .............................................................................................................27 
1.1 
BACKGROUND .......................................................................................................................... 27 
1.1.1 
Sickle Cell Disease (SCD) .................................................................................................. 27 
1.1.2 
Hydroxycarbamide in SCD ................................................................................................. 27 
1.1.3 
Renal abnormalities in SCD ................................................................................................ 27 
1.1.4 
Glomerular abnormalities and albuminuria ......................................................................... 31 
1.1.5 
Management of microalbuminuria/proteinuria in SCD patients: ........................................ 31 
1.1.6 
Hydroxycarbamide in SCAN management ......................................................................... 32 
1.2 
RATIONALE FOR THE STUDY ..................................................................................................... 35 
1.3 
RISK/BENEFIT ASSESSMENT ..................................................................................................... 35 
2. 
STUDY OBJECTIVES .....................................................................................................36 
2.1 
PURPOSE OF THE STUDY ........................................................................................................... 36 
2.2 
PRIMARY OBJECTIVE ................................................................................................................ 36 
2.3 
SECONDARY OBJECTIVES ......................................................................................................... 36 
3. 
STUDY DESIGN ...............................................................................................................37 
3.1 
STUDY DESIGN OVERVIEW ....................................................................................................... 37 
3.2 
RATIONALE FOR THE STUDY DESIGN ........................................................................................ 38 
3.3 
ENDPOINTS ............................................................................................................................... 40 
3.3.1 
Primary endpoint - Efficacy ................................................................................................ 40 
3.3.2 
Secondary endpoints - Efficacy .......................................................................................... 40 
3.3.3 
Secondary endpoints - Safety .............................................................................................. 41 
3.4 
STUDY DURATION .................................................................................................................... 41 
3.5 
IDENTIFICATION OF PATIENTS................................................................................................... 42 
3.6 
RANDOMISATION AND BLINDING .............................................................................................. 42 
3.6.1 
Randomisation .................................................................................................................... 42 
3.6.2 
Blinding/Unblinding ........................................................................................................... 42 
3.7 
WITHDRAWAL AND REPLACEMENT OF PATIENTS ...................................................................... 44 
3.7.1 
Withdrawal of patients ........................................................................................................ 44 
3.7.2 
Replacement of patients ...................................................................................................... 44 
3.8 
INDEPENDENT DATA MONITORING COMMITTEE (IDMC) ......................................................... 45 
3.9 
PREMATURE TERMINATION OR SUSPENSION OF THE STUDY ..................................................... 45 
4. 
STUDY POPULATION ....................................................................................................45 
4.1 
CHOICE OF TARGETED POPULATION .......................................................................................... 45 
4.2 
INCLUSION CRITERIA ................................................................................................................ 46 


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4.3 
EXCLUSION CRITERIA ............................................................................................................... 46 
4.4 
RANDOMISATION ...................................................................................................................... 47 
4.5 
SCREEN FAILURES ..................................................................................................................... 47 
5. 
SCHEDULE OF STUDY VISITS .....................................................................................49 
5.1 
SCREENING VISIT (V1, D-30) .................................................................................................... 51 
5.2 
INCLUSION VISIT (V2, D0) ........................................................................................................ 53 
5.3 
FOLLOW-UP VISITS.................................................................................................................... 54 
5.4 
EARLY TERMINATION FOLLOW-UP VISIT ................................................................................... 57 
5.5 
END OF THE STUDY ................................................................................................................... 58 
6. 
STUDY ASSESSMENTS AND PROCEDURES ..............................................................59 
6.1 
PHYSICAL EXAMINATION AND ASSESSMENT OF VITAL SIGNS .................................................... 59 
6.2 
ASSESSMENT OF URINE ALBUMIN AND URINE CREATININE FOR ACR EVALUATION .................. 59 
6.3 
ASSESSMENT OF EGFR ............................................................................................................. 60 
6.4 
ASSESSMENT OF HAEMATOLOGICAL AND BIOCHEMICAL PARAMETERS ..................................... 60 
6.5 
SEROLOGICAL ASSESSMENT ...................................................................................................... 61 
6.6 
PREGNANCY TEST ..................................................................................................................... 61 
6.7 
SEMEN CRYOPRESERVATION ..................................................................................................... 61 
6.8 
ASSESSMENT OF ADVERSE EVENTS ........................................................................................... 62 
6.9 
OPTIONAL BIOBANK ................................................................................................................. 62 
7. 
STUDY TREATMENTS ...................................................................................................62 
7.1 
RATIONALE FOR DOSE SELECTION ........................................................................................... 62 
7.2 
DOSE ADJUSTMENT AND TEMPORARY INTERRUPTION .............................................................. 62 
7.3 
IDENTITY OF STUDY TREATMENTS ........................................................................................... 63 
7.4 
SUPPLY AND STORAGE CONDITIONS OF THE STUDY PRODUCTS ............................................... 64 
7.5 
PACKAGING AND LABELLING OF THE STUDY PRODUCTS .......................................................... 64 
7.6 
CONCOMITANT TREATMENTS ................................................................................................... 65 
7.6.1 
Authorised medications during the study ............................................................................ 65 
7.6.2 
Unauthorised medications during the study ........................................................................ 65 
7.6.2.1 
Patients who have treatment which can modify the kidney function (see non-exhaustive list) in 
the last 3 months. ............................................................................................................................................ 65 
7.6.2.2 
Nephrotoxic drugs (most of these medicines are indicated for the treatment of chronic diseases 
which are among the exclusion criteria of the study): ..................................................................................... 65 
7.7 
COMPLIANCE ............................................................................................................................ 66 
8. 
ADVERSE EVENTS .........................................................................................................66 
8.1 
DEFINITIONS ............................................................................................................................. 66 
8.2 
COLLECTION AND ASSESSMENT OF ADVERSE EVENTS BY THE INVESTIGATOR........................... 68 
8.2.1 
Seriousness .......................................................................................................................... 69 
8.2.2 
Severity ............................................................................................................................... 69 
8.2.3 
Relationship to investigational product ............................................................................... 69 
8.2.4 
Action taken with study treatment ...................................................................................... 70 
8.2.5 
Outcome .............................................................................................................................. 70 
8.2.6 
Laboratory test abnormalities .............................................................................................. 70 
8.3 
REPORTING OF ADVERSE EVENTS AND SAFETY ISSUES BY THE INVESTIGATORS ........................ 70 
8.3.1 
Serious adverse events (SAEs) and safety issues ................................................................ 70 
8.3.2 
Non serious adverse events ................................................................................................. 71 
8.3.3 
Reporting of adverse events and safety issues after study closeout or termination ............. 71 
8.4 
REPORTING OF SUSARS AND SAFETY ISSUES  BY THE SPONSOR ................................................. 72 
9. 
DATA HANDLING ...........................................................................................................72 
9.1 
CASE REPORT FORM .................................................................................................................. 72 
9.2 
DATA MANAGEMENT ................................................................................................................ 73 


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10. 
STATISTICS .....................................................................................................................73 
10.1 
GENERAL STATISTICAL CONSIDERATIONS ................................................................................. 73 
10.2 
SAMPLE SIZE ............................................................................................................................. 74 
10.3 
ANALYSIS POPULATIONS .......................................................................................................... 74 
10.4 
EFFICACY ANALYSIS ................................................................................................................. 74 
10.4.1 
Primary endpoint ................................................................................................................. 75 
10.4.2 
Secondary endpoints ........................................................................................................... 75 
10.5 
SAFETY ANALYSIS .................................................................................................................... 75 
11. 
ETHICAL AND REGULATORY ASPECTS ..................................................................76 
11.1 
STUDY CONDUCT ...................................................................................................................... 76 
11.2 
COMPETENT AUTHORITIES AND ETHICS COMITTEES .................................................................. 76 
11.3 
AMENDMENTS ........................................................................................................................... 76 
11.4 
PATIENT INFORMED CONSENT .................................................................................................. 77 
12. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ............77 
13. 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................78 
13.1 
STUDY MONITORING ................................................................................................................ 78 
13.2 
AUDIT AND INSPECTION............................................................................................................ 78 
14. 
CONFIDENTIALITY, DATA HANDLING, AND RECORD KEEPING .......................79 
14.1 
PERSONAL DATA PROTECTION AND CONFIDENTIALITY ............................................................. 79 
14.2 
RECORD KEEPING ..................................................................................................................... 79 
15. 
INSURANCE AND FINANCES .......................................................................................80 
15.1 
INSURANCE ............................................................................................................................... 80 
15.2 
FINANCES ................................................................................................................................. 80 
15.3 
PATIENT PAYMENTS AND EXPENSES ......................................................................................... 80 
16. 
PUBLICATION POLICY .................................................................................................80 
17. 
REFERENCE LIST ..........................................................................................................81 
 


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LIST OF TABLES 
Table 1 Renal abnormalities in SCD ............................................................................................................ 29 
Table 2 Summary of studies reporting therapeutic interventions in SCD patients with 
proteinuria/microalbuminuria .......................................................................................................... 33 
Table 3 Flow chart of study visits and assessments ...................................................................................... 49 
Table 4 Assessments/procedures to be performed at screening visit (V1) .............................................. 51 
Table 5 Assessments/procedures to be performed at inclusion visit (V2) .................................................... 54 
Table 6 Assessments/procedures to be performed at V3 and at V5 for responder patients willing to 
continue the study ............................................................................................................................ 55 
Table 7 Assessments/procedures to be performed at V4 .............................................................................. 56 
Table 8 Assessments/procedures to be performed at V6 for responder patients willing to continue the study 
only .................................................................................................................................................. 57 
Table 9 Assessments/procedures to be performed at early termination follow-up visits .............................. 58 
 
LIST OF FIGURES 
Figure 1 Study scheme ................................................................................................................................... 38 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ACE 
Angiotensin-converting enzyme 
ACR 
Albumin-to-creatinine ratio 
ACS 
Acute chest syndrome 
AE 
Adverse event 
ANSM 
Agence Nationale de Sécurité du Médicament et des Produits de Santé 
ARB 
Angiotensin receptor blocker 
AST 
Aspartate aminotransferase 
BMI 
Body mass index 
bw 
bodyweight 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CM 
Concomitant medication 
CNIL 
Commission Nationale de l’Informatique et des Libertés 
CPP 
Comité de protection des Personnes 
CRA 
Clinical Research Associate 
CRO 
Clinical research organisation 
DRBC 
Dense Red Blood Cell 
eCRF 
electronic Case Report Form 
eGFR 
estimated Glomerular Filtration Rate 
EMA 
European Medicines Agency 
EPO 
ErythroPOietin 
ESCORT-HU 
European Sickle Cell Disease Cohort – Hydroxyurea 
EU 
European Union 
GFR 
HbA1c 
Glomerular Filtration Rate 
Glycated hemoglobin 
Hb 
Haemoglobin 
HbF 
Foetal haemoglobin 
HbSS 
Homozygous haemoglobin S 
HbSβ0 
Heterozygous haemoglobin S / null alleles 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethic Committee 
ITT 
Intention-To-Treat 
KDIGO 
Kidney Disease: Improving Global Outcomes 
LDH 
Lactate DeHydrogenase 
MCH 
Mean corpuscular haemoglobin 
MCHC 
Mean corpuscular haemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
NSAID 
Non-steroidal anti-inflammatory drug 
PP 
Per protocol 
PT 
Preferred term 
RAS 
Renin-angiotensin system 
SAE 
Serious adverse event 


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SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SCD 
Sickle Cell Disease 
SCN 
Sickle cell nephropathy 
SOC 
System organ class 
SmPC 
Summary of Product Characteristics 
VOC 
Vaso-occlusive crisis 
WBC 
White blood cell 
 
 
 
 


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TRADEMARKS 
The following trademarks are used in the present report. 
Note: In the protocol, the name(s) of the product(s) will be written without the superscript 
symbol ™ or ®. 
Trademark 
Generic name 
Siklos®  
Hydroxycarbamide 
 
 
 
 
 


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1. INTRODUCTION 
1.1 
BACKGROUND 
1.1.1 Sickle Cell Disease (SCD) 
Sicke cell haemoglobinopathies are a group of genetic disorders involving, at least, a 
mutation in the gene encoding the β-globin chain of the haemoglobin (Hb) molecule (βS 
globin). The subsequent substitution of valine for glutamic acid at the sixth codon of the β-
globin chain of the haemoglobin (Hb) molecule leads to the formation of abnormal Hb 
tetramer (HbS) [23]. Under deoxygenated states, this abnormal haemoglogin becomes 
polymerised, which distorts the red blood cells into a ‘sickle’ shape and alters their ability 
to carry oxygen throughout the body [24, 25].  
When the βS globin gene is inherited in a homozygous manner (HbSS), it may result in a 
severe disease, better known as Sickle Cell Anemia (SCA), which is characterised by 
profound anaemia and multiple organ involvement including cerebrovascular events, 
retinopathy, cardiovascular diseases, and renal damage. SCD affects millions of persons 
worldwide and in Europe around 3,000 babies are born homozygous for the defective Hb 
gene each year [26]. Combination of the βS allele with a null (Hbβ0) allele, also known as 
sickle cell beta-thalassemia, results in a condition very similar to HbSS-SCD [23, 27]. 
1.1.2 Hydroxycarbamide in SCD 
Hydroxycarbamide is one of the cornerstone treatments for the management of SCD 
patients. The precise mechanism involved in improvement of SCD symptoms in patients 
treated with hydroxcarbamide is unclear. Its efficacy in SCD patients is generally attributed 
to its ability to boost the levels of foetal Hb (HbF) [16]. Hydroxycarbamide is known to 
decrease the frequency of acute pain episodes and acute chest syndrome (ACS), the need 
for red blood cell transfusions, and the number of hospitalisations. Hydroxycarbamide also 
appears to improve patient survival [16, 28-31]. Siklos® is approved since 2007 in the 
European Union (EU) for the prevention of recurrent painful VOC, including acute ACS, 
in adult, adolescent and children above 2 years old suffering from symptomatic sickle cell 
syndromes and since 2017 in the United States of America (USA) to reduce the frequency 
of painful crises and the need for blood transfusions in pediatric patients aged 2 years and 
older with sickle cell anemia with recurrent moderate to severe painful crises. 
1.1.3 Renal abnormalities in SCD 
Over the last 20 years, improved care of patients with SCD has increased life expectancy 
[32]. With improved survival, more long-term complications have become evident [8, 32]. 
Sickle cell nephropathy (SCN) is one of the most frequent and severe complications 
experienced by patients with SCD and becomes a growing matter of concern [10]. It is a 
progressive condition that begins during childhood and encompasses a large spectrum of 
renal abnormalities including, but not limited to, urinary concentrating defect, haematuria, 


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renal papillary necrosis, renal tubular dysfunctions, glomerular disease, acute kidney 
injury, chronic kidney disease, and renal medullar carcinoma (Table 1) [21, 33]. In studies 
performed on large cohorts of SCD patients, 12 to 16% of adult patients were diagnosed 
with renal failure [2, 3]. In elderly patients, renal failure is a major contributor to death [4, 
5]. The average age at which a patient develops renal failure is 40 years, but previous works 
have reported the occurrence of SCN very early in childhood, as soon as 7 years of age [8, 
34].  
Acidic, hypertonic and hypoxic intrinsic environment of the renal medulla enable HbS 
polymerisation and erythrocyte sickling within the vasa recta – the capillary networks that 
supply blood to the medulla.   Erythrocytes sickling leads to occlusion of the blood vessels 
with impairment of blood flow, ischaemia, and infarction of the tubular cells. Repeated 
sickling causes progressive destruction of the vasa recta which results in turn in a urinary 
concentrating defect. The ischaemic damage may also stimulate the release of vasodilating 
substances such as prostaglandins and nitric oxide, which feed back to the glomerulus and 
tend to increase the glomerular filtration rate (GFR). Prolonged hyperfiltration triggers 
renal damage and proteinuria which in turn engenders glomerulosclerosis and reduction in 
kidney function [7, 8, 35, 36].   


