A Randomised, Double-Blind, Parallel-Group, Multicentre, Phase III Study to Evaluate the Effect of Ticagrelor Versus Placebo in Reducing the Rate of Vaso-Occlusive Crises in Paediatric Patients With Sickle Cell Disease (HESTIA3)
Phase: PHASE3
Conditions: Sickle Cell Disease
Sponsor: AstraZeneca

1(123) 
 
 
 
 
Clinical Study Protocol  
Drug Substance 
Ticagrelor 
Study Code 
D5136C00009 
Version 
3.0 
Date 
20 April 2020 
A Randomised, Double-Blind, Parallel-Group, Multicentre, Phase III Study 
to Evaluate the Effect of Ticagrelor versus Placebo in Reducing the Rate of 
Vaso-Occlusive Crises in Paediatric Patients with Sickle Cell Disease 
(HESTIA3) 
Sponsor: AstraZeneca AB, S-151 85 Södertälje, Sweden 

Clinical Study Protocol 
Drug Substance Ticagrelor  
Study Code D5136C00009 
Version 3.0 
Date 20 April 2020 
2(123) 
VERSION HISTORY 
Version 3.0, 20 April 2020 
3.9.4 Procedures for discontinuation in relation to coronavirus disease 2019 (COVID-19): 
new subsection added for Investigational Product (IP) discontinuation procedures  
 
6.3.10 Procedures in relation to COVID-19 infection: new subsection added for instructions 
to Investigators/study sites for recording of adverse events (AEs) and serious adverse events 
(SAEs) in relation to COVID-19 
 
Minor changes to wording were implemented throughout to reflect the decision to allow for 
the use of local laboratory testing as needed due to the COVID-19 situation.   
Other minor changes have been made for consistency and clarity.   
 
 
Version 2.0, 29 August 2018 
Throughout: minor non-substantive edits made for consistency and clarity. 
Synopsis: Study Design and Duration of treatment: changes made to clarify that the design 
allows for either a completed 24 months treatment or a common study end with at least 
12 months of treatment duration. 
Abbreviation list: added Common Study End Date (CSED) and Platelet Reactivity Index 
(PRI), revised CYP3A 
1.2.2 Dose, control group and treatment duration: updated to read as “Treatment duration is at 
least 12 months for study participants but no longer than 24 months for any patients.” 
1.4 Study Design: updated as above 
Figure 1, footnote b) updated for clarity 
1.5.2 Data Monitoring Committee: amended text with details on formal interim 
pharmacodynamic (PD) assessment process and frequency. 
3.2: Exclusion Criteria: clarified exclusion criterion #12 regarding excluded CYP3A 
inhibitors, substrates, or inducers. 

Clinical Study Protocol 
Drug Substance Ticagrelor  
Study Code D5136C00009 
Version 3.0 
Date 20 April 2020 
3(123) 
4.2.3 End of Study Visit: clarified to occur at 24 months or as a common study end date. 
5.1.2 Pain during a vaso-occlusive crisis (VOC): text added to highlight importance of 
providing training to caregivers not to influence the child when supporting in reporting of 
pain. 
5.8 Revised blood volumes (Table 5  Volume of blood to be withdrawn from each patient) 
7.7 Concomitant Medications: clarified text regarding CY3PA inhibitors, substrates, or 
inducers.   
Appendix D, Interview guide for VOC-triggered telephone calls: #3: specific questions added. 
Appendix E, Guide for scheduled telephone visits: clarifications related to use of 
contraceptives added. 
Appendix G: Drug Interactions: clarification regarding CYP3A inhibitors, substrates, or 
inducers. 
 
 
Version 1, 23 January 2018 
Initial creation 
 
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.  
 

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Clinical Study Protocol Synopsis 
Drug Substance Ticagrelor  
Study Code D5136C00009 
Version 3.0 
Date 20 April 2020 
5(123) 
• 
An ACS is an acute illness characterized by fever and/or respiratory symptoms, 
accompanied by a new pulmonary infiltrate on a chest X-ray. 
Objectives 
Primary Objective: 
Outcome Measure: 
To compare the effect of ticagrelor vs placebo for 
the reduction of VOCs, which is the composite of 
painful crisis and/or ACS, in paediatric patients 
with SCD 
Number of VOCs 
 
Secondary Objective: 
Outcome Measure: 
To compare the effect of ticagrelor vs placebo for 
the reduction of painful crises  
Number of painful crises 
To compare the effect on ticagrelor vs placebo for 
the reduction of ACS 
Number of ACSs 
To compare the effect of ticagrelor vs placebo for 
the reduction of duration of painful crises 
Duration of painful crises 
To compare the effect of ticagrelor vs placebo on 
the number of VOCs requiring hospitalisation or 
emergency department visits  
Number of VOCs requiring hospitalisation or 
emergency department visits  
To compare the effect of ticagrelor vs placebo on 
reduction of days hospitalised for VOC   
Number of days hospitalised for VOC 
To compare the effect of ticagrelor vs placebo on 
the number of acute SCD complicationsa 
Number of acute SCD complications 
To compare the effect of ticagrelor vs placebo on 
reduction of days hospitalised for acute SCD 
complicationsa 
Number of days hospitalised for acute SCD 
complications 
To compare the effect of ticagrelor vs placebo on 
the number of sickle cell-related red blood cell 
transfusions 
Number of sickle cell-related red blood cell 
transfusions  
To describe the health-related quality of life 
(HRQL) and fatigue 
HRQL total score and by dimension using 
Paediatric Quality of Life Inventory (PedsQL) 
SCD Module and Fatigue total score and by 
dimension using the PedsQL Multidimensional 
Fatigue Scale (age appropriate versions: 
2-4 years; 5-7 years; 8-12 years; 13-18 years) 
To describe absence from school or work due to 
SCD 
Proportion of days of absence from school or 
work (only if going to school or work at 
randomisation) 

Clinical Study Protocol Synopsis 
Drug Substance Ticagrelor  
Study Code D5136C00009 
Version 3.0 
Date 20 April 2020 
6(123) 
Secondary Objective: 
Outcome Measure: 
To describe the intensity of pain during VOC 
Intensity of worst pain daily during VOC 
- For patients ≤4 years of age, observer reported 
using the Face, Legs, Activity, Cry, 
Consolability Scale (FLACC) 
- For patient ages ≥5 to 18 years of age, 
self-reported using the Faces Pain Scale 
- Revised (FPS-R) 
To describe analgesics used during VOC 
Type of analgesics (opioid and non-opioid) use 
To describe patient acceptability of the formulation 
(palatability and swallowability) 
- For patients ≤4 years of age taking the tablet 
dispersed or whole, an observer assessment of 
palatability and swallowability will be 
undertaken  
- For patients ≥5 years of age taking the tablet 
dispersed or whole, palatability will be 
assessed and categorized using the Facial 
Hedonic Scale  
a 
The acute SCD complications will be defined in Section 5.1.5 in Clinical Study Protocol. 
Safety Objective: 
Outcome Measure: 
To assess long-term safety and tolerability of 
therapy with ticagrelor vs placebo 
Adverse Events/Serious Adverse Events, 
including bleeding 
Vital signs and laboratory safety variables 
 
Target subject population 
The target population is children aged ≥2 to <18 years of age and body weight of ≥12 kg 
diagnosed with homozygous sickle cell anaemia (HbSS) or sickle beta-zero-thalassaemia 
(HbS/β0). 
Patients that experienced at least 2 VOC events in the past 12 months prior to Visit 1 and fulfil 
eligibility criteria will be enrolled in this study. 
Duration of treatment 
Eligible patients will receive double-blind ticagrelor or placebo twice a day (bd) for at least 
12 months but no longer than 24 months.  The expected average follow-up is 18 months, 
assuming a uniformly distributed enrolment period of 12 months. 
Investigational product, dosage and mode of administration 
The double-blinded study drug dose will be weight dependent: 
• ≥12 to ≤24kg: Ticagrelor 15 mg or matching placebo, twice a day  
• >24 to ≤48 kg: Ticagrelor 30 mg or matching placebo, twice a day  
• >48 kg: Ticagrelor 45 mg or matching placebo, twice a day. 