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Table 1 
Renal abnormalities in SCD 
Renal abnormalities [7, 8, 33, 36]  
Causes 
Epidemiology 
Comments 
Urinary concentrating defect 
Distal tubular dysfunction due to the 
destruction of the vasa recta by 
repeated ischaemia. 
Among the most frequent renal 
abnormalities. In the BABY HUG 
trial, 20.1% (37/184) children were 
hyposthenuric [34].  
As early as infancy. Progresses with 
age. 
Acidification defect 
Distal tubular dysfunction due to 
impaired medullary perfusion. 
Retrospective analyses of over 
400 patients with SCD demonstrated 
that 40% of patients exhibited 
metabolic acidosis [37].  
 
Impaired potassium excretion 
Distal tubular dysfunction due to 
impaired medullary perfusion. 
 
Serum K level does not generally 
increase. However, hyperkalaemia 
may become apparent with 
progressive renal insufficiency or 
following use of ACE inhibitors.  
Increased secretion of uric acid and 
creatinine 
Hyperfunction of proximal tubule. 
 
Urate clearance decreases with age 
and the incidence of hyperuricemia 
increases as renal function 
deteriorates.  
Increased reabsorption of phosphate 
and β2-microglobulin 
Hyperfunction of proximal tubule. 
 
Associated with hyperphosphatemia. 
Haematuria 
Vascular occlusion in the renal 
medulla by sickled erythrocytes. 
Another cause of haematuria is 
papillary necrosis. Rarely caused by 
renal medullary carcinoma. 
Among the most frequent renal 
abnormalities.  
Usually painless and self-limited, 80–
90% unilateral. 
 
 


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Renal papillary necrosis 
Vascular occlusion in the renal 
medulla by sickled erythrocytes. 
Frequent renal abnormalities. Renal 
papillary necrosis has an incidence of 
2.3% in SCD patients [38].  
Typically associated with haematuria. 
Increased GFR 
Release of vasodilating substances 
during the process of sickling. 
Glomerular hyperfiltration has a 
prevalence of 30–51% in HbSS-SCD 
patients [39, 40].  
GFR rate declines towards normal 
during adolescence and falls to 
subnormal levels as patient’s age and 
chronic kidney disease progress. 
Glomerular abnormalities and 
proteinuria 
Glomerular hyperfiltration; 
cytokines; iron overload. 
In a recent prospective study involving 
300 SCD adult patients, the 
prevalence of albuminuria was 68%. 
Microalbuminuria was present in 42% 
of patients and macroalbuminuria in 
26% of patients [41].  
Proteinuria begins as 
microalbuminuria and progresses to 
overt proteinuria as the kidney 
sustains further damage resulting from 
the underlying SCD. 
Acute kidney injury 
Volume depletion; severe sepsis; 
rhabdomyolysis. 
Present in 4−11% of hospitalised 
patients with SCD [3, 42]. 
Haemodynamic stress of pregnancy 
may precipitate it. 
Chronic kidney disease 
Progressive parenchymal damage and 
chronic glomerular disease. 
Incidence of 4–18% in adults in USA 
[5, 43].  
 
ACE: Angiotensin-converting enzyme GFR: Glomerular filtration rate; SCD: Sickle Cell Disease. 


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1.1.4 Glomerular abnormalities and albuminuria 
Glomerular abnormalities are one of the most prominent features of SCN. It is characterised 
by an isolated glomerular enlargement and focal segmental glomerulosclerosis (FSGS), 
and an early increase in the GFR associated with proteinuria [6]. As observed in diabetic 
nephropathy, prolonged hyperfiltration firstly observed in SCD probably contributes to the 
progressive renal damage and the development of proteinuria. Hyperfiltration and 
proteinuria are two major causes of subsequent glomerulosclerosis and reduction in kidney 
function [6-8]. Proteinuria begins as microalbuminuria. As the kidney sustains further 
damage resulting from the underlying SCD, microalbuminuria progresses to 
macroalbuminuria and finally to overt proteinuria [8].  
Early detection of SCN is key to start effective therapeutic interventions that would prevent 
the progression of renal damage, before it becomes irreversible. Microalbuminuria is most 
often the first clinical indicator of glomerular damage in SCD. Microalbuminuria refers to 
a urinary albumin concentration that is abnormally high but not high enough to be picked 
up by a simple dipstick [44, 45]. According to the albuminuria staging system established 
by KDIGO (Kidney Disease: Improving Global Outcomes), microalbuminuria, also known 
as moderately increased albuminuria, refers to grade A2 albuminuria where urine albumin-
to-creatinine ratio (ACR) ranges from 30−300 mg/g or 3−30 mg/mmol and 
macroalbuminuria, also known as severely increased albuminuria, to grade A3 albuminuria 
where ACR is > 300 mg/g or 30 mg/mmol [19]. 
In a study conducted on 300 adult US patients, microalbuminuria occured in ∼42% of 
patients with HbSS SCD, although its prevalence can vary depending on age and SCD 
genotype [41]. Consistent with these US data, Haymann et al (2010) reported that the 
prevalence of microalbuminuria was around 40% among 280 adult French patients with 
HbSS SCD [40]. Of note, macroalbuminuria was reported in 20% to 40% of patients with 
HbSS SCD depending on the age, and might lead to nephrotic syndrome, revealing a broad 
spectrum of glomerular lesions, and ultimately, to renal failure [1, 6, 41].  
1.1.5 Management of microalbuminuria/proteinuria in SCD 
patients: 
Few therapeutic options are available for the treatment of SCD patients with 
proteinuria/microalbuminuria. Table 2 summarises studies reporting effects of various 
therapeutic interventions on proteinuria/microalbuminuria in SCD patients.  
Reducing proteinuria with inhibitors of the renin-angiotensin system (RAS inhibitors) 
(either angiotensin-converting enzyme [ACE] inhibitors or angiotensin receptor blockers 
[ARBs]) is a key factor to delay GFR deterioration in patients with either diabetic or non-
diabetic proteinuric renal disease [11]. Several studies in SCD patients have reported 
possible clinical benefit of these drugs on proteinuria levels but generally with small series 
and short follow-up time. Falk et al (1992) first showed in 10 SCD patients that 2 weeks of 
enalapril led to a 57% decrease in proteinuria that rebounded after treatment 


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discontinuation [1]. Other authors also found that proteinuria was reduced by 43.3 to 76.3% 
in 5 out of 7 SCD patients treated with fosinopril (10 mg daily) for 6 months [12]. These 
results are supported by a 6-month placebo-controlled study on 22 SCD patients, which 
indicated that captopril significantly reduces microalbuminuria and diastolic blood 
pressure [13]. A recent phase 2 open label study including 32 participants found that 
administration of an angiotensin-II-receptor-1 blocker during 6 months significantly 
decreased albuminuria (albumin-to-creatinine ratio) level [14]. In a prospective 
multicentric non-randomized trial including 42 SCD patients, Haymann et al showed that 
ACE inhibitors appears safe and effective in decreasing albuminuria [15].  Nevertheless, 
to date, no randomised, prospective clinical trials with adequate sample size have clearly 
demonstrated the potential benefit of RAS inhibitors, and their tolerance among SCD 
patients. 
In one retrospective review of 23 children with SCD, Alvarez et al (2006) suggested that 
chronic transfusions starting at an early age protect against microalbuminuria [46]. Another 
retrospective review failed to confirm this effect and reported similar microalbuminuria 
frequency in paediatric patients on chronic transfusions (26%) and in those receiving no 
treatment (24%) [47]. The potential renoprotective effects of transfusion therapy in SCD 
patients remain controversial and still need to be firmly established. 
1.1.6 Hydroxycarbamide in SCAN management 
Several observational studies, especially in the adult population, have provided evidence 
that hydroxycarbamide would be beneficial in SCD patients with impaired glomerular 
function and may therefore be considered as a promising therapeutic option in this 
indication. 
In the paediatric population, hydroxycarbamide treatment has been shown to have possible 
renal protective effects in individual studies, but this has not been consistently reported in 
the literature [47-49]. In the BABY HUG randomised clinical trial, Alvarez et al (2012) 
failed to show improvement in GFR in toddlers treated for 2 years with hydroxycarbamide 
[50]. No significant decrease in microalbuminuria was found in SCD children taking 
hydroxycarbamide for 3 years in the study  recently conducted by Aygun et al (2013) [51]. 
Since the study was carried out on a limited number of patients, no definite conclusion can 
be drawn. 
In SCD adult patients, no randomised, prospective clinical trial has evaluated the potential 
benefit of hydroxycarbamide on microalbuminuria in adult SCD patients. A case-control 
study reported that hydroxycarbamide treatment lessens proteinuria but not 
microalbuminuria in adult SCD patients, suggesting a possible kidney protection [52]. A 
cross-sectional study showed lower albuminuria levels and lower microalbuminuria 
prevalence in patients after ≥ 3 months of treatment with hydroxycarbamide compared to 
patients not treated with hydroxycarbamide [18]. These results are further supported by a 
recent cohort study showing significant decrease in urine ACR after 6 months of 


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hydroxycarbamide treatment (median hydroxycarbamide dose at month 6 was 15 [12–18] 
mg/kg per day) in 58 SCD adult patients [17].  
Table 2 
Summary of studies reporting therapeutic interventions in SCD patients 
with proteinuria/microalbuminuria 
Reference 
Number 
of 
patients 
Age 
Type of 
study 
Treatment(s) 
Outcomes 
Falk et al [1] 
381 
Adult 
Prospective 
Enalapril 
In 10 patients treated with 
enalapril, mean reduction 
in proteinuria of 57% 
from baseline after 
2 weeks. 
Foucan et al 
[13] 
22 
Adult 
Randomised 
prospective 
Captopril  
Significant decrease in 
microalbuminuria after 6 
months. 
Voskaridou 
et al [12] 
7 
Adult 
Prospective 
Fosinopril 
In 7 patients treated with 
fosinopril, 5 reduced the 
degree of proteinuria by 
43.3 to 76.3%. 
Alvarez et al 
[46] 
23 
Paediatric 
Retrospective 
Hydroxycarbamide 
or chronic 
transfusions 
Patients who did not have 
microalbuminuria started 
transfusions at a younger 
age (7.78 ± 3.7 years) 
compared to those who 
had microalbuminuria 
(12.2 ± 1.9 years). 
Lebensburger 
et al  [47] 
144 
Paediatric 
Retrospective 
Hydroxycarbamide 
or chronic 
transfusions 
Lower microalbuminuria 
frequency in 
hydroxycarbamide-
treated patients compared 
to those not receiving this 
drug (13% and 24%, 
respectively).  
Similar microalbuminuria 
frequency for patients on 
chronic transfusions 
(26%). 
Aygun et al 
[51] 
23 
Paediatric 
Prospective 
Hydroxycarbamide 
Microalbuminuria did not 
decrease in children 
taking hydroxycarbamide 
for 3 years. 
Alvarez et al 
[50] 
193 
Paediatric 
Randomised 
prospective 
Hydroxycarbamide 
No improvement in 
glomerular filtration rate 
in young children treated 
for 2 years with 
hydroxycarbamide. 
Silva Junior 
et al [52] 
26 
Adult 
Prospective 
Hydroxycarbamide 
Significant decreases in 
proteinuria but not in 
microalbuminuria. 


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Laurin et al 
[18] 
149 
Adult 
Cross-
sectional 
Hydroxycarbamide 
Lower albuminuria levels 
and lower 
microalbuminuria 
prevalence in patients 
after ≥ 3 months of 
treatment compared to 
untreated patients. 
Bartolucci et 
al [17] 
58 
Adult 
Prospective 
Hydroxycarbamide 
Significant decrease in 
urine albumin-to-
creatinine ratio after 
6 months of treatment 
(highest decline in the 
subgroup of patients with 
baseline 
microalbuminuria). 
SCD: Sickle Cell Disease. 


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1.2 
RATIONALE FOR THE STUDY 
Early recognition of SCN and focus on the early steps of the natural history of this 
nephropathy, together with the recognition of the associated clinical and biologic risk 
factors are of major interest to make it possible to initiate kidney-protective therapy at early 
stages of renal impairment. Microalbuminuria is most often the first clinical indicator of 
glomerular damage in SCD [53]. A broad spectrum of glomerular diseases has been 
described in SCD patients, with elevated albuminuria, isolated glomerular enlargement and 
focal segmental glomerulosclerosis (FSGS) being the most frequent lesions [21, 33]. In this 
first trial we suggest to evaluate the effect of hydroxycarbamide (Siklos®) on albuminuria. 
Siklos® was granted an orphan drug designation in the European Union (EU) in 2003 for 
the treatment of Sickle Cell Syndrome and in the United States of America (USA) in July 
2013 for the treatment of SCD in patients under 18 years of age. Siklos® was authorised for 
marketing in Europe in June 2007 for the prevention of recurrent painful vaso-occlusive 
crises (VOC) including ACS in adults, adolescents, and children older than 2 years 
suffering from symptomatic Sickle Cell Syndrome (see Summary of Product 
Characteristics [SmPC]) and since 2017 in the USA to reduce the frequency of painful 
crises and the need for blood transfusions in pediatric patients from 2 years of age and older 
with sickle cell anemia with recurrent moderate to severe painful crises.  
Siklos® is a proprietary formulation of hydroxycarbamide available in 2 dosages (i.e. a 
1000 mg scored film-coated tablet and a 100 mg scored film-coated tablet) that enables 
flexible dosing in 50, 100 mg and 250 mg intervals to meet the specific needs of SCD 
patients, specifically young patients. 
The purpose of this randomised, prospective clinical trial is to confirm results from 
previous observational studies and to demonstrate the renal protective effect of Siklos® in 
adult SCD patients with albuminuria treated over a period of 6 months. It is designed to 
support an extension of Siklos® approved indication to treatment of SCD patients with renal 
dysfunction. 
1.3 
RISK/BENEFIT ASSESSMENT 
Siklos® 100 mg or 1000 mg film-coated tablets is a widely accepted medical treatment for 
patients with SCD. During the study, Siklos® will be used according to the recommended 
dose regimen in the EU label (15 mg/kg bodyweight [bw]/day) and will be adjusted 
according to patient response and tolerance to treatment.  
Known undesirable effects of Siklos® are documented in the SmPC of Siklos effective at 
the time of the eventThe most frequently reported adverse reaction is bone marrow 
depression with neutropenia as the most common manifestation. In the present study, blood 
counts will be monitored closely throughout treatment with Siklos®. If blood counts are 
within the toxic range, Siklos® will be temporarily discontinued until blood counts recover. 