Clinical Study Protocol Synopsis 
Drug Substance Ticagrelor  
Study Code D5136C00009 
Version 3.0 
Date 20 April 2020 
7(123) 
Statistical methods 
The primary analysis will be based on the intent-to-treat (ITT) principle.  The number of 
VOCs will be analysed using negative binomial regression.  The response variable is the 
number of VOCs experienced by a patient over the treatment period.  Patient follow-up time 
(log-transformed) will be included as an offset in the linear predictor to adjust for patients 
having different exposure times.  Additional covariates to be adjusted for in the linear 
predictor will be treatment group (placebo as reference group) and hydroxyurea therapy 
(Yes/No).  The treatment effect will be tested at a 5% significance level.  If the negative 
binomial distribution is not appropriate, a Wilcoxon rank sum test will be used.  Ticagrelor 
data will be pooled and analysed irrespective of dose. 

Clinical Study Protocol 
Drug Substance Ticagrelor  
Study Code D5136C00009 
Version 3.0 
Date 20 April 2020 
8(123) 
TABLE OF CONTENTS 
PAGE 
TITLE PAGE ........................................................................................................... 1 
VERSION HISTORY .............................................................................................. 2 
CLINICAL STUDY PROTOCOL SYNOPSIS ....................................................... 4 
TABLE OF CONTENTS ......................................................................................... 8 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................... 13 
1. 
INTRODUCTION ................................................................................................. 16 
1.1 
Background and rationale for conducting this study ............................................. 16 
1.2 
Rationale for study design, doses and control groups ............................................ 18 
1.2.1 
Overall rationale and study population .................................................................. 18 
1.2.2 
Dose, control group and treatment duration........................................................... 18 
1.3 
Benefit/risk and ethical assessment ....................................................................... 19 
1.4 
Study design ........................................................................................................... 21 
1.5 
Study governance and oversight ............................................................................ 23 
1.5.1 
Steering Committee ............................................................................................... 23 
1.5.2 
Data Monitoring Committee .................................................................................. 23 
2. 
STUDY OBJECTIVES .......................................................................................... 24 
2.1 
Primary objective ................................................................................................... 24 
2.2 
Secondary objectives ............................................................................................. 25 
2.3 
Safety objectives .................................................................................................... 26 
2.4 
Exploratory objectives ........................................................................................... 26 
3. 
SUBJECT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL ...................... 26 
3.1 
Inclusion criteria .................................................................................................... 26 
3.2 
Exclusion criteria ................................................................................................... 27 
3.3 
Subject enrolment and randomisation .................................................................... 28 
3.4 
Procedures for handling incorrectly enrolled or randomised subjects ................... 29 
3.5 
Methods for assigning treatment groups ................................................................ 29 
3.6 
Methods for ensuring blinding ............................................................................... 30 
3.7 
Methods for unblinding .......................................................................................... 30 
3.8 
Restrictions ............................................................................................................ 30 
3.9 
Permanent discontinuation or temporary stop of investigational product ............. 31 
3.9.1 
Permanent discontinuation ..................................................................................... 31 

Clinical Study Protocol 
Drug Substance Ticagrelor  
Study Code D5136C00009 
Version 3.0 
Date 20 April 2020 
9(123) 
3.9.2 
Temporary discontinuation .................................................................................... 32 
3.9.3 
Procedures for permanent discontinuation of a subject from investigational 
product ................................................................................................................... 32 
3.9.4 
Procedures and guidance for temporary IP discontinuation in relation to 
coronavirus disease 2019 (COVID-19) ................................................................. 33 
3.10 
Criteria for withdrawal ........................................................................................... 34 
3.10.1 
Screen failures ........................................................................................................ 34 
3.10.2 
Withdrawal of the informed consent ...................................................................... 34 
3.11 
Discontinuation of the study .................................................................................. 34 
4. 
STUDY PLAN AND TIMING OF PROCEDURES ............................................. 35 
4.1 
Screening period .................................................................................................... 40 
4.2 
Treatment period .................................................................................................... 40 
4.2.1 
Physical visits at study sites during the treatment period ...................................... 40 
4.2.2 
Telephone visits during treatment period .............................................................. 41 
4.2.3 
End of study visit ................................................................................................... 41 
4.2.4 
Safety follow-up visit ............................................................................................. 41 
4.2.5 
Unscheduled visits ................................................................................................. 41 
5. 
STUDY ASSESSMENTS ..................................................................................... 42 
5.1 
Efficacy assessments .............................................................................................. 42 
5.1.1 
Vaso-occlusive crisis ............................................................................................. 42 
5.1.1.1 
Collection of VOC ................................................................................................. 42 
5.1.1.2 
Training in the collection of VOC events .............................................................. 43 
5.1.2 
Pain during a VOC ................................................................................................. 44 
5.1.3 
Health-related quality of life (HRQL) ................................................................... 45 
5.1.4 
Absence from school/work due to SCD ................................................................. 46 
5.1.5 
Acute SCD complications ...................................................................................... 46 
5.2 
Safety assessments ................................................................................................. 46 
5.2.1 
Laboratory safety assessments ............................................................................... 46 
5.2.2 
Physical examination ............................................................................................. 48 
5.2.3 
ECG ........................................................................................................................ 48 
5.2.3.1 
Resting 12-lead ECG ............................................................................................. 48 
5.2.4 
Vital signs .............................................................................................................. 48 
5.2.4.1 
Weight and height .................................................................................................. 48 
5.2.4.2 
Pulse rate and blood pressure ................................................................................. 48 
5.3 
Other assessments .................................................................................................. 49 
5.3.1 
Palatability and swallowability .............................................................................. 49 
5.4 
Pharmacokinetics ................................................................................................... 49 
5.4.1 
Collection of samples ............................................................................................. 49 
5.4.2 
Determination of drug concentration ..................................................................... 49 
5.4.3 
Storage and destruction of pharmacokinetic samples ............................................ 50 