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The Investigator can also decide in patient’s health interest to withdraw the patient from 
the study. 
The safety profile of Siklos® is still under evaluation. Upon request of the European 
Medicines Agency (EMA), the ESCORT-HU (European Sickle Cell Disease Cohort – 
Hydroxyurea) study has been implemented in some countries in Europe for the collection 
of information about long-term safety of Siklos®. Investigators and patients participating 
in the SIKAMIC study will be promptly informed about any new safety signal revealed by 
the ESCORT-HU study.  
2. STUDY OBJECTIVES 
2.1 
PURPOSE OF THE STUDY 
The purpose of this phase IIb, international (France and Africa), multicentre, double-blind, 
randomised, placebo-controlled study is to determine the effect of hydroxycarbamide on 
albuminuria after 6 months of treatment in SCD adult patients.  
2.2 
PRIMARY OBJECTIVE 
The primary objective of this trial is to demonstrate the effect of 6-month treatment with 
hydroxycarbamide against placebo in achieving at least a 30% decrease of the albuminuria 
(albumin to creatinine ratio; ACR) baseline value in adult sickle cell patients.  
 
2.3 
SECONDARY OBJECTIVES 
The secondary objectives are: 
• To compare the estimated GFR (eGFR) according to CKD-EPI formula* between 
hydroxycarbamide and placebo group in order to evaluate a possible renal 
protective effect of hydroxycarbamide on eGFR at 6 months. 
• To compare the proportion of patients in hydroxycarbamide versus placebo group 
with an improvement in the albmuminuria stage, i.e. a shift from grade A3 to grade 
A2 albuminuria (macro- to microalbuminuria), from grade A2 to grade A1 
albuminuria (micro- to normoalbuminuria) or from grade A3 to grade A1 
albuminuria (macro- to normoalbuminuria), according to the KDIGO staging 
system at 6 months. 
• 
To compare the proportion of patients in hydroxycarbamide and placebo group with 
a renal disease progression supported by an increase in albuminuria at 6 months, as 
compared to baseline. 
• 
To identify clinical and biological markers associated with response to treatment. 
*eGFR (millilitres per minute per 1.73 m2) = 141 × min (Scr/k,1)α × max(Scr/k,1)-1.209 × 0.993Age × 
1.018 (for women), where Scr is serum creatinine, k is 0.7 for women and 0.9 for men, α is -0.329 


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for women and -0.411 for men, min indicates the minimum of Scr/k or 1, and max indicates the 
maximum of Scr/k or 1. 
• To describe the evolution of ACR from inclusion to month 6.  
• To describe the evolution of eGFR from inclusion to month 6. 
• To describe the evolution of ACR of responder patients from inclusion to month 
12.  
• To describe the evolution of eGFR of responder patients from inclusion to month 
12. 
• 
To evaluate the safety of hydroxycarbamide throughout the entire study period. 
• To evaluate the impact of the study treatment on SCD-related events throughout 
the entire study period. 
• 
Optional exploratory objective: to identify any biomarker predictive of SCN 
(BIOBANK). 
 
3. STUDY DESIGN 
3.1 
STUDY DESIGN OVERVIEW 
The design of this study is a Phase-IIb, prospective, two-armed, parallel-design, 
international, multicentric, randomized, double blind placebo-controlled trial in adult 
patients with HbSS or HbSβ0 SCD and ACR between 3 and 100 mg/mmol.  
The patients will be recruited in approximately 30 centres in France and 4 in Africa. After 
having given written informed consent (ICF), around 140 patients will be screened to 
determine their eligibility according to inclusion/exclusion criteria. In fine, around 96 
patients (32 patients in France and 64 patients in Africa) will be randomised. At the 
screening visit (V1), patients will be examined to establish eligibility according to 
inclusion/exclusion criteria. The screening visit (V1) will take place no more than 30 days 
prior to the inclusion visit (V2, Day 0) and will allow albuminuria (ACR between 3 and 
100 mg/ mmol) to be confirmed by 3 positive urine samples taken one day apart. 
At the inclusion visit (V2), the eligible patients will be randomised to receive in a 1:1 ratio: 
• Hydroxycarbamide (Siklos®) 15 mg/kg bw/day: hydroxycarbamide group 
• Placebo 15 mg/kg bw/day: placebo group 
Randomization will be stratified according to ACR baseline value (≤ or >30 mg/mmol). 
The treatment will be administered for 6 consecutive months. In case of consent 
withdrawal, unacceptable toxicity or non-compliance to the protocol, the study treatment 
will be discontinued. Only patients qualified as responders after 6 months of treatment will 
be offered to continue to receive the study treatment and their follow-up will be extended 
to 6 additional months. 
Patients will attend a total of 4 visits at the clinical centre:  
• one screening visit (V1), 


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• one inclusion/randomisation visit (V2), 
• 2 visits during the treatment phase (V3 and V4). 
Patients qualified as ‘responders’ willing to continue the study will continue the treatment 
and attend two additional visits (V5 and V6) at the clinical centre. 
 
An overview of the study design is provided in Figure 1. 
 
 
Figure 1 
Study scheme 
 
 
bw: bodyweight; D: Day; M: Month; V: Visit.  
V1: screening visit; V2: inclusion visit; V3−V6: follow-up visits  
3.2 
RATIONALE FOR THE STUDY DESIGN 
The study has been designed as randomised and double-blind to allow unbiased study 
assessments. 
No evidence-based treatments are currently available for adult SCD patients with early 
signs of kidney injury. Although a potential benefit of RAS inhibitor has been observed 
there is, to date, no clear evidence supporting an association between RAS inhibitors 
administration and a reduction of albuminuria and proteinuria in patients with SCD 
(Table 2). Similarly, the renoprotective effects of transfusion therapy remains controversial 


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and have not been formally confirmed by prospective clinical trials (Table 2). In the 
absence of a reference treatment, a head-to-head study would not be an adequate strategy; 
therefore, the study has been designed as placebo-controlled. 
 


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3.3 
ENDPOINTS 
3.3.1 
Primary endpoint - Efficacy 
The primary endpoint of this study is the proportion of patients in the hydroxycarbamide 
and placebo groups achieving at least a 30% decrease in ACR baseline value at 6 months 
after treatment initiation. Patients who do not achieve at least a 30% decrease of the ACR 
baseline value at month 6 will be considered non-responders.  
 
Rationale for the selection of the primary endpoint:  
The GFR is usually reported as primary endpoint in renal disease. However due to the 
changes of GFR at the beginning of the renal impairment with hyperfiltration, the ACR 
ratio will be more accurate as primary endpoint. 
Albuminuria is increased excretion of urinary albumin and a marker of kidney damage. 
Persistent increased protein in the urine (two positive tests over 3 or more months) is the 
principal marker of kidney damage, acting as an early and sensitive marker in many types 
of kidney disease. A 30% decrease in ACR (so-called ‘responders’) is commonly used in 
diabetic studies to determine the efficacy of various therapeutic interventions on 
albuminuria.  
3.3.2 
Secondary endpoints - Efficacy 
The secondary efficacy endpoints are: 
• The absolute mean change from baseline in eGFR in the hydroxycarbamide and 
placebo groups at 6 months after treatment initiation. 
• The absolute mean change from baseline in ACR in the hydroxycarbamide and 
placebo groups at 6 months after treatment initiation.  
• The proportion of patients with an improvement in the albmuminuria stage according 
to the KDIGO staging system : 
- 
Proportion of patients with a shift from grade A3 to grade A2 albuminuria 
(macro- to microalbuminuria) at 6 months 
- 
Proportion of patients with a shift from grade A2 to grade A1 albuminuria 
(micro- to normoalbuminuria) at 6 months 
- 
Proportion of patients with a shift from grade A3 to grade A1 albuminuria 
(macro- to normoalbuminuria) at 6 months. 
• The proportion of patients progressing from microalbuminuria to macroalbuminuria 
in the hydroxycarbamide and placebo groups at 6months after treatment initiation. 
• 
Evolution curve of ACR of the hydroxycarbamide and placebo groups from 
treatment initiation to month 6. 
• 
Evolution curve of eGFR of the hydroxycarbamide and placebo groups from 
treatment initiation to month 6. 


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• 
Evolution curve of ACR of responder patients willing to continue the study after 6 
months, from treatment initiation to month 12. 
• 
Evolution curve of eGFR of responder patients willing to continue the study after 
6 months, from treatment initiation to month 12. 
•  
• The identification of clinical and biological markers associated with response to 
treatment. 
3.3.3 
Secondary endpoints - Safety 
The secondary safety endpoints are: 
• 
The incidence of treatment-emergent AEs and SAEs. 
• 
The baseline values and the absolute mean changes from baseline in clinical 
parameters (BMI, diastolic and systolic blood pressure, heart rate) in the 
hydroxycarbamide and placebo groups at 6 months after treatment initiation. This 
analysis will also be performed at 12 months for responder patients willing to 
continue the study after month 6.  
• 
The baseline values and the absolute mean changes from baseline in haematological 
parameters (WBC, platelets, MCV, MCHC, MCH, Hb, HbF, free Hb*, %DRBCs*, 
endogenous EPO* and ferritin) in the hydroxycarbamide and placebo groups at 6 
months after treatment initiation. This analysis will also be performed at 12 months 
for responder patients willing to continue the study after month 6. 
• 
The baseline values and the absolute mean changes from baseline in haemolysis 
markers (LDH, AST, ALT, BUN, conjugated and total bilirubin, reticulocytes) in 
the hydroxycarbamide and placebo groups at 6 months after treatment initiation. 
This analysis will also be performed at 12 months for responder patients willing to 
continue the study after month 6. 
• 
The rate of SCD-related clinical events (such as VOC including ACS requiring 
hospitalisation for at least 48 hours, number and duration [days] of hospitalisations, 
absence of blood transfusions and any SC complications: priapism, cholelithiasis, 
retinopathy….) in the hydroxycarbamide and placebo groups at 6 months after 
treatment initiation. This analysis will also be performed at 12 months for responder 
patients willing to continue the study after month 6. 
Optional exploratory endpoint : Biomarkers predictive of SCN may be identified 
(BIOBANK) for patients included in french sites. 
* In centres able to do these analyses 
3.4 
STUDY DURATION 
The total duration of the study is expected to be approximately 61 months, after the 
protocol has been approved by the regulatory authorities and the Independent Ethics 


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Committee (IEC) and the initiation of the centres. This includes the periods necessary for 
patient recruitment (49 months) and patient follow-up (12 months). 
Each patient will be enrolled in the study for a duration of 6 months, during which he/she 
will be taking the placebo or the study treatment (i.e. hydroxycarbamide) on a daily basis. 
The study duration will be extended to 12 months for patients qualified as responders 
willing to continue to participate in the trial. 
3.5 
IDENTIFICATION OF PATIENTS 
At the screening visit, once a patient has signed the ICF, he/she will be assigned a 6-digit 
identification number. The first 3 digits will identify the investigational centre (001) and 
the last 3 digits will correspond to the chronological entry order of the patient in the study 
of that specific centre (001-099). The first selected patient in centre 001 will therefore be 
allocated the patient identification number 001-001. The following patients will 
subsequently be assigned the identification numbers 001-002, 001-003…The patient will 
retain this identification number throughout the study (all documents, blood samples…). 
If a selected patient becomes ineligible for the study, his/her identification number will not 
be reallocated to another patient. Individuals who do not meet the criteria for participation 
in this study (screen failure) may actually be rescreened and rescreened participants will 
be assigned the same participant number as for the initial screening.  
3.6 
RANDOMISATION AND BLINDING 
3.6.1 Randomisation 
A total of approximately 96 patients will be randomly assigned in a 1:1 ratio to either 
hydroxycarbamide or placebo according to a central computer-generated randomisation 
scheme. Randomisation numbers will be allocated sequentially according to a central 
allocation system (IWRS, Interactive Web Response System) to limit selection bias. The 
randomisation number for each patient will be composed of 3 digits (from 001 to 999) and 
will be allocated at V2 (inclusion) after verifying the eligibility criteria. 
The 24-hour web based randomisation system will be created using the system that is 
developed and maintained by ICTA.  
Randomisation will be stratified according to ACR baseline value (≤ or >30 mg/mmol).  
The randomisation list will be prepared by ICTA under the responsibility of the statistician. 
3.6.2 Blinding/Unblinding  
The study is double-blind, which means neither the patients nor the Investigator or other 
site personnel or the Sponsor or designee will be aware of the randomisation. Blinding will 
be maintained by the following measures: 
1. The study treatments will be packaged according to a computer-generated 
randomisation code prepared for all study centres. 


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2. The randomisation code will not be available to any person involved in the conduct and 
evaluation of the study until the study database is declared clean and is frozen. Freezing 
consists in preventing any change in the database. After the randomisation table will be 
loaded, the database will be locked and released to the statistician. 
3. Hydroxycarbamide and placebo tablets will be presented as identical tablets concerning 
the colour, size, shape, and weight. They will be packed in identical bottles, bearing an 
identification label.  
 
Unblinding of individual patient treatment 
Breaking of blind for an individual patient by the Investigator will only be made if the 
safety of a patient can no longer be guaranteed and unblinding is an absolute requirement 
to decide a further treatment of the patient.  
Code breaking for any other reason than safety will be considered as ‘major violation’ and 
will lead to the exclusion of the patient from the study. 
Unblinding will be achieved by the Investigator through the IWRS integrated in the eCRF 
system and as per the corresponding manual that will be provided to each centre.  
An alert via email (sikamic@addmedica.com) will be automatically sent by IWRS in case 
of request of unblinding by one investigator. If the reason of unblinding is a SAE, the 
investigator will immediately complete and send by email the “SAE Form” to the sponsor. 
In any case, the treatment received by the patient and the patient number must not be 
indicated on the form. 
 
A sponsor’s pharmacovigilance representative will also be commited to unblinding 
decision in case of major safety issue. 
 
Breaking the blind code must remain exceptional and performed only in case of emergency 
for the patient. In this eventuality, the following information must be recorded in the source 
document and captured in the eCRF: the date when the randomisation code was broken, 
the name(s) of the person(s) conducting the code break, and the reason for the code break. 
The unblinding result should not be reported. Care should be taken to store the unblinding 
information such that the information is kept confidential. 
 
 


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3.7 
WITHDRAWAL AND REPLACEMENT OF PATIENTS 
3.7.1 Withdrawal of patients 
Patient withdrawal decision can araise from the patient himself, the investigator or the 
IDMC. 
- 
Patients have the right to withdraw their consent at any time and irrespective 
of the reason.  
- 
The Investigator has also the right to withdraw patients from the study for 
the following reasons (including but not limited to):  
• 
Patients transfused more than twice during the study, 
• 
Patients’ inadequate cooperation and compliance with the protocol, 
• 
Any life-threatening AE assessed by the Investigator to be related to 
study procedure or administration of study treatment, 
• 
Patients experiencing at least 3 VOC or 1 ACS during the study, 
• 
Patients with an increase in ACR requiring, upon investigator’s 
judgement, a treatment with ACE or ARA2, 
• 
Development of an intercurrent illness requiring hospitalisation or 
surgery enforcing a stop of study treatment for more than 15 days,  
• 
Loss to follow-up. 
 
- IDMC stopping rules defined in IDMC Charter (See Section 3.8). 
 
An excessive rate of withdrawals can render the study uninterpretable; therefore, 
unnecessary withdrawal of patients should be avoided. 
Should a patient decide to withdraw, all efforts will be made to collect data as thoroughly 
as possible. When possible, the patients will be assessed using the procedures planned, the 
end-of-study visit and the end-of-study form will be completed (see Section 5.4) and the 
reason for withdrawal should be documented in the eCRF. 
Every effort will be made to contact patients who fail to return for a planned visit. If all 
these attempts to contact the participant fail, the investigator can then declare the 
participant “lost to follow-up”. The investigator should document all these attempts in the 
source medical file. 
Patients who have been withdrawn from the study cannot be re-included in the study. Their 
identification and randomisation number must not be re-used. 
3.7.2 Replacement of patients 
Patients with inadequate cooperation and compliance with the protocol may be considered 
not evaluable and may be replaced, up to the limit of 20% of replaced patients. 


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3.8 
INDEPENDENT DATA MONITORING COMMITTEE (IDMC) 
An Independent Data Monitoring Committee (IDMC) will be established prior to study 
enrolment. All members will be independent from the Sponsor.  
The IDMC experts will review cumulative study data every 3 to 6 months to evaluate the 
safety, study conduct, and scientific validity and integrity of the study. The IDMC will 
make recommendations regarding the continuation, suspension or termination of the 
clinical study. 
Composition, role and frequency of IDMC meetings are detailed in the IDMC Charter. 
 
3.9 
PREMATURE TERMINATION OR SUSPENSION OF THE STUDY 
ADDMEDICA S.A.S. reserves the right to temporarily suspend or prematurely terminate 
this study at any time for reasonable medical or administrative reasons such as failure to 
enrol patients, suspected lack of efficacy or questionable safety of the study treatment. The 
sponsor should promptly inform the Investigators/institutions, the IECs and the regulatory 
authority(ies) of the termination or suspension and the reason(s) for the termination or 
suspension. The Investigators/institutions should also promptly inform the study patients, 
and should ensure appropriate therapy and follow-up for the patients.  
In addition, ADDMEDICA S.A.S. has the right to discontinue a single centre at any time 
during the study for medical or administrative reasons such as unsatisfactory enrollment, 
Good Clinical Practice (GCP) noncompliance, inaccurate or incomplete data collection, 
falsification of records, failure to adhere to the study protocol. 
 
4. STUDY POPULATION 
4.1 
CHOICE OF TARGETED POPULATION 
Renal impairment is common to any clinical phenotypes of SCD however, hemolytic 
phenotype seems more exposed [21]. Because severe patients with vaso-occlusive phenotype 
have less renal injuries and are already treated with HU, they will be excluded from the 
study. 
Clinical guidelines recommend the prescription of renin angiotensin system inhibitors (RAS 
inhibitors) (either ACE inhibitors or angiotensin receptor blockers [ARBs]) only in case of 
macroalbuminuria with ACR ≥ 100 mg/mmol. Hence patients with ACR ≥ 100 mg/mmol 
will be excluded from the study. 
Variations in GFR in SCD at early stages of kidney injury are not fully understood, although 
the occurrence of hyperfiltration with an increased GFR and concomitant microalbuminuria 
is likely the first sign of renal impairment. A recent study presented at the last American 


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Society of Hematology meeting by Biemond et al. demonstrated a clear correlation between 
the long-term subclinical renal function deterioration and microalbuminuria in 167 SC 
patients [22]. However, as clinical relevance of a decrease in GFR in hyperfilttrating patients 
is not ascertained in the current state of knowledge, patients with renal hyperfiltration will 
not be included in the study. 
4.2 
INCLUSION CRITERIA 
The inclusion criteria are to be verified at the screening and inclusion visits (V1 and V2). 
Patients must meet ALL the following inclusion criteria to participate in the study:  
1. Signed and dated Informed Consent Form (ICF) by a legally competent patient. 
2. Patients above 18 years. 
3. Patients with HbSS or HbSβ0 SCD.  
4. Patients with a value of albuminuria, assessed by ACR, over 3 mg/mmol and inferior to 
100 mg/mmol confirmed by 3 positive urine samples taken one day apart. 
5. Female patients of childbearing or postmenopausal female with last period < 12 months 
before screening agreeing to use a highly effective form of contraception (oral, injected 
or implanted hormonal contraception, intrauterine device, diaphragm, condom, 
abstinence) during the trial and for 3 months after hydroxycarbamide discontinuation. 
6. Male patients with partners of childbearing potential agreeing to use an effective 
contraception during the study and for 3 months after hydroxycarbamide 
discontinuation. Men with pregnant or lactating women should be advised to use barrier 
method contraception (condom) to prevent the foetus or neonate from exposure to 
hydroxycarbamide. 
7. Patients who are covered by insurance scheme according to local regulatory 
requirements. 
4.3 
EXCLUSION CRITERIA 
The exclusion criteria are to be verified at the screening and inclusion visits (V1 and V2). 
Patients meeting AT LEAST one of the following exclusion criteria must not be enrolled 
in the study: 
1. Patients who had severe VOC requiring hospitalisation or ACS within the last 4 weeks 
preceding screening visit. 
2. Patients treated with hydroxycarbamide for any reason within the previous 6 months. 
3. Patients who have had chronic blood transfusion or transfusion in the last 3 months. 
4. Patients with a history of hypertension (systolic blood pressure ≥ 140 or diastolic blood 
pressure 
≥ 90 mmHg) 
treated 
with 
antihypertensive 
agent 
belonging 
to 
pharmacological class RAS inhibitor. 
5. Patients who have symptoms suggestive of urinary tract infection or patients with gross 
haematuria. 


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6. Patients with a concomitant primary kidney disease. 
7. Patients with any systemic condition that could result in a glomerulopathy not related to 
SCD (e.g. diabetes mellitus, active hepatitis B or C infections, systemic lupus 
erythematosus, inflammatory arthropathies). 
8. Patient with a stage 3, 4 or 5 chronic kidney disease (eGFR < 60 mL/min per 1.73 m2). 
9.  Patients with eGFR ≥ 140 ml/min/1,73m² (due to the lack of information regarding the 
magnitude, direction and significance of the trends in eGFR evolution that could be 
expected in this population). 
10. Patients requiring long-term treatment with drugs potentially nephrotoxic (see non-
exhaustive list). 
11. Patients requiring ACE inhibitors or ARBs within the 3 months before inclusion 
regardless of the indication. 
12. Patients requiring long-term treatment with non-steroidal anti-inflammatory drugs. 
13. Patients who have treatment which can modify the kidney function (see non-exhaustive 
list) in the last 3 months. 
14. Patients known to be infected with HIV. 
15. Female patients who are pregnant or lactating. 
16. Unreliable patients including non-compliant patients, patients with known alcoholism 
or drug abuse or with a history of a serious psychiatric disorder as well as patients 
unwilling to give informed consent or to abide by the requirements of the protocol. 
17. Simultaneous participation in other clinical trials of an investigational medicinal 
product or previous participation within 30 days before inclusion. 
18. Persons in detention by judicial or administrative decision. 
19. Patients with chronic conditions that upon investigator judgment may lead to a limited 
life expectancy. 
 
4.4 
RANDOMISATION 
Eligible patients will be randomised in a 1:1 ratio to either hydroxycarbamide or placebo. 
The randomisation will be stratified by baseline ACR (≤30 mg/mmol and >30 mg/mmol). 
 
4.5 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical trial but 
are not subsequently randomly assigned to the study intervention or entered in the study. 
A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure participants, to meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements and to respond to queries from regulatory 


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authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any serious adverse event (SAE). 
 
Individuals experiencing any event or condition during the screening period (screen failure) 
leading to exclusion from the study according to exclusion criteria of this protocol may be 
re-screened once the reason for exclusion is solved.  
 
Rescreened participants will be assigned the same participant number as for the initial 
screening.  
 
 


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5. SCHEDULE OF STUDY VISITS 
Study assessments will be performed from screening (V1) to end-of-study visit (V6, 
Month 12). Patients will attend a total of 6 visits at the clinical centre. The detail of study 
visits and assessments is provided hereafter and in Table 3 Flow chart of study visits and 
assessments.  
 
Table 3 
Flow chart of study visits and assessments 
 
FLOW CHART OF STUDY VISITS AND ASSESSMENTS 
 
 
 
 
Pre-treatment 
phase 
Treatment phase 
 
Screenin
g 
 
Inclusion 
(Random
isation) 
Follow-
up visit 
Follow-
up or 
End of 
study 
visit1 
Follow-
up Visit2  
Follow-
up Visit2 
 
End of 
study/  
Early 
termination 
Visit number 
V1 
V2 
V3 
V4 
V5 
V6 
 
Schedule (month/day) 
D-30 - 
D0 
D0 
M3 
D90±14 
M6 
D182±14 
M9 
D273±14 
M12 
D365±14 
 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
Randomisation 
 
X 
 
 
 
 
 
Demographic information 
X 
 
 
 
 
 
 
Medical and surgical history 
X 
 
 
 
 
 
 
Previous medication(s)3 
X 
 
 
 
 
 
 
Concomitant medication(s) (CM) 
X 
X 
X 
X 
X 
X 
X 
Physical examination and blood pressure 
X 
X 
X 
X 
X 
X 
X 
Semen cryopreservation4 
X 
 
 
 
 
 
 
Haematology5 
Blood sampling 
Results 
Prescription6 
Biobank blood sample7 
 
X 
 
 
X 
 
 
X 
X 
 
 
X 
X 
 
 
 
X 
X 
 
X 
 
X 
X 
 
 
 
X 
X 
 
X 
 
X 
X 
 
X 
Biochemistry8 
Blood sampling    
Results 
 
X 
 
 
 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
Screening for HIV, HBV, HCV 
Blood sampling 
Results 
 
X 
 
 
 
X 
 
 
 
 
 
Pregnancy test9 for women 
Blood sampling 
 
X 
 
 
 
 
 
 
 


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ACR: Albumin-to-Creatinine Ratio; AE: Adverse Event; CM: Concomitant Medication; D: Day; HBV: 
Hepatitis B Virus; HCV: Hepatitis C Virus; HIV: Human Immunodeficiency Virus; M: Month; SCD: 
Sickle Cell Disease; V: Visit. 
1For unresponsive patients or responsive patients unwilling to continue the study, this visit will be the End of 
study visit. 
2Additional visits only for patients qualified as responders and willing to continue the study. 
3Previous blood transfusions and previous administration of hydroxycarbamide will be reported. 
4Not required if semen cryopreservation was already performed in the past. If semen volume or viable sperm 
cell amount is insufficient for cryopreservation of the collected sample, a spermogram will be performed and 
conserved in CECOS during the whole duration of the study. A control spermogram could be performed in 
patients at least 6 months and at most 9 months after the last dose of treatment. 
5The following assessments will be performed: WBC and differential counts, platelets, MCV, MCHC, MCH, 
Hb, HbF, free Hb, %DRBCs, reticulocytes, endogenous EPO, and ferritin 
6At V2, prescription will be given for hematology assessment in local lab 1 month after treatment initiation. 
7Optional exploratory biobank: blood and urine samples for patients from French sites only. 
8The following assessments will be performed: LDH, AST, ALT, BUN, conjugated and total bilirubin and 
blood creatinine for glomerular filtration rate (GFR) calculation. The CKD-EPI formula will be used for 
eGFR calculation. In addition, fasting glycemia and Glycated haemoglobin (HbA1c) may be assessed before 
V2 upon investigator decision. 
eGFR (millilitres per minute per 1.73 m2) = 141 × min (Scr/k,1)α × max(Scr/k,1)-1.209 × 0.993Age × 1.018 (for 
women), where Scr is serum creatinine, k is 0.7 for women and 0.9 for men, α is -0.329 for women and -
0.411 for men, min indicates the minimum of Scr/k or 1, and max indicates the maximum of Scr/k or 1. eGRF 
calculation will be automated in the eCRF, based on serum creatinine level, age and sex. 
9Pregnancy tests will be performed on blood. 
10At V1 and V3 for all patients, and at V5 for patients qualified as responders and willing to continue the 
study: patients will receive a prescription and a collection kit for urine analysis. First morning urine samples 
will be collected between 6. 30 and 8. 30 a.m. during 3 consecutive days before V2 and V4 for all patients, 
and before V6 for patients qualified as responders willing to continue the study. Assessments of hematuria, 
Result 
 
X 
Check of contraceptive use 
X 
X 
X 
X 
X 
X 
X 
Urine analysis : 
 
 
 
 
 
 
 
prescription and a collection kit for urine 
analysis 
X10 
 
X10 
 
X10 
 
 
ECBU and  Hematuria during 3 
consecutive days 
X10 
 
 
X10 
 
X10 
X10 
Urine albumine and urine creatinine for 
ACR during 3 consecutive days 
X10 
 
 
X10 
 
X10 
X10 
Results 
 
X11 
 
X12 
 
X12 
X 
Intermediate local analysis of urine 
albumin and urine creatinine for ACR on 
one day 
 
 
 X 
 
 X 
 
 
Biobank blood and urine sample7 
X 
 
 
X 
 
X 
X 
Dispensation of study treatment13 
 
X 
X 
X14 
X14 
 
 
Compliance to study treatment 
 
 
X 
X 
X 
X 
X 
Assessment of AEs 
 
X 
X 
X 
X 
X 
X 
Diary cards (reporting of drug 
intake/AE/CM/SCD events) 
 
 
 
 
 
 
 
- Dispensing 
 
X 
X 
X 
X 
 
 
- Collection/review 
 
 
X 
X 
X 
X 
X 


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CBEU, urine albumin and urine creatinine for ACR evaluation will be performed at a local lab or at 
investigator’s site. 
11At V2, ACR result will be reported in the CRF and used for randomization. 
12In case of ACR≥100 mg/mmol, a local assessment of ACR will be performed one month later to confirm 
ACR result. Patients will receive a prescription and a collection kit for local ACR assessment on first morning 
urine samples collected during 3 consecutive days. 
13This study is double-blinded. 
14Only for patients qualified as responders and willing to continue the study.  
5.1 
SCREENING VISIT (V1, D-30) 
Before performing any specific study procedures, patients must have signed a written 
informed consent form (ICF). 
The following screening assessments (Table 4) will be performed prior to the initiation of 
treatment, in order to verify the inclusion/exclusion criteria and to collect baseline values 
of the patient. The data will be reported in the electronic case report form (eCRF) for each 
consenting patient. 
Table 4 
Assessments/procedures to be performed at screening visit (V1) 


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Socio-demographic information 
Gender, month and year of birth, continent of origin.  
Medical history 
− SCD genotype (beta mutation) 
− Assessment of SCD disease (list of organs impaired by 
the disease) 
− Other relevant medical history 
Previous medications 
− SCD treatment history: blood transfusions (start and 
end dates), hydroxycarbamide (start and end dates, last 
dose).  
− SCN treatment history: ACE inhibitors and ARBs (start 
and end dates). 
Concomitant medications 
Collection of concomitant medications received within the 
30 days prior to inclusion. 
Physical examination 
General appearance (report any abnormal signs), body 
weight, height, physical examination focused on the 
criteria specified in the CRF. 
Vital signs 
Resting systolic and diastolic blood pressure, heart rate, 
body temperature. 
Haematology 
WBC including differential counts, platelets, MCV, 
MCHC, MCH, Hb, free Hb, HbF, %DRBCs, reticulocytes, 
endogenous EPO, and ferritin. 
Optional : Blood samples to identify any biomarkers  
predictive of SCN will be collected and sent to the central 
biobank laboratory 
Biochemistry 
Creatinine (for eGFR calculation), LDH, AST, ALT, 
conjugated and total bilirubin, BUN. Fasting glycemia and 
glycated haemoglobin (HbA1c) levels upon investigator 
judgement 
Virology 
Screening for HIV, HBV and HCV 
Pregnancy test (for women) and 
check of contraceptive use 
Pregnancy tests will be performed on blood. 
Semen cryopreservation 
If not already done, semen cryopreservation will be done 
before inclusion (except for vasectomized patients). If 
semen volume or amount of viable cells in the collected 
sample is insufficient for cryopreservation, a spermogram 
will be performed and conserved in CECOS during the 
whole duration of the study. A control spermogram could be 
performed in patients at least 6 months and at most 9 months 
after the last dose of treatment. 
 