Clinical Study Protocol 
Drug Substance Ticagrelor  
Study Code D5136C00009 
Version 3.0 
Date 20 April 2020 
10(123) 
5.5 
Pharmacodynamics ................................................................................................ 50 
5.5.1 
Vasodilator-stimulated phosphoprotein ................................................................. 50 
5.5.2 
Collection of samples ............................................................................................. 50 
5.5.3 
Storage and destruction of pharmacodynamics samples ....................................... 51 
5.6 
Genetics (Not applicable) ...................................................................................... 51 
5.7 
Biomarker analysis (Not applicable)...................................................................... 51 
5.8 
Volume of blood .................................................................................................... 51 
6. 
SAFETY REPORTING AND MEDICAL MANAGEMENT .............................. 52 
6.1 
Definition of adverse events .................................................................................. 52 
6.2 
Definitions of serious adverse event ...................................................................... 52 
6.3 
Recording of adverse events .................................................................................. 53 
6.3.1 
Time period for collection of adverse events ......................................................... 53 
6.3.2 
Follow-up of unresolved adverse events ................................................................ 53 
6.3.3 
Variables ................................................................................................................ 53 
6.3.4 
Causality collection ................................................................................................ 54 
6.3.5 
Adverse events based on signs and symptoms ...................................................... 54 
6.3.6 
Adverse events based on examinations and tests ................................................... 54 
6.3.7 
Liver biochemistry and evaluation of Hy’s Law ................................................... 55 
6.3.8 
Assessment of bleeding events .............................................................................. 55 
6.3.9 
Vaso-occlusive crisis (VOCs) and acute SCD complications ............................... 55 
6.3.10 
Procedures in relation to COVID-19 infection ...................................................... 55 
6.4 
Reporting of serious adverse events....................................................................... 56 
6.4.1 
Reporting of SAEs that are also endpoints in the study ......................................... 57 
6.5 
Overdose ................................................................................................................ 57 
6.6 
Pregnancy ............................................................................................................... 57 
6.6.1 
Maternal exposure .................................................................................................. 57 
6.6.2 
Paternal exposure ................................................................................................... 58 
6.7 
Medication error ..................................................................................................... 58 
6.8 
Management of IP-related toxicities ...................................................................... 59 
7. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS .................... 59 
7.1 
Identity of investigational product(s) ..................................................................... 59 
7.2 
Dose and treatment regimens ................................................................................. 60 
7.2.1 
Treatment during double-blind randomisation period ........................................... 60 
7.2.2 
Dose increase during study .................................................................................... 60 
7.3 
Labelling ................................................................................................................ 61 
7.4 
Storage ................................................................................................................... 61 
7.5 
Compliance ............................................................................................................ 61 

Clinical Study Protocol 
Drug Substance Ticagrelor  
Study Code D5136C00009 
Version 3.0 
Date 20 April 2020 
11(123) 
7.6 
Accountability ........................................................................................................ 61 
7.7 
Concomitant medication and other treatments ...................................................... 61 
7.7.1 
Blood transfusions ................................................................................................. 62 
7.7.2 
Other concomitant treatment .................................................................................. 62 
7.8 
Post study access to study treatment (Not applicable) ........................................... 62 
8. 
STATISTICAL ANALYSES BY ASTRAZENECA OR DELEGATE ............... 63 
8.1 
Statistical considerations ........................................................................................ 63 
8.2 
Sample size estimate .............................................................................................. 63 
8.3 
Definitions of analysis sets .................................................................................... 63 
8.3.1 
Full analysis set ...................................................................................................... 63 
8.3.2 
Safety analysis set .................................................................................................. 63 
8.3.3 
PK analysis set ....................................................................................................... 64 
8.3.4 
PD analysis set ....................................................................................................... 64 
8.4 
Outcome measure for analyses .............................................................................. 64 
8.5 
Methods for statistical analyses ............................................................................. 64 
8.5.1 
Analysis of the primary variable ............................................................................ 64 
8.5.2 
Analysis of the secondary variables ....................................................................... 65 
8.5.3 
Analysis of the exploratory variables..................................................................... 66 
8.5.4 
Analysis of the safety variables ............................................................................. 66 
9. 
STUDY AND DATA MANAGEMENT BY ASTRAZENECA .......................... 67 
9.1 
Training of study site staff ..................................................................................... 67 
9.2 
Monitoring of the study ......................................................................................... 67 
9.2.1 
Source data ............................................................................................................. 67 
9.2.2 
Study agreements ................................................................................................... 67 
9.2.3 
Archiving of study documents ............................................................................... 68 
9.3 
Study timetable and end of study ........................................................................... 68 
9.4 
Data management by AstraZeneca or delegate ...................................................... 68 
10. 
ETHICAL AND REGULATORY REQUIREMENTS ......................................... 69 
10.1 
Ethical conduct of the study ................................................................................... 69 
10.2 
Subject data protection ........................................................................................... 69 
10.3 
Ethics and regulatory review ................................................................................. 69 
10.4 
Informed consent ................................................................................................... 70 
10.5 
Changes to the Clinical Study Protocol and Informed Consent Form ................... 70 
10.6 
Audits and inspections ........................................................................................... 71 
11. 
LIST OF REFERENCES ....................................................................................... 72 
 

Clinical Study Protocol 
Drug Substance Ticagrelor  
Study Code D5136C00009 
Version 3.0 
Date 20 April 2020 
12(123) 
 
LIST OF TABLES 
Table 1 
Data Monitoring Committee meeting schedule .............................................. 24 
Table 2 
Schedule of Assessments - Physical visits at study sites ................................ 36 
Table 3 
Schedule of Assessments - Telephone visits during treatment period ............ 39 
Table 4 
Laboratory variables ....................................................................................... 47 
Table 5 
Volume of blood to be withdrawn from each patient ..................................... 51 
 
LIST OF FIGURES 
Figure 1 
Study Flow Chart ............................................................................................ 22 
 
LIST OF APPENDICES 
Appendix A Additional Safety Information ........................................................................ 76 
Appendix B 
International Airline Transportation Association (IATA) 6.2 Guidance 
Document ........................................................................................................ 78 
Appendix C 
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law .................................................................................. 79 
Appendix D Interview Guide for VOC-triggered Telephone Calls .................................... 83 
Appendix E 
Guide for Scheduled Telephone Visits ........................................................... 87 
Appendix F 
Palatability and Swallowability Assessment .................................................. 93 
Appendix G Drug Interactions ............................................................................................ 96 
Appendix H Pain Assessment.............................................................................................. 98 
Appendix I 
HRQL Assessment ........................................................................................ 101 

Clinical Study Protocol 
Drug Substance Ticagrelor  
Study Code D5136C00009 
Version 3.0 
Date 20 April 2020 
13(123) 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this Clinical Study Protocol. 
Abbreviation or special 
term 
Explanation 
ACS 
Acute chest syndrome 
ADP 
Adenosine diphosphate 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
β-hCG 
beta-human chorionic gonadotropin 
bd 
bis in die (twice a day) 
BP 
Blood pressure 
CRF 
Case report form 
COVID-19 
Coronavirus disease 2019 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organisation 
CSA 
Clinical Study Agreement 
CSED 
Common Study End Date 
CSR 
Clinical Study Report 
CV 
Coefficient of variation 
CYP3A 
Cytochrome P450 3A 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee, synonymous to Institutional Review Board (IRB) 
and Independent Ethics Committee (IEC) 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EOS 
End of study 
eDevice 
Electronic device 
FLACC Scale 
Face, Legs, Activity, Cry, Consolability Scale 
FPS-R 
Faces Pain Scale - Revised 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
Hb 
Haemoglobin 
HBsAg 
Hepatitis B surface antigen 
HbSC 
sickle cell-haemoglobin C 
HbSS 
Homozygous sickle cell anaemia 