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Urinalysis 
- Patients will receive a prescription for urine analysis 
(Hematuria, CBEU and ACR). They will also be 
provided with kit and guidelines for urine sample 
collection and storage. They will be asked to collect at 
home first morning urine samples on 3 consecutive days 
for the evaluation of ACR. Samples will be collected 
between 6.30 and 8.30 a.m. and the patient will bring the 
sample to a local laboratory of his/her choice or to the 
investigator’s site every day or the 3 samples on the third 
day at the most convenient for the patient. The laboratory 
will be the same for the subsequent analyses.  
- Optional : Urine samples to identify any biomarkers  
predictive of SCN will be collected and sent to the central 
biobank laboratory 
 
ACR: Albumin-creatinine ratio; ALT: Alanine Amino Transférase; AST: Aspartate aminotransferase; BUN: 
Blood urea nitrogen; CBEU: Cytobacteriological examination of the urine; eGFR: estimated glomerular 
filtration rate; EPO; erythropoietin; Hb: Heamoglobin; HbF; Foetal haemoglobin; HBV: Hepatitis B Virus; 
HCV: Hepatitis C Virus; HIV: Human Immunodeficiency Virus; LDH: Lactate dehydrogenase; MCH: Mean 
corpuscular haemoglobin; MCHC: Mean corpuscular haemoglobin concentration; MCV: Mean corpuscular 
volume; SCD: Sickle Cell Disease; WBC: White blood count; %DRBCs: percentage of dense red blood cells. 
 
The Investigator will also explain to the patient the modalities of the treatment, and review 
the unauthorised treatments during the study. 
5.2 
INCLUSION VISIT (V2, D0) 
Patients who have signed the ICF, who have successfully completed the screening visit, 
who meet all inclusion criteria and do not demonstrate any exclusion criteria will be 
included in the study and will be randomised to either hydroxycarbamide or placebo. 
Assessments/procedures to perform during the inclusion visit are described in Table 5. 
 


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Table 5 
Assessments/procedures to be performed at inclusion visit (V2) 
Concomitant medications 
Collection of concomitant medications received since 
screening. 
Physical examination 
General appearance (report of any abnormal signs), body 
weight, height, physical examination focused on the 
criteria specified in the CRF. 
Vital signs 
Resting systolic and diastolic blood pressure, heart rate, 
body temperature. 
Recording and assessment of AEs  
AEs, SAEs. 
Contraceptive use 
Use of contraceptive will be checked. 
Urinalysis 
Collection of Hematuria and CBEU results. 
Randomisation 
Collection of ACR evaluation result for randomisation 
Dispensation of study treatment by 
pharmacist 
According to the randomisation. The study is double-
blinded. 
Prescription 
for 
complete 
hematology assessment in local lab  
Complete hematology assessment will be performed in 
local lab 1 month after treatment initiation at least. 
Diary cards 
Patients will be provided with diary cards. 
AE: Adverse event; ACR: Albumin-creatinine ratio; CBEU: Cytobacteriological examination of the urine; 
SAE: Serious Adverse event.  
5.3 
FOLLOW-UP VISITS 
As described in the flow chart, 4 follow-up visits are planned:  
• Visit 3 will be performed at the clinical centre 3 months ± 14 days after treatment 
initiation. 
• Visit 4 will be performed at the clinical centre 6 months ± 14 days after treatment 
initiation. 
• Visit 5 will be performed at the clinical centre 9 months ± 14 days after treatment 
initiation for responder patients willing to continue the study. 
• Visit 6 will be performed at the clinical centre 12 months ± 14 days after treatment 
initiation for responder patients willing to continue the study. 
Assessments/procedures to perform during these visits are described in Table 6 (V3 and 
V5), Table 7 (V4) and Table 8 (V6). 
 


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Table 6 
Assessments/procedures to be performed at V3 and at V5 for responder 
patients willing to continue the study  
Concomitant medications 
Collection of concomitant medications received since last 
visit. 
Physical examination 
General appearance (report any abnormal signs), body 
weight, height, physical examination focused on the 
criteria specified in the CRF. 
Vital signs 
Resting systolic and diastolic blood pressure, heart rate, 
body temperature. 
Contraceptive use 
Use of contraceptive will be checked at each visit. 
Haematology 
WBC including differential counts, platelets, MCV, 
MCHC, MCH, Hb, free Hb, HbF, %DRBCs, reticulocytes, 
endogenous EPO, and ferritin. 
Biochemistry 
Creatinine (for eGFR calculation), haemolysis markers 
(LDH, AST, ALT, BUN, conjugated and total bilirubin). 
Urinalysis 
- Local first-morning urine albumin and urine creatinine 
for assessment of ACR,  
- CBEU, Hematuria 
Patients will receive a prescription for urine analysis 
(hematuria, CBEU and ACR). They will also be provided 
with kit and guidelines for urine sample collection and 
storage. They will be asked to collect at home first morning 
urine samples on 3 consecutive days for the evaluation of 
ACR at V4 and at V6 for responder patients willing to 
continue the study. Samples will be collected between 6.30 
and 8.30 a.m. and the patient will bring the sample to a 
local laboratory of his/her choice or to the investigator’s 
site every day or the 3 samples on the third day at the most 
convenient for the patient. The laboratory will be the same 
for all analyses of the patient. 
Recording and assessment of AEs  
Treatment-emergent AEs, SAEs, and SCD-related events. 
Dispensation of study treatment 
According to the randomisation. The study is double-
blinded. 
Compliance to study treatment 
Patients will have to return the packaging of the used study 
treatment as well as the unused study treatment. 
Diary cards 
Completed diary cards will be collected and reviewed. 
Patients will be provided with new diary cards. 
ACR: Albumin-creatinine ratio; AE: Adverse event;; ALT: Alanine Amino Transférase; AST: Aspartate 
aminotransferase; BUN: Blood urea nitrogen; CBEU: Cytobacteriological examination of the urine; eGFR: 
estimated glomerular filtration rate; EPO; erythropoietin; Hb: Haemoglobin; HbF; Foetal haemoglobin; 
LDH: Lactate dehydrogenase; MCH: Mean corpuscular haemoglobin; MCHC: Mean corpuscular 
haemoglobin concentration; MCV: Mean corpuscular volume; SAE; Serious adverse event; SCD: Sickle Cell 
Disease; V: Visit; WBC: White blood count; %DRBCs: percentage of dense red blood cells. 
 


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Table 7 
Assessments/procedures to be performed at V4 
Concomitant medications 
Collection of concomitant medications received since last 
visit. 
Physical examination 
General appearance (report any abnormal signs), body 
weight, height, physical examination focused on the 
criteria specified in the CRF. 
Vital signs 
Resting systolic and diastolic blood pressure, heart rate, 
body temperature. 
Contraceptive use 
Use of contraceptive will be checked at each visit. 
Haematology 
WBC including differential counts, platelets, MCV, 
MCHC, MCH, Hb, free Hb, HbF, %DRBCs, reticulocytes, 
endogenous EPO, and ferritin. 
Optional : Blood samples to identify any biomarkers  
predictive of SCN will be collected and sent to the central 
biobank laboratory 
Biochemistry 
Creatinine (for eGFR calculation), haemolysis markers 
(LDH, AST, ALT, BUN, conjugated and total bilirubin). 
Urinalysis 
- Collection of hematuria, CBEU and ACR results. In case 
of omission, the patient will be reminded to collect urine 
samples on 3 consecutive days as early as possible. 
Optional : Urine samples to identify any biomarkers  
predictive of SCN will be collected and sent to the central 
biobank laboratory 
Recording and assessment of AEs  
Treatment-emergent AEs, SAEs, and SCD-related events. 
Dispensation of study treatment 
According to the randomisation and only for patients 
qualified as responders willing to continue to participate in 
the trial. The study is double-blinded. 
Compliance to study treatment 
Patients will have to return the packaging of the used study 
treatment as well as the unused study treatment. 
Diary cards 
Completed diary cards will be collected and reviewed. 
Patients will be provided with new diary cards. 
ACR: Albumin-creatinine ratio; AE: Adverse event;; ALT: Alanine Amino Transférase; AST: Aspartate 
aminotransferase; BUN: Blood urea nitrogen; CBEU: Cytobacteriological examination of the urine; eGFR: 
estimated glomerular filtration rate; EPO; erythropoietin; Hb: Haemoglobin; HbF; Foetal haemoglobin; 
LDH: Lactate dehydrogenase; MCH: Mean corpuscular haemoglobin; MCHC: Mean corpuscular 
haemoglobin concentration; MCV: Mean corpuscular volume; SAE; Serious adverse event; SCD: Sickle Cell 
Disease; V: Visit; WBC: White blood count; %DRBCs: percentage of dense red blood cells. 
 
 


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Table 8 
Assessments/procedures to be performed at V6 for responder patients 
willing to continue the study only 
Concomitant medications 
Collection of concomitant medications received since last 
visit. 
Physical examination 
General appearance (report any abnormal signs), body 
weight, height, physical examination focused on the 
criteria specified in the CRF. 
Vital signs 
Resting systolic and diastolic blood pressure, heart rate, 
body temperature. 
Contraceptive use 
Use of contraceptive will be checked at each visit. 
Haematology 
WBC including differential counts, platelets, MCV, 
MCHC, MCH, Hb, free Hb, HbF, %DRBCs, reticulocytes, 
endogenous EPO, and ferritin. 
Optional : Blood samples to identify any biomarkers  
predictive of SCN will be collected and sent to the central 
biobank laboratory 
Biochemistry 
Creatinine (for eGFR calculation), haemolysis markers 
(LDH, AST, ALT, BUN, conjugated and total bilirubin). 
Urinalysis 
Collection of hematuria, CBEU and ACR results. In case 
of omission, the patient will be reminded to collect urine 
samples on 3 consecutive days as early as possible. 
Optional : Urine samples to identify any biomarkers  
predictive of SCN will be collected and sent to the central 
biobank laboratory 
Recording and assessment of AEs  
Treatment-emergent AEs, SAEs, and SCD-related events. 
Compliance to study treatment 
Patients will have to return the packaging of the used study 
treatment as well as the unused study treatment. 
Diary cards 
Completed diary cards will be collected and reviewed. 
End-of-study form 
Will be completed by the Investigator.  
ACR: Albumin-creatinine ratio; AE: Adverse event;; ALT: Alanine Amino Transférase; AST: Aspartate 
aminotransferase; BUN: Blood urea nitrogen; CBEU: Cytobacteriological examination of the urine; eGFR: 
estimated glomerular filtration rate; EPO; erythropoietin; Hb: Haemoglobin; HbF; Foetal haemoglobin; 
LDH: Lactate dehydrogenase; MCH: Mean corpuscular haemoglobin; MCHC: Mean corpuscular 
haemoglobin concentration; MCV: Mean corpuscular volume;  SAE; Serious adverse event; SCD: Sickle 
Cell Disease; V: Visit; WBC: White blood count; %DRBCs: percentage of dense red blood cells. 
5.4 
EARLY TERMINATION FOLLOW-UP VISIT 
In case of premature termination of the study, the patient will come for an early termination 
follow-up visit. The Investigator will try to collect all the information related to the end-
of-study visit and the end-of-study form will be completed. Assessments/procedures to 
perform are described in Table 9. 


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Table 9 
Assessments/procedures to be performed at early termination follow-up 
visits 
Concomitant medications 
Collection of concomitant medications received since last 
visit. 
Physical examination 
General appearance, body weight, height, physical 
examination focused on the criteria specified in the CRF. 
Vital signs 
Resting systolic and diastolic blood pressure, heart rate, 
body temperature. 
Contraceptive use 
Use of contraceptive will be checked at each visit. 
Haematology 
WBC including differential counts, platelets, MCV, 
MCHC, MCH, Hb, free Hb, HbF, %DRBCs, reticulocytes, 
endogenous EPO, and ferritin. 
Optional : Blood samples to identify any biomarkers  
predictive of SCN will be collected and sent to the central 
biobank laboratory 
Biochemistry 
Creatinine (for eGFR calculation), haemolysis markers 
(LDH, AST, ALT, BUN, conjugated and total bilirubin). 
Urinalysis 
- Hematuria, CBEU 
- Patients will receive a prescription for urine analysis. 
They will be asked to collect at home first morning urine 
samples on 3 consecutive days for the measurement of 
urine albumin and urine creatinine for assessment of 
ACR. Samples will be collected between 6.30 and 8.30 
a.m. and the patient will bring the sample to a local 
laboratory of his/her choice or to the investigator’s site 
every day or the 3 samples on the third day at the most 
convenient for the patient. The laboratory will be the 
same for all analyses of the patient. 
- Optional : Urine samples to identify any biomarkers  
predictive of SCN will be collected and sent to the central 
biobank laboratory 
Recording and assessment of AEs  
Treatment-emergent AEs, SAEs, SCD-related events. 
Compliance to study treatment 
Patients will have to return the packaging of the used study 
treatment as well as the unused study treatment. 
Diary cards 
Completed diary cards will be collected and reviewed. 
End-of-study form 
Will be completed by the Investigator.  
ACR: Albumin-creatinine ratio; AE: Adverse event; ALT: Alanine Amino Transférase; AST: Aspartate 
aminotransferase; BUN: Blood urea nitrogen; CBEU: Cytobacteriological examination of the urine; eGFR: 
estimated glomerular filtration rate; EPO; erythropoietin; Hb: Haemoglobin; HbF; Foetal haemoglobin; 
LDH: Lactate dehydrogenase; MCH: Mean corpuscular haemoglobin; MCHC: Mean corpuscular 
haemoglobin concentration; MCV: Mean corpuscular volume; SAE; Serious adverse event; SCD: Sickle Cell 
Disease; V: Visit; WBC: White blood count; %DRBCs: percentage of dense red blood cells. 
5.5 
END OF THE STUDY 
The study will be considered closed after the last patient has completed his/her last, 
planned, study-related visit. 
 