Clinical Study Protocol 
Drug Substance Ticagrelor  
Study Code D5136C00009 
Version 3.0 
Date 20 April 2020 
14(123) 
Abbreviation or special 
term 
Explanation 
HbS/β0 
Sickle beta-zero-thalassaemia 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HRQL 
Health-related quality of life  
IATA 
International Air Transport Association 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
ICI 
International Co-ordinating Investigator: If a study is conducted in 
several countries the International Co-ordinating Investigator is the 
Investigator co-ordinating the Investigators and/or activities 
internationally.  
ID 
Identification 
IP 
Investigational product  
IXRS 
Interactive Voice/Web Response System 
LDH 
Lactate dehydrogenase 
LFT 
Liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
NSAIDs 
Non-steroidal anti-inflammatory drugs 
P2Y12 
G protein-coupled platelet receptor for adenosine diphosphate (ADP) 
PedsQL 
Paediatric Quality of Life Inventory 
P-gp 
P-glycoprotein 
PD 
Pharmacodynamic 
PI 
Principal Investigator  
PK 
Pharmacokinetic 
PRI 
Platelet Reactivity Index 
PRU 
P2Y12 reaction units 
PT 
Prothrombin time 
RBC 
Red blood cell 
SAE 
Serious adverse event  
SAP 
Statistical Analysis Plan 
SC 
Steering Committee 
SCD 
Sickle cell disease 
SD 
Standard Deviation 
TAMMV 
Time averaged mean of the maximum velocity 
TCD 
Transcranial Doppler 
TCDi 
Transcranial Doppler imaging technique 

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Version 3.0 
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Abbreviation or special 
term 
Explanation 
TIA 
Transient Ischemic Attack 
ULN 
Upper limit of normal 
VASP 
Vasodilator-stimulated phosphoprotein 
VOC 
Vaso-occlusive crisis 
WBDC 
Web Based Data Capture 
 
 

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1. 
INTRODUCTION 
1.1 
Background and rationale for conducting this study 
Sickle cell disease (SCD) is a genetic, autosomal, recessive blood disorder resulting an altered 
haemoglobin β-chain (HbS).  When the altered haemoglobin is deoxygenated it aggregates 
into large polymers, distorting the shape of the red cells to sickle-shaped.  A vaso-occlusive 
crisis (VOC) is a severe, acute painful episode that occurs when sickle-shaped red blood cells 
obstruct the microcirculation and restrict blood flow to an organ or tissue, resulting in 
ischaemia, necrosis and organ damage.  The clinical presentation varies depending on the 
localisation of the obstruction and there are also specific SCD complications, such as acute 
chest syndrome (ACS) where the pulmonary vasculature is affected.  Vaso-occlusion is 
initiated and sustained by complex interactions among sickle cells, endothelial cells and 
constituents of plasma.  Activated platelets participate in the process by promoting the 
adhesion of sickle cells to the endothelium, and through the formation of platelet-leukocyte 
aggregates, which augment the inflammatory state and contribute to vaso-occlusion.  In 
patients with SCD, platelets are activated during the non-crisis “steady state” and are further 
activated during painful episodes and markers of platelet inhibition have been shown to 
correlate with the frequency of pain crises (Ataga et al 2012). 
There is a significant unmet need regarding treatment options to reduce VOCs in SCD.  
Curative treatment with bone marrow transplantation is only available to a very limited 
number of patients.  Until recently, the only pharmacological treatment approved for reduction 
of VOCs was hydroxyurea (hydroxycarbamide).  Hydroxyurea reduces the rate of painful 
crises, ACS and the need for blood transfusions in adults and children with SCD 
(Charache et al 1995, Wang et al 2011), but patients need to be closely monitored since 
hydroxyurea causes myelodepression and has other side effects.  Moreover, hydroxyurea is 
not approved for use in children in all markets.  In July 2017, the United States (US) FDA 
approved L-glutamine for the reduction of acute complications of SCD; however, with the 
limited experience with L-glutamine and current approval only in US, the role of this 
compound in the treatment paradigm remains to be established.  Although the frequency of 
SCD complications are reduced with hydroxyurea and with L-glutamine, most patients 
continue to suffer from these complications despite treatment.    
Inhibition of platelet activation has been proposed as a potential therapeutic option in the 
treatment of SCD.  The antiplatelet drug ticlopidine, which has a similar mechanism of action 
as ticagrelor (prevention of adenosine diphosphate [ADP]-mediated platelet activation), 
significantly reduced the frequency of VOCs in patients with SCD (Cabannes et al 1984).  
Another G protein-coupled platelet receptor for ADP (P2Y12) inhibitor, prasugrel, was 
recently investigated in children with SCD.  The Phase III study in paediatric patients showed 
a numerical reduction in number of VOC events (component of painful crises and/or ACS), 
with fewer painful crises in prasugrel group than on placebo (66% versus 72%), but no 
difference in ACS (9% in each group); however, the differences versus placebo did not reach 
statistical significance (Heeney et al 2016).  Of note is that the prasugrel doses used in this 
study only resulted in a mean platelet inhibition of approximately 20% 

Clinical Study Protocol 
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Date 20 April 2020 
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(Jakubowski et al 2017).  Too low platelet inhibition may have contributed to the insufficient 
efficacy in this study (Heeney et al 2016).   
Ticagrelor (BRILINTA™) is an oral, direct-acting, selective, reversibly-binding P2Y12 
receptor antagonist that prevents ADP-mediated platelet activation and aggregation.  
Ticagrelor, 90 mg twice a day (bd), was first approved in 2010 to reduce the rate of 
cardiovascular death, myocardial infarction, and stroke in adult patients with acute coronary 
syndromes, and is currently approved in >100 countries.  An extended indication for ticagrelor 
60 mg bd to include adult patients with a history of myocardial infarction was approved in 
2015. 
An additional mechanism of action with ticagrelor, increasing local endogenous adenosine 
levels (Nylander et al 2013), may contribute to a vasodilatory effect observed in healthy 
subjects and in patients with acute coronary syndromes as measured by coronary blood flow 
(Wittfeldt et al 2013, Alexopoulus et al 2013), which could help increase oxygen supply to 
ischaemic tissues during a VOC.   
A programme is currently ongoing to assess the potential therapeutic benefits of ticagrelor in 
reduction of the occurrence of VOCs in children with SCD.  The HESTIA1 study 
(D5136C00007) investigated pharmacokinetics/pharmacodynamics (PK/PD), safety and early 
signs of efficacy of ticagrelor in 45 patients aged 2 to 17 years.  Ticagrelor exposure increased 
approximately proportionally to dose and the PK/PD relationship in children with SCD and 
appeared similar to what has been previously observed in adults with cardiovascular disease.  
Ticagrelor was well tolerated and no bleedings were reported during treatment.  There were no 
apparent effects on symptoms related to SCD, but the number of patients and short study 
duration limit the conclusions on efficacy in this study.  In addition, a ticagrelor study in 87 
young adults (aged 18 to 30 years) with SCD compared effects from ticagrelor 10 mg, 45 mg 
or placebo given twice daily for 12 weeks (HESTIA2 study, D5136C00008).  The proportion 
of days with pain as well as analgesic use decreased in all groups, including placebo, with no 
apparent differences between groups.  Ticagrelor was well tolerated in young adults, bleeding 
events were few and reported with similar frequency as placebo and no major bleeding 
occurred.  No safety concerns were raised in HESTIA1 or HESTIA2. 
In summary, there is a high unmet need for treatment options in SCD and there is a scientific 
rationale, supported by clinical data, that platelet inhibition has the potential to reduce the risk 
for acute vaso-occlusions.  This study will evaluate the efficacy, safety and tolerability of 
ticagrelor versus placebo in children with SCD during treatment for at least 12 months and up 
to approximately 24 months. 
Detailed information on ticagrelor is found in the Investigator’s Brochure (IB).  