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6. STUDY ASSESSMENTS AND PROCEDURES 
Study assessments will be performed from screening to end-of-study visit (V4, Month 6 or 
V6, Month 12 for patients qualified as responders willing to continue to participate in the 
trial) or early termination visit according to the flow-chart. Patients will attend a total of 4 
(for all patients) to 6 (for responder patients willing to continue the study) visits at the clinic 
centre. All clinical laboratory analyses will be performed at the local laboratory, in 
compliance with good clinical practice and local requirements.  
6.1 
PHYSICAL EXAMINATION AND ASSESSMENT OF VITAL SIGNS 
The following examinations and assessments will be performed at each visit: 
- 
Vital signs: Respiratory rate, Body temperature, Heart rate and Blood 
pressure. Both systolic and diastolic resting blood pressure will be 
measured. The arm with the highest mean diastolic blood pressure at 
screening will be used for subsequent measurements. 
- 
Body weight 
- 
Height 
- 
Physical examination 
6.2 
ASSESSMENT OF URINE ALBUMIN AND URINE CREATININE FOR 
ACR EVALUATION 
Urine albumin and urine creatinine will be assessed in order to calculate ACR, according 
to the flowchart.   
- 
For assessment of urine albumin and urine creatinine on 3 consecutive days, 
patients will be provided with guidelines on urine collection, storage and 
delivery procedures. They will receive a prescription for urine analysis and 
a kit for urine collection. They will be asked to collect at home first morning 
urine samples in polyethylene containers on 3 consecutive days between 
6.30 and 8.30 a.m. Urine sample will be stored at room temperature until 
the patient brings the sample to a local laboratory of his/her choice or to the 
investigator’s site every day or the 3 samples on the third day at the most 
convenient for the patient. For one patient, the laboratory must be the same 
during the entire duration of the study.  
- 
Intermediate local analysis of urine albumin and urine creatinine will be 
done on first-monrning urine on site or in a medical laboratory for ACR 
calculation, in order to better determine the dynamic of the response.  
- 
If one of the three ACR values before randomization, at 6 or 12 months is 
considered to be very different from the other two values by the investigator, 
the patient will be asked to perfom an additional assessment of ACR in the 
following days. 


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- 
In case of ACR≥100 mg/mmol at 3, 6 or 9 months, an additional assessment 
of ACR will be performed one month later to confirm ACR result. Patients 
will receive a prescription and a collection kit for ACR assessment on first 
morning urine samples collected during 3 consecutive days. Urine sample 
will be stored at room temperature until the patient brings the sample to a 
local laboratory of his/her choice or to the investigator’s site every day or 
the 3 samples on the third day at the most convenient for the patient. 
 
6.3 
ASSESSMENT OF EGFR 
To date, MDRD study equation (Modification of diet in renal disease) and CKD-EPI 
equation (Chronic Kidney Disease Epidemiology Collaboration) are the most used formula 
to estimate the GFR (estimated GFR or eGFR). But unfortunately these equations have 
been developed from creatinine level, age and body weight of the patient in general 
population. However SCD population is different: slim people, non-Caucasian with an 
increase of tubular secretion of creatinine and sometimes hyperfiltration. 
CKD-EPI equation is particularly accurate to estimate high GFR values, including 
glomerular hyperfiltration, and thus should be recommended to screen SCD adult patients 
at high risk for SCD nephropathy. 
The eGRF will be calculated from the serum creatinine, age, and sex of the patient using 
the CKD-EPI formula, which has been demonstrated to be the best method to estimate GFR 
in SCD patients [20]:  
eGFR (millilitres per minute per 1.73 m2) = 141 × min (Scr/k,1)α × max(Scr/k,1)-1.209 × 
0.993Age × 1.018 (for women), where Scr is serum creatinine, k is 0.7 for women and 0.9 
for men, α is -0.329 for women and -0.411 for men, min indicates the minimum of Scr/k or 
1, and max indicates the maximum of Scr/k or 1.  
eGFR calculation will be automated in the eCRF. 
 
6.4 
ASSESSMENT OF HAEMATOLOGICAL AND BIOCHEMICAL 
PARAMETERS  
Heamatological and biochemical parameters will be assessed by the local laboratory. The 
following assessments wil be performed according to the flowchart: 
- 
Haematology: Red blood cell (RBC) count and Mean Corpuscular Volume, 
Dense Red Blood Cells (%DRBC), reticulocytes, Hemoglobin (Hb), free 
Hemoglobin (free Hb) and Fetal hemoglobin (HbF), Mean Corpuscular 
Hemoglobin (MCH) and Mean Corpuscular Hemoglobin Concentration 
(MCHC), hematocrit, White Blood Cell counts, neutrophils, lymphocytes, 


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monocytes, eosinophils, basophils and platelet counts, endogenous EPO and 
ferritin concentrations. 
- 
Blood biochemistry :  
 Renal function: blood Creatinine. 
 Haemolysis biochemical markers: Lactate Deshydrogenase (LDH), 
aspartate aminotransferase (AST), ALT, BUN, conjugated and total 
bilirubin. 
 
Fasting glycemia and glycated haemoglobin (HbA1c) levels upon 
investigator judgement 
An approximate volume of 20 mL of blood will be required for the set of assays on a given 
day. 
- 
Urinalysis: Hematuria and CBEU either locally, according to the flowchart. 
 For local assessment of hematuria and CBEU, patients will be 
provided with guidelines on urine collection, storage and delivery 
procedures. They will receive a prescription for urine analysis and a 
kit for urine collection. Urine samples will be stored at room 
temperature and the patient brings the sample to a local laboratory 
of his/her choice or to the investigator’s site every day or the 3 
samples on the third day at the most convenient for the 
patient.Intermediate analysis of hematuria and CBEU will be 
performed locally. 
6.5 
SEROLOGICAL ASSESSMENT 
Screening for HIV, HBV, HCV will be performed on blood samples. An approximate 
volume of 2.5 mL of blood will be required for the set of assays on a given day. 
 
6.6 
PREGNANCY TEST 
A pregnancy test will be performed on blood at screening. An approximate volume of 2.5 
mL of blood will be required for the set of assays on a given day. 
 
6.7 
SEMEN CRYOPRESERVATION 
Semen cryopreservation will be performed between screening and inclusion visit.  
If semen volume or amount of viable cells in the collected sample is insufficient for 
cryopreservation, a spermogram will be performed and conserved in CECOS during the 
whole study duration. A control spermogram could be performed in patients at least 6 
months and at most 9 months after the last dose of treatment. 
 
 


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6.8 
ASSESSMENT OF ADVERSE EVENTS 
Adverse events experienced during the trial will be recorded both in the source documents 
and in the eCRF. Patients will be asked to document all experienced medically relevant 
events in the patient diary. Events reported in the patient diary cards will be reviewed by 
the investigator at each visit. In addition, patients will be queried at each visit about the 
medical events experienced.  
SCD-related events will be recorded at each visit. 
Treatment-emergent adverse events (AEs) and serious AEs (SAEs) will be assessed at V2 
(inclusion), V3 (Month 3), V4 (Month 6), V5 (Month 9) and V6 (Month 12). Full details 
of safety assessments are presented in Section 8. 
 
6.9 
OPTIONAL BIOBANK 
A biobank of patient’s sera blood and urine samples will be created.  Urine samples (in 
protease inhibitor-containing tubes) and blood samples (1 heparin and 1 EDTA tubes) will 
be collected at V1 (Screening), V4 (Month 6) and V6 (Month 12) on patients having given 
written informed consent (ICF) for sample collection, storage and use for the BIOBANK 
exploratory analyses. Urine and sera blood will be processed, aliquoted and stored until 15 
years after the end of the study (Last Patient Last Visit). Of note, sample collection at V6 
will only be performed for patients qualified as responders willing to continue to participate 
in the trial. 
The precise analyses that will be performed on these samples will depend on advances in 
the identification of SCN mechanisms and biomarkers until the end of the SIKAMIC trial. 
Unused samples will be destroyed 15 years after the end of the study. 
 
7. STUDY TREATMENTS 
7.1 
RATIONALE FOR DOSE SELECTION 
According to the EU label, the posology should be based on the patient’s bodyweight and 
the recommended starting dose is 15 mg/kg bw/day. In a recent cohort study, this dose was 
found to significantly lessen urine ACR in SCD adult patients with microalbuminuria 
treated for 6 months with hydroxycarbamide [17]. The median hydroxycarbamide dose 
reported by authors at month 6 was 15 [12–18] mg/kg bw/day. 
Therefore, in the present study, hydroxycarbamide will be prescribed at a dose of 
15 mg/kg bw/day in line with label recommendations and previous works in the field. 
7.2 
DOSE ADJUSTMENT AND TEMPORARY INTERRUPTION 
Possible adjustments of daily dose may be needed: 


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• If blood counts are within the toxic range (neutrophils < 1,500/mm³, platelets 
< 80,000/mm³, haemoglobin < 4.5 g/dL, reticulocytes < 80,000 mm³ if 
haemoglobin concentration < 9 g/dL), the treatment will be temporarily 
discontinued until blood counts recover or the dose reduced, upon investigator’s 
judgement. The dose may be reduced to 12.5 mg/kg bw/day or 10 mg/kg bw/day. 
In case of treatment discontinuation, treatment may then be reinstituted at a reduced 
dose of 12.5 mg/kg bw/day or 10 mg/kg bw/day, upon investigator’s judgement. 
 
Administration Schedule : 
The tablet(s) will be taken once daily, preferably in the morning before breakfast, where 
necessary, with a glass of water or a very small amount of food.  
Patients assigned to the placebo group will receive placebo tablets according to the same 
schedule as patients in the hydroxycarbamide group. 
7.3 
IDENTITY OF STUDY TREATMENTS 
Both hydroxycarbamide and placebo will be formulated and supplied as identical tablets 
concerning the colour, size and shape. They will be packed in identical plastic bottles. 
 
Hydroxycarbamide group 
Name of the medicinal product: Siklos® 100 mg or 1000 mg film-coated tablets. 
Active ingredient: hydroxycarbamide 100 mg or 1000 mg. 
Excipients: sodium stearyl fumarate, silicified microcrystalline cellulose and basic 
butylated methacrylate copolymer. 
Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents. 
Anatomical Therapeutic Chemical (ATC) code: L01XX05. 
Pharmaceutical forms:  
Siklos® 100 mg: off-white oblong-shaped, film-coated tablet with half-scoring on 
both sides. 
Siklos® 1000 mg: off-white, capsule-shaped, film-coated tablet with triple scoring 
on both sides.  
Dosage: 15 mg/kg bw/day, tablet(s) taken preferably in the morning before breakfast. 
Route of administration: oral. 
Special precautions for storage: do not store above 30°C.  
Manufacturer: Delpharm 
 
Placebo group 


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Composition: sodium stearyl fumarate, sodium starch glycolate (type A), silicified 
microcrystalline cellulose and basic butylated methacrylate copolymer. 
Pharmaceutical forms: placebo tablets formulated to be identical in appearance to Siklos® 
100 mg or 1000 mg. 
Route of administration: oral. 
Special precautions for storage: do not store above 30°C.  
Manufacturer: Delpharm 
7.4 
SUPPLY AND STORAGE CONDITIONS OF THE STUDY PRODUCTS 
The study products will be manufactured, tested, handled, and stored in accordance with 
Good Manufacturing Practice (GMP) requirements for clinical trials and used in 
accordance with the protocol.  
The study products will be sent to the pharmacy of centre with the appropriate documents. 
As soon as the pharmacist receives the study products, she/he must fill in and sign the 
acknowledgement of receipt form in the IWRS. A copy must be kept with the Pharmacist 
for his/her study file and the original must be returned to the Sponsor. 
The treatments must be stored in a dry, secured area, at room temperature and will be under 
the direct responsibility of pharmacist at that study centre. None of the study products 
should be stored above 30ºC. Study treatments will be dispensed by the Pharmacist at V2 
(D0, inclusion), and V3 (Month 3). Dispensation will also be done at V4 (Month 6) and V5 
(Month 9) for patients qualified as responders willing to continue to participate in the trial. 
The Pharmacist is required to keep appropriate documentation of the delivery, use and 
destruction, or the return of unused, used or partially used packages of study products. The 
documentation must include dates, quantities, patient numbers, batch/serial numbers or 
other identification number, expiry dates and the means to identify the patient to whom it 
was given. 
All treatments supplied by the Sponsor and given to the pharmacy must be adequately 
accounted for during periodic monitoring visits as the study progresses. All study products, 
used or unused, will be destroyed by the centre at the end of the study. 
7.5 
PACKAGING AND LABELLING OF THE STUDY PRODUCTS 
The study products will be labelled in accordance with GMP requirements for clinical 
trials. All the procedures to keep the blind conditions as well as the packaging and labelling 
procedures will be conducted by Creapharm. 
The study products will be packaged in plastic bottles of 60 tablets of 100 mg and 30 tablets 
of 1000 mg. 


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7.6 
CONCOMITANT TREATMENTS 
7.6.1 Authorised medications during the study 
Concomitant medication, as long as it is not mentioned under Section 4.3, is allowed but 
has to be documented in the eCRF. Information to be provided are: trademark or 
International Non-proprietary Name, route, dose, frequency, reason for therapy, date of 
onset and of cessation. The patient should not take any concomitant treatment without the 
Investigator’s knowledge. 
7.6.2 Unauthorised medications during the study 
The following concomitant medications that might interfere with the clinical results are 
prohibited over the course of the study: 
 
7.6.2.1 Patients who have treatment which can modify the kidney function (see non-
exhaustive list) in the last 3 months. 
The drugs listed below may have direct action on kidneys and could modify parameters of 
evaluation of renal function (e.g. diuretics, NSAIDS…). For this reason, the use of these 
drugs must be limited or preferably stopped before the enrolment of the patient. This list is 
not exhaustive and any drug which could potentially act on renal function must be avoided.  
• ACE inhibitors or ARBs (prohibited except in a rescue way). 
• NSAIDs: in case of NSAID therapy, treatment should be discontinued at least for the 
15 days prior to any urine sample collection for ACR assessment. 
• Any other treatment that might alter kidney function: their use must be restricted and 
taken into consideration at the start and all along the study. 
- Diuretics 
- Sartans 
- Aliskiren 
- Sacubitril/valsartan 
- Gliflozin drugs 
7.6.2.2 Nephrotoxic drugs (most of these medicines are indicated for the treatment of 
chronic diseases which are among the exclusion criteria of the study): 
The drugs listed below may potentially causes renal damages. These medicines must not 
be used during the study 
- Antibiotics : aminosides, vacomycin, dalbavancin, teicoplanin, telavancin, 
cefalotin, polymyxins, fluoroquinolones, sulfamides 
- Antifungals : Amphotericin B, voriconazole 
- Antivirals : tenofovir, adefovir, aciclovir, valaciclovir, famciclovir, ganciclovir, 
cidofovir, foscarnet 
- Antiparasitics : pentamidine 
- Platinum-derivatives : carboplatine, cisplatine, oxaliplatine 


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- Other chemotherapeutic agents : ifosfamide, raltitrexed, eribulin, cabazitaxel, 
aldesleukin, sorafenib 
- Immunosuppressive agents : cyclosporine, tacrolimus, sirolimus, everolimus 
- Intravenous immunoglobulin (IVIG) products, especially IVIG products stabilized 
with sucrose 
- Iron-chelating agents : deferasirox, deferoxamine 
- osmotic agents : mannitol 
- Mood stabilizers : lithium 
- Iodinated contrast agents 
- Antiplatelet agents : ticagrelor, cangrelor 
- Antilipemic agents : fibrates 
- Blood glucose lowering drugs : exenatide, dulaglutide, liraglutide 
 
This list of medication is not exhaustive and the investigator should ensure that 
nephrotoxicicity is not among the side effects of any medicine prescribed during the course 
of the study. 
7.7 
COMPLIANCE 
Subject compliance will be critical and will therefore be monitored in multiple ways.  
Patients will receive instructions and guidelines about the medication intake procedure and 
will be required to report on a diary card any deviation to the treatment administration 
schedule. 
At each visit after inclusion (V2, D0), the patient will be asked to bring back the bottles of 
the test drug used during the previous study period. The study centres will verify the 
treatment compliance by counting the number of placebo or hydroxycarbamide tablets left 
from the previous visit and by reviewing information recorded in the diary card and will 
document these quantities in the appropriate section of the eCRF.  
Patients will be regarded as compliant if the calculated compliance is at least 80% of the 
study medication required to be taken during the study, unless a dose is withheld due to 
AEs or other unavoidable reasons (requires approval by the Investigator). Patients deemed 
to be non-compliant will be withdrawn from the study and the end-of-study form will be 
filled out. 
 
8. ADVERSE EVENTS 
8.1 
DEFINITIONS 
ADVERSE EVENT (AE) 
According to International Conference on Harmonisation (ICH) Guideline, an AE is any 
untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event can therefore be any unfavourable and unintended sign 


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(including an abnormal laboratory finding), symptom or disease temporally associated with 
the use of the medicinal (investigational) product, whether or not the event is considered 
causally related to the use of the investigational product.  
 
SERIOUS ADVERSE EVENT (SAE) 
If an adverse event meets any of the following criteria, it is considered a serious adverse 
event (SAE): 
Death of Patient: 
An event that results in the death of a patient. 
Life-Threatening: 
An event that, in the opinion of the investigator, would 
have resulted in immediate fatality if medical 
intervention had not been taken.  This does not include 
an event that would have been fatal if it had occurred 
in a more severe form. 
Hospitalization: 
An event that results in an admission to the hospital for 
any length of time.  This does not include an emergency 
room visit or admission to an outpatient facility (see 
exceptions below). 
Prolongation of 
Hospitalization: 
An event that occurs while the study patient is 
hospitalized and prolongs the patient's hospital stay. 
Congenital Anomaly/birth 
defect: 
An anomaly detected at or after birth, or any anomaly 
that results in fetal loss. 
Persistent or Significant 
Disability/Incapacity: 
An event that results in a condition that substantially 
interferes with the activities of daily living of a study 
patient.  Disability is not intended to include 
experiences of relatively minor medical significance 
such as headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle). 
Important Medical Event: 
An important medical event that may not be 
immediately life-threatening or result in death or 
hospitalization, but based on medical judgment may 
jeopardize the patient or may require medical or 
surgical intervention to prevent any of the outcomes 
listed above (i.e., death of patient, life threatening, 
hospitalization, 
prolongation 
of 
hospitalization, 
congenital anomaly, or persistent or significant 
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Additionally, any elective or spontaneous abortion or 
stillbirth is considered an important medical event.  
Examples 
of 
such 
events 
include 
allergic 
bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or 
convulsions 
that 
do 
not 
result 
in 
inpatient 
hospitalization, 
or 
the 
development 
of 
drug 
dependency or drug abuse. 
 
Exceptions: 
• Planned hospitalization for medical/surgical procedure 
• Routine health assessment requiring admission for baseline/trending of health 
status documentation (e.g.: routine colonoscopy) 
• Medical/surgical admission for purpose other than remedying ill health state 
(planned prior to entry in study trial; appropriate documentation required) 
• Admission encountered for other life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (e.g. lack of housing, economic 
inadequacy, care-giver respite, family circumstances, administrative) 
 
SAFETY ISSUES 
All unexpected events that might materially influence the benefit-risk assessment of the 
medicinal product or that would lead to changes in the administration of a medicinal 
product, in overall conduct of a clinical trial, in the study documents. 
Examples of such unexpected events include an increase in the rate of occurrence of 
expected serious adverse reactions which may be clinically important, a significant hazard 
to the patient population, such as lack of efficacy of a medicinal product, or a major safety 
finding from a newly completed animal study (such as carcinogenicity), a temporary halt 
of a trial for safety reasons if the trial is conducted with the same investigational medicinal 
products in another country by the same sponsor. 
8.2 
COLLECTION AND ASSESSMENT OF ADVERSE EVENTS BY THE 
INVESTIGATOR 
The investigator will monitor each patient for AEs on a routine basis throughout the study. 
The investigator will assess and record any SAE data in detail, including the date of onset, 
description, severity, duration and outcome (when known), relationship of the event to the 
study drug, an event diagnosis, if known, and any action(s) taken.  
Whenever possible, diagnosis or syndrome name should be preferred to symptoms. For all 
AEs, the investigator must seek to obtain all the information in order to adequately 


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determine the outcome of the AE and assess whether it meets the criteria for classification 
as an SAE as well as to determine causal relationship. 
8.2.1 Seriousness  
Refer to the definition given in Section 8.1. (Serious adverse event) 
8.2.2 Severity  
The following definitions will be used to rate the severity for any adverse event being 
collected as an endpoint/data point in the study and for all serious adverse events. 
Mild: 
The adverse event is transient and easily tolerated by the patient. 
Moderate: 
The adverse event causes the patient discomfort and interrupts the 
patient's usual activities. 
Severe: 
The adverse event causes considerable interference with the 
patient's usual activities and may be incapacitating or life 
threatening. 
The term ‘severe’ is often used to describe the intensity (severity) of a specific event (as in 
mild, moderate or severe myocardial infarction); the event itself, however, may be of 
relatively minor medical significance (such as severe headache). This criterion is not the 
same as ‘serious’, which is based on patient/event outcome or action criteria usually 
associated with events that pose a threat to a patient’s life or functioning. Seriousness (not 
severity) serves as a guide for defining regulatory obligations. 
8.2.3 Relationship to investigational product  
The following definitions will be used to assess the relationship of the adverse event to 
the use of product: 
At least a reasonable 
Possibility 
The temporal relationship of the AE to study treatment 
administration makes a causal relationship possible, and 
other 
medications, 
therapeutic 
interventions, 
or 
underlying conditions do not provide a sufficient 
explanation for the observed event. 
No Reasonable Possibility 
The temporal relationship of the AE to study treatment 
administration makes a causal relationship unlikely or 
remote, or other medications, therapeutic interventions, or 
underlying conditions provide a sufficient explanation for 
the observed event. 


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8.2.4 Action taken with study treatment 
The Investigator will report the dose reduction, dose interruption, or study treatment 
discontinuation (if any) following an AE. He/she will also report the addition of other 
medications to treat the AE.  
8.2.5 Outcome 
At the time of the last observation, the Investigator will classify the event as:  
• Resolved: The AE is no longer present at any intensity – symptoms have completely 
abated. 
• Resolving: The AE is being resolved  
• Resolved with sequelae: The AE is resolved but has resulted in consecutive 
symptom(s) or has not returned to baseline. 
• Not resolved: The AE has not resolved, but is still present with the same intensity.  
• Fatal: This AE directly caused or contributed to patient´s death. 
• Unknown: There is no information available on the outcome of the event. 
8.2.6 Laboratory test abnormalities 
All laboratory test values captured as part of the study should be recorded on the 
appropriate laboratory test results pages of the CRF. When capturing AE laboratory 
abnormalities, the clinical, rather than the laboratory term should be used by the reporting 
investigator wherever possible (e.g., anemia versus low hemoglobin value) and graded 
according to the NCI CTCAE v 4.0. Laboratory abnormalities corresponding to grades 3, 
4, 5 should be considered serious and reported by the investigator to the sponsor as SAEs 
under the timelines defined in the next section.  
Exception: 
In the context of this study, neutropenia with polymorphonuclear neutrophil count > 1.5 x 
109/L should not be considered as SAE (see also section 8.3.2 below). 
8.3 
REPORTING OF ADVERSE EVENTS AND SAFETY ISSUES BY THE 
INVESTIGATORS 
8.3.1 Serious adverse events (SAEs) and safety issues 
The investigator shall notify the sponsor, immediately on the day of awareness, of any SAE 
or safety issue if it occurs: 
• 
from the date of consent signature, 
• 
throughout the duration of the follow-up period of the subject. 
Any patient excluded from the study due to a SAE will be followed at the same rate as 
the other patients.  
 


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TYPE OF 
EVENT 
NOTIFICATION PROCEDURES 
TIME TO NOTIFICATION OF 
SPONSOR 
Non-serious 
AE 
In the case report form 
No immediate notification 
Serious AE 
Initial SAE declaration form + 
written report, if necessary 
Sponsor notified immediately 
Safety issue 
Declaration form + written report, 
if necessary 
Sponsor notified immediately 
Pregnancy 
Pregnancy declaration form 
As soon as pregnancy is 
confirmed 
 
The forms must be sent to the sponsor: 
ADDMEDICA 
pv@addmedica.com  
16 rue Montrosier 
92200 Neuilly-sur-Seine 
Tel:  +33 (0)1 72 69 01 86 
http://www.addmedica.com  
 
All these events (SAE or safety issue) must be followed until they are fully resolved. 
Additional information (additional declaration form) concerning the outcome of the event, 
if not mentioned in the first report, will be sent to the Sponsor by the Investigator. 
The occurrence of pregnancy during the period or immediately after a clinical trial, is not 
a SAE. However, a pregnancy must be notified within the same timelines as a SAE as it 
will have a special follow-up until its full term. Any anomaly observed in the foetus or the 
child will then be notified. Any voluntary abortion, medical abortion or spontaneous 
abortion requires a pregnancy notification and if it requires hospitalisation, it must be 
transmitted according to the same procedure as a SAE.  
8.3.2 Non serious adverse events 
The Investigator will report all the AEs on the AE form of the eCRF. The start date, actions 
undertaken, and outcome must be reported, and the Investigator must evaluate the events 
in terms of severity, intensity, and causality with respect to the study treatment. 
 
Exception: in the context of this study, as it is a well-known undesirable effect of Siklos® 
described in the SmPC, neutropenia with polymorphonuclear neutrophil count > 1.5 x 
109/L should not be considered serious. 
 
8.3.3 Reporting of adverse events and safety issues after study 
closeout or termination 
 


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The Investigator should also notify the Sponsor of any serious adverse events related to the 
study product occurring at any time after a subject has discontinued or terminated study 
participation.  
 
8.4 
REPORTING OF SUSARS AND SAFETY ISSUES  BY THE SPONSOR 
Suspected unexpected serious adverse reactions (SUSARs) will be reported by the sponsor 
to the French National Competent Authority (ANSM) and the Eudravigilance Clinical Trial 
Module (EVCTM) within the following timelines: 
• 
Immediately (ANSM) after knowledge by the sponsor for “fatal and life-
threatening” events, and follow-up information is subsequently communicated 
within an additional 8 days 
• 
All other suspected serious unexpected adverse reactions shall be reported to 
the ANSM and EVCTM as soon as possible but within a maximum of 15 days 
of first knowledge by the sponsor 
The sponsor informs the ANSM and the Ethics Committee of safety issues and measures 
taken, as applicable. 
9. DATA HANDLING 
9.1 
CASE REPORT FORM 
Data collection is the responsibility of the clinical trial staff at the site under the supervision 
of the site investigator. The investigator is responsible for ensuring the accuracy, 
completeness, legibility, and timeliness of the data reported by signing the eCRF.  
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data.  
Data recorded in the electronic case report form (eCRF) derived from source documents 
should be consistent with the data recorded on the source documents.  
Clinical data (including adverse events (AEs), concomitant medications, expected adverse 
reactions data and clinical laboratory data will be entered into the eCRF, a 21 CFR Part 11-
compliant web-based data capture system provided by ICTA (Dijon, France), on an 
ongoing basis right after patient’s visits. The data will be stored on ICTA’s server for 20 
years and returned to sponsor on demand.  
The following data will be directly uploaded from IWRS to the eCRF:  
• 
ACR baseline level (≤ or >30 mg/mmol),  
• 
Planned and actual treatment batch number, 
• 
Actual date of treatment dispensation.  
The data capture system includes password protection and internal quality checks, such as 
automatic checks, to identify data that appear inconsistent, incomplete, or inaccurate. 
Clinical data will be entered directly from the source documents. 


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The eCRF modules will be designed by ICTA’s Data Management Department and 
developed by ICTA’s Information Technology Department in accordance to CDASH 
(CDISC) whenever possible. 
 
9.2 
DATA MANAGEMENT 
SAS® software version 9.2 or later will be used for data management process and data will 
be recorded in the clinical database stored in a secured folder.  
The Data Management Department of ICTA (Dijon, France) is responsible for data 
processing including drafting of the Data Management Plan, development of the database 
structure, drafting of the Data Validation Plan (list of edit checks and cleaning listings), 
data transfer(s) and data coding: medical history and adverse events will be coded using 
the latest available version of the MedDRA at the time of coding. Prior and concomitant 
medications will be coded using World Health Organization (WHO) drug dictionary (last 
version available).  
A review of the data will be performed according to the CRO standard operating procedure.  
Database status will be declared as final when all data has been entered, cleaned by the 
Data Manager, validated by the monitor and the investigator or delegate. After declaration 
of a final database, the data will be exported from the SQL database to SAS datasets and 
both the database and the SAS datasets will be locked and protected from changes. All 
statistical analyses for the final analysis will be performed on the locked SAS datasets. 
 
10. STATISTICS 
10.1 
GENERAL STATISTICAL CONSIDERATIONS 
An overview of study analyses is included in this section. The detailed methodology of the 
statistical analyses will be documented in a statistical analysis plan (SAP). The SAP will 
be written by the Clinical Research Organisation (CRO) in charge of the study and will be 
validated by the Sponsor prior to performing the analysis. The SAP must be signed before 
the database lock. 
Quantitative variables will be presented in terms of count, mean, standard deviation, 
median, first and third quartiles (Q1 and Q3), and range (minimum and maximum values), 
and corresponding 95% confidence intervals (CIs). 
For qualitative variables, the number and percentage of patients in each category will be 
reported with corresponding CIs where applicable. 
All efficacy analyses will be adjusted by stratification factors. If one or more strata appear 
to have few patients for analysis, small strata will be pooled together. The method will be 
described in the SAP.  