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1.2 
Rationale for study design, doses and control groups 
1.2.1 
Overall rationale and study population 
Patients diagnosed with homozygous sickle cell (HbSS) or sickle beta-zero-thalassemia 
(HbS/β0) will be eligible.  Patients with clinically milder variants 
(eg, sickle cell-haemoglobin C [HbSC]) will not be eligible, since they usually have a lower 
frequency of painful crises (Ashley-Koch et al 2000).  The different pattern of SCD 
manifestations in patients with HbSC (Gill et al 1995) could introduce heterogeneity into the 
study population.  In addition, there are data to suggest that platelet activation in HbSS is 
elevated compared with HbSC (Blann et al 2007); thus, patients with HbSC may be less likely 
to benefit from P2Y12 inhibition. 
To be eligible for the study, patients must have experienced at least 2 VOCs (defined as 
painful crisis and/or ACS) events in the past 12 months prior to Visit 1, indicating that the 
severity of the patient’s disease justifies preventive chronic long-term treatment.  The intent is 
to enrol only children aged 2 years or above, since VOCs become more frequent with age.  
Above 2 years of age, children may have experienced more than 1 VOC, and established a 
pattern of frequency such that an intervention to reduce the rate of VOCs can be justified and 
meaningfully evaluated (Gill et al 1995, Platt et al 1991).  Thus, the unmet need to prevent 
VOCs is most evident in children from 2 years of age and above. 
Due to ticagrelor mechanism of action and the potential to reduce symptoms caused by 
ischaemia during a vaso-occlusion, a composite endpoint with painful crises and/or ACS has 
been selected for the primary endpoint, see Section 2.1.  Painful crisis is the most common 
reason for emergency department visits for patients with SCD with a significant impact on 
young patients’ lives, affecting them physically and emotionally.  Acute chest syndrome is a 
potentially life-threatening condition involving vaso-occlusion, eg, when caused by 
pulmonary infarction or indirectly because of fat embolism secondary to bone marrow 
infarction, and/or a pulmonary infection (Vichinsky et al 2000).  Both painful crises and/or 
ACS are identified by patients/parents as the acute SCD-related complications having the 
most impact on their lives (The Voice of the Patient 2014), and these endpoints are commonly 
used for evaluation of clinical outcome in trials in SCD.  See Section 5.1.1 for the specific 
definition of the primary endpoint events in this study. 
Secondary endpoints are included to broaden the understanding of effects in patients with 
SCD and to also assess potential benefits on symptomatic disease burden and health-related 
quality of life (HRQL). 
1.2.2 
Dose, control group and treatment duration 
The ticagrelor PK/PD modelling and simulation work based on the results from HESTIA1 and 
HESTIA2 studies identifies 15, 30 and 45 mg bd, depending on body weight, as relevant 
doses in the HESTIA3 study.  These doses are predicted to result in a platelet activity 
measured as P2Y12 reaction units ([PRU] as measured by VerifyNow®) of less than 180, 
corresponding to >35% platelet inhibition in terms of reduction in PRU assuming a baseline 

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PRU of 280 (which was the baseline PRU observed in HESTIA1, and similar to prasugrel 
Phase III DOVE study [Heeney et al 2016]).  
The predicted platelet inhibition in HESTIA3 is similar to what was observed in the 45 mg bd 
dose group in the HESTIA2 study in young adults, where after 1 week of treatment the mean 
percentage decrease from baseline PRU was 48% before morning dose and 81% at 2 hours 
after dose.  The 45 mg bd dose group was well tolerated and events of bleeding were of the 
same number and similar compared to the placebo and the 10 mg bd dose groups.  Given the 
reversible mechanism of action for ticagrelor, the level of P2Y12 inhibition during ticagrelor 
treatment is expected to vary within a dosing interval and peak around 2 hours after dosing.  
When developing the dosing strategy for this study, the target for platelet inhibition was 
guided by the results from the recent prasugrel Phase III study in paediatric patients with SCD 
aged 2 to 17 years, showing insufficient efficacy with a mean PRU of 207 (ie, approximately 
20% reduction from baseline) (Jakubowski et al 2017).  The lack of therapeutic benefit with 
prasugrel may have been related to a too low platelet inhibition (Heeney et al 2016), and 
consequently, doses for HESTIA3 were selected to achieve a greater level of platelet 
inhibition.  Moreover, a study with ticlopidine in adolescents and adult patients with SCD 
showing significant reductions in VOC (Cabannes et al 1984) used doses that generally 
provide <60% inhibition of platelet aggregation, which provides further support for the 
platelet inhibition target and the selected doses for the HESTIA3 study.  
There are no other drugs approved for reduction of VOCs in children with SCD with a similar 
mechanism of action as ticagrelor.  Hydroxyurea is approved for use in children with SCD in 
some markets and more recently, L-glutamine was approved by the US FDA.  Evaluation of 
ticagrelor when given in addition to standard of care including these medications, where 
available and when considered medically appropriate, is considered acceptable for studying 
the efficacy and safety of ticagrelor in this patient group as compared with placebo. 
Treatment duration is at least 12 months for study participants, but no longer than 24 months 
for any patients.  The expected average follow-up is 18 months, assuming a uniformly 
distributed enrolment period of 12 months.  Considering inclusion of patients with at least 
2 VOCs in the past year, this treatment duration is considered long enough to evaluate effects 
on VOC events as well as to capture safety and tolerability data supporting a potential future 
long-term use of ticagrelor. 
1.3 
Benefit/risk and ethical assessment 
The aim with ticagrelor treatment in paediatric patients with SCD is to reduce the rate of 
VOCs, with an acceptable safety profile.  Considering that the anticipated benefit would be 
mostly symptom reduction and that patients with SCD suffer from anaemia, the acceptance for 
bleedings will be low. 
Episodes with VOCs are the most common cause for emergency room visits for children with 
SCD.  The pain associated with VOC can be excruciating and have a significant impact on the 
child’s life, and significantly disturbs routine activities such as food intake, sleep and school 