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Patient dispositions, protocol deviations, demographic and baseline characteristics will be 
summarized using descriptive statistics.  
Individual patient listings will be provided and graphical presentations will be provided for 
selected endpoints. 
Analyses will be performed using SAS® software version 9.2 or higher. 
10.2 
SAMPLE SIZE 
According to the primary endpoint, a responder is defined as a patient achieving at least a 
30% decrease of the ACR baseline at 6 months. Assuming a 1:1 treatment allocation ratio, 
the sample size of 86 evaluable patients will achieve 80% power to detect an absolute 
difference of 25% in responder rates (35% in the Hydroxycarbamide group and 10% in the 
Placebo group) using a Chi-2 test with the normal approximation method.  
The 2-sided significance level is set at 5%.  
Assuming that around 10% of randomised patients will not be evaluable for the primary 
outcome measures, 96 patients (48 in each group) should be randomised in this study.  
 
 
10.3 
ANALYSIS POPULATIONS 
The statistical analyses will be based on the modified intention-to-treat (mITT), per 
protocol (PP) and safety populations, with the mITT population used for the primary 
efficacy analysis. 
The modified Intent-To-Treat (mITT) population is defined as all randomised patients who 
received at least one dose of the study medication and with at least one assessment post-
baseline of the primary efficacy measure. 
The Per-Protocol (PP) efficacy population is defined as all patients from the mITT 
population without any major protocol deviation. 
The safety (SAF) population is defined as all randomised patients who received at least one 
dose of the study medication. 
 
10.4 
EFFICACY ANALYSIS 
To control the familywise Type I error rate for the evaluation of the efficacy endpoints, the 
secondary endpoint, absolute mean changes from baseline in eGFR, will be statistically 
tested at the two-sided 0.05 significance level only if the primary efficacy endpoint is 
statistically significant at the 2-sided 0.05 significance level. If the primary endpoint does 
not reach statistical significance, the planned analysis for this secondary analysis will be 


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considered as exploratory with a descriptive p-value and no conclusion of significance can 
be determined. 
The primary efficacy population will be mITT. 
10.4.1 Primary endpoint 
The responder rate (ie. percentage of patients achieving at least 30% decrease of the ACR 
baseline value at 6 months) will be provided in each group with its 95% confidence interval.  
Patients requiring a therapeutic change from HC to ACE or ARB inhibitors will be 
considered as non-responder. Patients with no ACR measure at 6 months will be considered 
as non-responder. A sensitivity analysis will be done with a Last Observation Carried 
Forward (LOCF) imputation for patients with no measure at 6 months and no requirements 
for a therapeutic change.  Other sensitivity analyses might be defined in the SAP.   
Both treatment groups will be compared using a Cochran-Mantel-Haenszel method with 
the stratification variable (ACR baseline ≤30 vs >30 mg/mmol) as adjusted factor.  
Hypothesis testing will be performed at the two-sided 5% significance level. The 95% 
confidence interval of the difference between the groups will be also provided. The mITT 
population will be the main population of analysis for this criterion. 
10.4.2 Secondary endpoints 
Each secondary efficacy criterion will be summarised at each time point using descriptive 
statistics. 
If the primary endpoint is statistically significant, then the secondary endpoint, absolute 
mean changes from baseline in eGFR, will be tested at the 5% significance level. An 
Analysis of Covariance (ANCOVA) with treatment group and baseline eGFR as fixed 
effects will be performed.  For patients with missing value, a Multiple Imputation method 
will be used. Details to implement this approach will be provided in the SAP. 
All other secondary endpoint testing will be considered as exploratory.  
10.5 
SAFETY ANALYSIS 
This analysis will be performed on the safety population. 
Only Treatment-Emergent Adverse Events (TEAEs), defined as any AE with an onset date 
on or after the first dose of study treatment or any ongoing event that worsens after the date 
of the first dose of study treatment, will be analysed. Other Adverse Events will be listed. 
The incidence of overall TEAEs, Drug-Related TEAEs, SAEs, Grade 3-4 of TEAEs, and 
TEAEs leading to dose reduction or treatment discontinuation will be provided in each 
treatment group and overall during the first 6 month-period. Both treatment groups will be 


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descriptively summarised by System Organ Class (SOC) and Preferred Terms (PT) and 
compared using a Chi-2 (or a Fisher Exact test, if the Chi-2 conditions of application are 
not met) at two-sided 5% significance level. 
The incidence of overall TEAEs, Drug-Related TEAEs, SAEs, Grade 3-4 of TEAEs, and 
TEAEs leading to dose reduction or treatment discontinuation will also be provided from 
month 6 to month 12 in each treatment group and overall for patients qualified as 
responders willing to continue the study. 
The Medical Dictionary for Regulatory Activities (MedDRA) will be used for the 
classification of AEs. This will permit to describe the incidence of above AEs by System 
Organ Class and Preferred Term. 
Other safety endpoints such as vital signs and laboratory data will be descriptively 
summarised. 
 
11. ETHICAL AND REGULATORY ASPECTS 
11.1 
STUDY CONDUCT 
This study will be conducted in accordance with all applicable regulatory requirements 
including the general ethical principles outlined in the Declaration of Helsinki, Fortaleza, 
October 2013 and in compliance with this protocol, the requirements of ICH Harmonised 
Guideline E6(R2) – Guideline for Good Clinical Practice, t. as well as any European and/or 
local applicable laws and regulations relating to the conduct of the study. 
 
11.2 
COMPETENT AUTHORITIES AND ETHICS COMITTEES 
This protocol and other documents (e.g. Investigator’s Brochure, Patient Information, etc.) 
will be submitted by the Sponsor/CRO to an IEC/IRB and competent local authorities. 
Before starting the study, the investigator must have received written approval of the Study 
Protocol and the Patient Information Consent Form from the IEC/IRB and the competent 
local authorities.  
The IEC/IRB and the competent local authorities approval must reveal the Study Protocol 
version as well as the documents reviewed. 
 
11.3 
AMENDMENTS 
Changes to any aspect of the study, such as modification(s) of the protocol, the written ICF, 
the written information provided to patients, and/or other procedures will be made only 
with the agreement of the Sponsor and must be submitted to the CPP and Competent 
Authorities for approval. With the exception of an amendment needed to eliminate hazards 


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to the patients in the study, all substantial amendments may only be put into practice once 
written approval from the CPP and Competent Authorities has been obtained. 
11.4 
PATIENT INFORMED CONSENT 
Prior to a patient’s participation in the study, written informed consent must be obtained 
after the Investigator has fully informed the patient  of all pertinent aspects of the study. 
The patient must be given sufficient time to consider the information and the opportunity 
to ask questions and have those questions answered. The ICF must be signed and personally 
dated by the patient and by the Investigator according to ICH GCP. The patient must 
receive a copy of the signed and dated ICF and any other written information provided to 
the patients. 
Any change to the information sheet and the consent form constitutes a substantial 
amendment and must be submitted for approval to the CPP and Competent Authorities. 
The new ICF must be signed and personally dated by the patient and by the Investigator 
and the patient must receive a copy of this signed and dated ICF. 
Prior to their participation in this study, patients will receive a complete and most recent 
approved version of the patient’s information sheet (in easily comprehensible terms) and 
an ICF. The objectives, methods, and duration of participation, the main limitations of the 
protocol, and the possible risks incurred will be specified. The patient is reminded that 
he/she can refuse to take part in this study and can, at any time and without personal 
prejudice, withdraw his/her consent. 
For medical research using identifiable human material or data, such as research on 
material or data contained in biobanks or similar repositories, physicians must seek 
informed consent for its collection, storage and/or reuse.  
 
12. SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
A source document is an original record or certified copy of an original record of clinical 
findings, observations or any other medical or paramedical activities performed during the 
clinical study, necessary for the transcription and the verification of the collected data. 
Examples of these original documents and data records include concomitant medication 
forms, laboratory reports, patients diaries, records of AEs and follow-up of AEs, and study 
treatment accountability records. 
According to GCP guidelines, upon request of the Clinical Research Associate (CRA), 
auditor, or Competent Authority, the Investigator must provide direct access to all 
requested source data/documents. 
Source documents along with all other study-related documents (copies of all ICFs, eCRFs 
CD-ROM, any correspondence related to the study…) must be kept in the Investigator's 


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file throughout the study, and then, must be stored in the study centre's archives of at least 
15 years as per the European Directive 2003/63/ EC and according to local legal 
requirements. 
13. QUALITY CONTROL AND QUALITY ASSURANCE 
13.1 
STUDY MONITORING 
In accordance with applicable regulations, GCP, and CRO standard operating procedures, 
an initiation visit will be performed at the study centre before any patients are included in 
the study. The aim of this visit is to review the protocol and data collection procedures with 
the study personnel as well as to provide a reminder of the Investigator’s responsibilities 
according to ICH GCP. 
During the study, the CRA will regularly contact the centre and will perform on-site 
monitoring visits. The extent, nature, and frequency of on-site visits will be based on the 
patient inclusion rate and will be discussed with the Investigator. The aim of these contacts 
and visits is to check the progress of the study, review all the collected study data, conduct 
source document verification, identify any issues and address their resolution. This will be 
done in order to verify that the data are authentic, accurate and complete, the safety and 
rights of patients are being protected, and the study is being conducted in accordance with 
the approved protocol (and any amendments), GCP, and all applicable regulatory 
requirements. 
The Investigator agrees to allow the CRA direct access to all relevant documents and to 
allocate his/her time and the time of the study personnel to discuss any issues. 
Upon completion of the study, the CRA, with the collaboration of the Investigator, will 
ensure that: 
• All data queries have been finalised, 
• The centres’ study records are complete. 
Details of clinical site monitoring will be documented in a Clinical Monitoring Plan (CMP) 
which describes in detail who will conduct the monitoring, at what frequency monitoring 
will be done, at what level of detail monitoring will be performed, and the distribution of 
monitoring reports.  
13.2 
AUDIT AND INSPECTION 
To ensure compliance with GCP and all applicable regulatory requirements, the Sponsor 
or a CRO designated by the Sponsor may conduct a quality assurance audit of the 
investigator centre. Regulatory Agencies may also conduct regulatory inspections. Such 
audits or inspections can occur at any time during or after completion of the study. If an 
audit or inspection occurs, the investigator centre agrees to allow the auditor/inspector 
direct access to all relevant documents and to allocate his/her time and the time of the study 
personnel to the auditor/inspector to discuss findings and any relevant issues. 


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14. CONFIDENTIALITY, DATA HANDLING, AND 
RECORD KEEPING 
14.1 
PERSONAL DATA PROTECTION AND CONFIDENTIALITY 
All relevant legislation on Data Protection will be followed. Information regarding 
patients’ identity obtained as a result of this study is considered confidential and disclosure 
to unauthorised individuals is prohibited.  
Patients will not be identified by their names or date of birth. As soon as they have signed 
their ICF, patients will be given a unique identification number that will be used throughout 
the study. Patients will be identified with centre number and patient number in the eCRF. 
In all other documents and materials, patients will only be identified with a patient 
identification code (centre number and patient number). 
According to GCP requirements, the Investigator will maintain a ‘patient identification log’ 
with the name and contact details of each patient. This log and the signed consent forms 
will be kept in strict confidence by the Investigator. 
 
The patients will be informed by the information and consent form that their personal data 
collected for the purpose of the study will be kept confidential and will be processed by the 
Sponsor and its representatives. The patients will also be informed of their rights according 
to General Data Protection Regulation and French law. 
14.2 
RECORD KEEPING 
The investigator undertakes to adequately maintain all study documentation and records to 
ensure full documentation of the study conduct and enable subsequent verification of study 
data. 
Following closure of the study, the Investigators must archive, in a safe and secure location, 
all study records including patient medical files, original ICFs, source documents, eCRFs 
CD-ROM, copies of the study product accountability forms, copies of the CPP/regulatory 
authorities’ approval, and all correspondence. The trial-related documents must be retained 
as strictly confidential at the Investigator's centre for at least 15 years according to the 
European Directive 2003 / 63 / EC and local legal requirements. The Investigator or his/her 
institution should take measures to prevent accidental or premature destruction of these 
documents. 
The Investigator must notify the Sponsor of any changes in the archiving arrangements, 
including, but not limited to: archival at an off-site facility and transfer of ownership of the 
records in the event the Investigator leaves the site. The Investigator must obtain Sponsor 
written permission before disposing of any records, even if retention requirements have 
been met. 


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Samples will be retained for a maximum of 15 years after the last patient visit, or for a 
shorter period if local regulations and/or CPP imposes shorter time limits. 
15. INSURANCE AND FINANCES 
15.1 
INSURANCE 
The Sponsor, ADDMEDICA S.A.S., certifies that a medical insurance policy (with HDI 
Global SE, Tour Opus 12 La défense 9, 77 Esplanade du Général de Gaulle F92914 Paris 
la Défense Cedex - policy number : 01013166-14003) has been taken out, which covers 
the liability of the Investigator in case of damage or injury resulting from this study, in 
accordance with Articles 3.2 and 6.3 of Directive 2001/20/EC of the European Parliament. 
This insurance does not relieve the Investigators of any obligation to maintain their own 
liability insurance policy as required by applicable law. 
15.2 
FINANCES 
The funding of research is supported by the Sponsor (investigator time, study costs, patients 
compensation for travel expenses…). 
ADDMEDICA S.A.S. will fairly compensate the centre/the principal investigator for 
conducting the clinical study. The rate of compensation will take into account factors such 
as required procedures, time commitment, and study complexity. 
According to French national law (article L.4113.6 of the French Health Code): 
• The financial agreement related to the study will be submitted for opinion to the CNOM 
(French National Medical Order) and the investigator will then transmit to the CDOM 
(French Departmental Medical Order) the financial agreement with the letter of 
submission to the CNOM for information 
• The sponsor will inform the CNOM of the agreement implementation. 
According to the 2011-2012 French law dated December 29, 2011 and its implementing 
decree 2013-414 of 21 May 2013, the sponsor will publish the existence of this agreement 
as well as benefits in kind or in cash providing directly or indirectly to the investigator. 
15.3 
PATIENT PAYMENTS AND EXPENSES 
Patients will not be paid for participating in the study but their travel expenses will be 
reimbursed.  
16. PUBLICATION POLICY 
All the results of this study are the property of the Sponsor and have to be considered as 
confidential. 
Upon completion of the data analysis, a final report, including a review of the objectives 
and methods, a presentation and discussion of the results is drawn up according to ICH 


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Guidelines 
(Structure 
and 
Content 
of 
Clinical 
Study 
Reports, 
ICH-E3, 
CPMP/ICH/137/95). Global results of the research are communicated to the Investigators. 
According to the local regulation, the patient can ask the Investigator for the results. 
The Sponsor acknowledges the importance of publication of information collected or 
generated for this study by the study sites. Final data will be appropriately communicated 
when available, through presentation at national and/or international congresses. Final 
results of this study will also be submitted for review and publication to an appropriate 
scientific and medical journal. Authorship of any publications relating to the study shall be 
determined by mutual agreement and will follow the International Committee of Medical 
Journal Editors (ICMJE) guidelines. 
Additionally, this study and its results may be submitted for inclusion in all appropriate 
Health Authority study registries. 
 
 
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