Clinical Study Protocol 
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Study Code D5136C00009 
Version 3.0 
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activities during several days.  The painful crises are repeatedly described as the most 
challenging symptom of their disease by patients with SCD.  An ACS is a serious and 
potentially life-threatening condition that may lead to respiratory failure or multi organ failure, 
and is a common cause of death in SCD patients.  Most cases of ACS require hospitalisation 
for >1 week (Vichinsky et al 2000).  Besides the acute symptoms, the ischaemia during 
vaso-occlusion causes tissue damage that over time leads to impaired organ function (eg, renal 
failure) or complications such as bone necrosis, joint pain or cognitive impairment.  
Pharmacological treatments options to prevent VOC events in children are few and side 
effects can be dose-limiting (hydroxyurea).  With previous studies of anti-platelet drugs 
suggesting potential to reduce VOCs (Cabannes et al 1984, Heeney et al 2016) and the high 
unmet need for new treatments, there is a clear value in continuing to investigate the role of 
anti-platelet therapies in the reduction of VOCs. 
Inherent to their reduction in platelet reactivity, antiplatelet agents increase the risk of 
bleeding.  Ticagrelor has been on the market since 2010 for use in adult patients with coronary 
artery disease to reduce the risk for cardiovascular events.  The safety profile has been 
thoroughly evaluated in large trials.  The PEGASUS study (D5132C00001) evaluated the 
combination of ticagrelor 60 or 90 mg bd with aspirin in adult patients with a history of 
myocardial infarction.  This dual anti-platelet therapy resulted in more bleeding events overall 
compared to aspirin alone; however, the majority of these bleedings were of lesser severity 
(eg, epistaxis, bruising and hematomas).  In the adult clinical programme for ticagrelor, 
including several large cardiovascular outcome studies, the number of reported events of fatal 
bleeding have been low and similar for ticagrelor and comparators (ie, clopidogrel, placebo, 
and aspirin).  Doses in HESTIA3 have been selected to result in a less pronounced level of 
platelet inhibition (~35% to 80%) than doses used in adult patients with cardiovascular disease 
(>80%), and unlike in these patients, ticagrelor will not be combined with aspirin in 
HESTIA3.  A lower bleeding risk is therefore anticipated in HESTIA3 than in previous adult 
cardiovascular outcome studies.  Selected doses for HESTIA3 are within the range evaluated 
in children and young adults (HESTIA1 and HESTIA2).  No safety concerns were raised from 
these studies, and there was no indication of an increased bleeding risk with ticagrelor.  
Prasugrel and clopidogrel are other drugs in the P2Y12 inhibitor class, but unlike ticagrelor, 
which reversibly inhibits the P2Y12 receptors on platelets, these are irreversible P2Y12 receptor 
inhibitors.  The recent paediatric Phase III study with prasugrel in children with SCD 
(Heeney et al 2016) investigated doses resulting in around 20% platelet inhibition, with no 
significant difference in the safety endpoints, including the frequency of bleeding events 
requiring medical intervention, compared to placebo.  Although not in children with SCD, the 
CLARINET study with clopidogrel randomised 906 infants aged ≤92 days with congenital 
heart disease to clopidogrel or placebo for a median of 5.8 months (Wessel et al 2013) using 
doses shown to give an average platelet inhibition of 45% to 50% (Wessel et al 2013, 
Li et al 2008).  No increased bleeding risk was observed for clopidogrel compared to placebo 
in this study. 
In HESTIA3, measures will be taken to minimise bleeding risk in participating patients.  The 
eligibility criteria, restrictions and discontinuation criteria are tailored to exclude patients with 
increased risk for bleeding from participation, and other medications impacting platelet 

Clinical Study Protocol 
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Study Code D5136C00009 
Version 3.0 
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activity or the coagulation system are restricted.  Frequent monitoring of patients is included 
in the protocol.  An independent Data Monitoring Committee (DMC) will review unblinded 
study results regularly during the trial and will have increased attention on bleeding events.  
The procedures during study visits are not considered to increase risk above routine care.  
Topical anaesthesia will be offered prior to blood sampling, and sampling will be coordinated 
in time as much as possible to reduce discomfort to children.  
This study will evaluate ticagrelor efficacy and safety when added to standard of care 
treatments in SCD.  Hence, study participants are not withheld from any other treatments that 
may be used in SCD (eg, hydroxyurea) during the trial, which is important considering the use 
of a placebo control group. 
In summary, considering the high unmet need for treatments reducing the rate of such severe 
and serious conditions as VOCs in paediatric patients in SCD, previous trials in SCD 
populations with similar drugs suggesting potential for beneficial effects, and previous 
paediatric trials in patient with SCD or other diagnoses not raising safety concerns, and the 
specific measures taken in the HESTIA3 study to minimise the risk to study participants, the 
benefit-risk balance for participants in this study is considered favourable.  
1.4 
Study design  
This is an international, multicentre, double-blind, randomised, parallel-group, 
placebo-controlled Phase III study to evaluate the effect of ticagrelor versus placebo in 
reducing the rate of VOCs in paediatric patients with SCD (Figure 1).  During the treatment 
period, patients will be monitored for occurrence of VOCs and other acute SCD 
complications. 
Study participants should receive standard of care for SCD, adjusted to the individual patient 
at the discretion of the Investigator, including routine health care screening examinations and 
immunisations according to local guidelines and health care programmes.  Study drug will be 
given on the background of standard treatments for SCD.  However, restrictions apply to some 
medications and interventions that may be necessary for the patient's health and well-being 
during the study.  Temporary hold of study drug dosing could therefore be needed in case of 
short-term treatment with a medication not to be combined with study drug or in case of 
surgical interventions.  Patients are to be followed for up to 24 months or until a common 
study end date (CSED) is reached defined as 12 months after the last patient is randomised. 
The target population are children aged ≥2 to <18 years of age and body weight of ≥12 kg 
diagnosed with HbSS or HbS/β0. At least 50 evaluable patients should be recruited in each of 
the age groups, ≥2 years to <12 years and ≥12 years to <18 years. 
 

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Clinical Study Protocol 
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Study Code D5136C00009 
Version 3.0 
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1.5 
Study governance and oversight 
1.5.1 
Steering Committee 
A Steering Committee (SC) has been appointed for this study and has provided expert advice 
on, eg, the overall design, including the development of the protocol.  The SC will continue to 
advice on any protocol amendments and will monitor study conduct, result interpretation and 
reporting of the study.  The SC can propose to AstraZeneca their recommendations regarding 
study modifications or a potential early stop to the study based on the information received 
from the DMC.  The SC is comprised of designated international academic leaders and 
non-voting members of the Sponsor, and will operate under a SC charter.  
The Sponsor has the overall responsibility of the study.  
1.5.2 
Data Monitoring Committee 
A DMC composed of independent SCD paediatric experts and including a platelet expert and 
statistician, will be appointed for this study and will report to the SC.  The DMC will be 
responsible for safeguarding the interests of the patients in the study by assessing the safety of 
the intervention during the study, and for reviewing the overall conduct of the clinical study.  
The DMC will have access to unblinded individual data and be able to evaluate these while 
the study is ongoing.  The DMC meeting schedule is shown in Table 1.  Additional meetings 
could be initiated by the DMC chair or the Sponsor as needed.  
The DMC will consider recommending study termination for any episode of bleeding deemed 
related to the ticagrelor treatment that is fatal, or is a spontaneous intracranial haemorrhage, or 
if the accumulating data suggest a strong likelihood of excessive haemorrhagic events 
possibly related to ticagrelor that require medical intervention as reported by the Investigator.  
Study termination will also be considered if the number of fatal or life-threatening serious 
adverse events (SAEs), including but not limited to bleedings, is greater in ticagrelor-treated 
patients compared to placebo. 
The DMC will make recommendations on the progression of the study based on the totality of 
data (eg, AEs, safety laboratory variables, ticagrelor exposure and platelet inhibition) or other 
findings putting patients at undue risk.  The Sponsor has the final decision on study 
progression including amendments, etc. 
Additionally, the DMC will do a formal interim PD assessment when 60 patients have had 
their PK/PD sampling after 4 weeks in the study.  In this interim PD assessment, the mean of 
pre-dose and 2 hours post dose PRI values at 4 weeks will be calculated for each individual 
and compared to their respective baseline values.  The population mean of the platelet 
inhibition in the ticagrelor arm is expected to be above 35% during the study.  If there is a risk 
of not achieving the targeted inhibition level of 35% to 80% in the study, the first task of the 
DMC would be to investigate if the PK values and the PK/PD relationship are as expected and 
in line with earlier documented PK/PD data of ticagrelor.  If any finding is deemed by the 
DMC to not be in accordance with expected PK and PD data and all other reasons for the 
unexpected findings are ruled out, they will contact the Sponsor and ask for proof of treatment 

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Study Code D5136C00009 
Version 3.0 
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compliance and potentially escalate the issue the Steering Committee regarding a potential 
amending of the study in order to evaluate the need for a dose change based on new modelling 
and simulations including the new data. 
A DMC charter will be prepared to detail precise roles and responsibilities and procedures to 
ensure maintenance of the blinding and integrity of the study in the review of accumulating 
data and interactions with the SC.   
Table 1 
Data Monitoring Committee meeting schedule 
Evaluation 
Number of patients randomized 
Completed visit (months) 
1 
40 patients completed Visit 4 or 10 patients 
completed Visit 6 
4 (1) or 6 (3) 
2 
60 patients (formal interim PD assessment) 
4 (1) 
3 
80 patients 
6 (3) 
4 
80 patients 
9 (6) 
5 
All patients 
4 (1) 
6 
All patients 
9 (6) 
x 
Patients remaining in study 
As neededa 
a As deemed necessary by the DMC chair and/or Sponsor. 
PD pharmacodynamic. 
2. 
STUDY OBJECTIVES 
A VOC is the composite of a painful crisis and/or an ACS (Howard et al 2015, 
Yawn et al 2014).  Each component is defined as:  
A painful crisis is an onset or worsening of pain that lasts at least 2 hours, for which there is 
no explanation other than vaso-occlusion and which requires therapy with oral or parenteral 
opioids, parenteral non-steroidal anti-inflammatory drugs (NSAIDs), or other analgesics 
prescribed by a health care provider in a medical setting (such as a hospital, clinic, or 
emergency room visit) or at home. 
An ACS is an acute illness characterized by fever and/or respiratory symptoms, accompanied 
by a new pulmonary infiltrate on a chest X-ray. 
2.1 
Primary objective 
Primary Objective: 
Outcome Measure: 
To compare the effect of ticagrelor vs placebo for 
the reduction of VOCs, which is the composite of 
painful crisis and/or ACS, in paediatric patients 
with SCD 
Number of VOCs 

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2.2 
Secondary objectives 
Secondary Objective: 
Outcome Measure: 
To compare the effect of ticagrelor vs placebo for 
the reduction of painful crises  
Number of painful crises 
To compare the effect on ticagrelor vs placebo for 
the reduction of ACS 
Number of ACSs 
To compare the effect of ticagrelor vs placebo for 
the reduction of duration of painful crises 
Duration of painful crises 
To compare the effect of ticagrelor vs placebo on 
the number of VOCs requiring hospitalisation or 
emergency department visits  
Number of VOCs requiring hospitalisation or 
emergency department visits  
To compare the effect of ticagrelor vs placebo on 
reduction of days hospitalised for VOC   
Number of days hospitalised for VOC 
To compare the effect of ticagrelor vs placebo on 
the number of acute SCD complicationsa 
Number of acute SCD complications 
To compare the effect of ticagrelor vs placebo on 
reduction of days hospitalised for acute SCD 
complicationsa 
Number of days hospitalised for acute SCD 
complications 
To compare the effect of ticagrelor vs placebo on 
the number of sickle cell-related red blood cell 
(RBC) transfusions 
Number of sickle cell-related RBC transfusions  
To describe the health-related quality of life 
(HRQL) and fatigue 
HRQL total score and by dimension using 
Paediatric Quality of Life Inventory (PedsQL) 
SCD Module and Fatigue total score and by 
dimension using the PedsQL Multidimensional 
Fatigue Scale as presented in Appendix I (age 
appropriate versions) 
To describe absence from school or work due to 
SCD 
Proportion of days of absence from school or 
work (only if going to school or work at 
randomisation) 
To describe intensity of pain during VOC 
Intensity of worst pain daily during VOC 
- For patients ≤4 years of age, observer reported 
using the Face, Legs, Activity, Cry, 
Consolability Scale (FLACC) 
- For patient ages 5 to 18 years of age, 
self-reported using the Faces Pain Scale 
Revised (FPS-R) 
To describe analgesics use during VOC 
Type of analgesics (opioid and non-opioid) use 

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To describe patient acceptability of the formulation 
(palatability and swallowability) 
- For patients ≤4 years of age taking the tablet 
dispersed or whole, an observer assessment of 
palatability and swallowability will be 
undertaken  
- For patients ≥5 years of age taking the tablet 
dispersed or whole, palatability will be 
assessed and categorised using the Facial 
Hedonic Scale 
a 
The acute SCD complications are defined in Section 5.1.5. 
 
2.3 
Safety objectives 
 
2.4 
Exploratory objectives 
3. 
SUBJECT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL 
Each patient must meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule. 
3.1 
Inclusion criteria 
For inclusion in the study, patients must fulfil the following criteria: 
1. Provision of signed and dated informed consent prior to any study specific procedures not 
part of standard medical care (local regulations and international guidelines are to be 
followed in determining the assent/consent requirements for children). 
2. Male or female paediatric patients aged ≥2 to <18 years and body weight of ≥12 kg (at 
Visit 1), diagnosed with HbSS or HbS/β0 as confirmed by high-performance liquid 
Safety Objective: 
Outcome Measure: 
To assess long-term safety and tolerability of 
therapy with ticagrelor vs placebo 
AEs/SAEs, including bleeding 
Vital signs and laboratory safety variables 
Exploratory Objective: 
Outcome Measure: 
To compare the effect of ticagrelor vs placebo for 
the reduction of duration of ACS 
Duration of ACS 
To assess the pharmacokinetics (PK) of ticagrelor 
and AR-C124910XX in paediatric patients with 
SCD using a population PK model 
Population PK parameters such as oral 
clearance (CL/F) and ticagrelor exposure (AUC) 
Observed plasma concentrations of ticagrelor 
and the active metabolite AR-C124910XX 
To assess the effect of ticagrelor on platelet 
aggregation 
PRI measured by vasodilator-stimulated 
phosphoprotein (VASP) assay 

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chromatography or haemoglobin electrophoresis. 
Note:  Diagnosis of SCD (if not confirmed prior to screening and records available on the 
medical file) should be confirmed for HbSS or HbS/β0 by high-performance liquid 
chromatography or haemoglobin electrophoresis, performed at the site’s local lab, in order 
to confirm the type of mutation. 
3. Have experienced at least 2 VOCs (painful crisis and/or ACS) as judged by the 
Investigator in the past 12 months prior to Visit 1.  These VOCs need to be documented in 
the patient’s medical records or in other documents that can be reconciled.  
4. If ≤16 years old, must have had transcranial Doppler (TCD) within the past year prior to 
Visit 1.  If this is not the case, a TCD examination must be done before proceeding in the 
study. 
5. If ≥10 years old, must have had an ophthalmological examination within the past year 
prior to Visit 1.  If this is not the case, the patient must be examined by an ophthalmologist 
before proceeding in the study.  If local guidelines dictate ophthalmological examination 
at younger ages, those local guidelines should be followed. 
6. If treated with hydroxyurea, the weight-adjusted dose must be stable for 3 months before 
screening. 
7. Suitable venous access for the study-related blood sampling 
8. Prior to dosing on day of randomisation (Visit 2), a negative urine (dipstick) pregnancy 
test performed at Screening (Visit 1) and at Visit 2 must be available for female patients of 
childbearing potential. 
9. Females of childbearing potential (after menarche) must not become pregnant during 
study.  Sexually active females must use a highly effective method of contraception which 
results in a low failure rate (ie, less than 1% per year).  If use of effective contraception 
cannot be secured in sexually active females, the patient cannot be included in this study.  
Refer to Section 3.8 for highly effective methods of contraception. 
3.2 
Exclusion criteria 
Patients should not enter the study if any of the following exclusion criteria are fulfilled: 
1. History of transient ischaemic attack (TIA) or cerebrovascular accident (ischaemic or 
haemorrhagic), severe head trauma, intracranial haemorrhage, intracranial neoplasm, 
arteriovenous malformation, aneurysm, or proliferative retinopathy. 
2. Findings on TCD: Current or previous values for time averaged mean of the maximum 
velocity (TAMMV) that are Conditional or Abnormal.  Patients with Conditional 
TAMMV values or higher (≥153 cm/sec using TCD imaging technique [TCDi] which is 
corresponding to ≥170 cm/sec by the non-imaging technique).  Both the middle cerebral 
artery and the internal carotid artery should be considered.  Any other criteria that would 
locally be considered as TCD indications for chronic transfusion would also exclude the 
patient. 
3. Active pathological bleeding or increased risk of bleeding complications according to 
Investigator 
4. Haemoglobin <6 g/dL from test performed at Screening (Visit 1) 
5. Platelets <100 x 109/L from test performed at Screening (Visit 1) 
6. Undergoing treatment with chronic red blood cell transfusion therapy 

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7. Chronic use of NSAIDs defined as continuous intake >3 days per week that cannot be 
discontinued 
8. Receiving chronic treatment with anticoagulants or antiplatelet drugs that cannot be 
discontinued 
9. Moderate or severe hepatic impairment defined as laboratory values of alanine 
aminotransferase (ALT) >2 × upper limits of normal (ULN), total bilirubin >2 × ULN 
(unless judged by the Investigator to be caused by haemolysis), albumin <35 g/L 
(3.5 g/dL) and International normalised ratio (INR) >1.4, or symptoms of liver disease (eg, 
ascites) from test performed at Screening (Visit 1). 
10. Renal failure requiring dialysis 
11. Patient considered to be at risk of bradycardic events (eg, known sick sinus syndrome or 
second or third-degree atrioventricular block) unless already treated with a permanent 
pacemaker. 
12. Concomitant oral or intravenous therapy with strong cytochrome P450 3A (CYP3A) 
inhibitors, CYP3A substrates with narrow therapeutic indices, or strong CYP3A inducers 
(see full list in Appendix G), which cannot be stopped at least 5 half-lives before 
randomisation. 
13. Active untreated malaria.  Patients with suspected malaria at Screening (Visit 1) will be 
tested. 
14. Known hypersensitivity or contraindication to ticagrelor 
15. Patients who are currently pregnant or breastfeeding, or planning to become pregnant 
during the study or have given birth less than 3 months prior to Screening (Visit 1) 
16. Any condition which, in the opinion of the Investigator, would make it unsafe or 
unsuitable for the patient to participate in this study 
17. Concern for the inability of the patient or caregiver (defined as legally authorised 
representative) to comply with study procedures and/or follow-up 
18. Previous randomisation in the present study 
19. Participation in another clinical study with an IP or device during the last 30 days 
preceding screening. 
20. Involvement of member of patient’s family, or patient self, in the planning and/or conduct 
of the study (applies to both AstraZeneca staff and/or staff at the study site).  
Procedures for withdrawal of incorrectly enrolled patients see Section 3.3. 
3.3 
Subject enrolment and randomisation 
Investigator(s) should keep a record, the patient screening log, of patients who entered 
pre-study screening. Enrolment can occur 7-28 days before randomisation. 
The Investigator(s) will: 
1. Obtain signed informed consent/assent (per local requirements) from caregiver of the 
potential patient and from the patient (if applicable) before any study specific procedures 
are performed.  
2. Assign (using the Interactive Voice/Web Response System [IXRS]) potential patient a 
unique enrolment number, beginning with ‘E + 4-digit site number + 3-digit patient 

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number starting with 501.  For example, the first patient at site 9999 would be assigned the 
patient number: E9999001.  This number will be used for identification (ID) throughout 
the study and will not be used for any other participant. 
3. Determine patient eligibility.  See Sections 3.1 and 3.2. 
4. Assign eligible patient unique randomisation code (patient number), by accessing IXRS.   
Patients who have not been randomised can be re-enrolled in the study if they meet eligibility 
criteria at a later date; however, no patient can be re-randomised.  Any re-enrolment of 
patients must be done in consultation of the Sponsor’s Study Physician and any decision must 
be captured in the patient’s medical notes.  If a patient withdraws from participation in the 
study, then his/her enrolment/randomisation code cannot be reused. 
3.4 
Procedures for handling incorrectly enrolled or randomised 
subjects 
Patients who fail to meet the eligibility criteria must not, under any circumstances, be enrolled 
or receive IP.  There can be no exceptions to this rule.  Patients who are enrolled, but 
subsequently found not to meet all the eligibility criteria must not be randomised or initiated 
on treatment, and must be withdrawn from the study. 
Where a patient does not meet all the eligibility criteria but is randomised in error, or 
incorrectly started on treatment, the Investigator should inform the AstraZeneca Study 
Physician or representative immediately, and a discussion should occur between the 
AstraZeneca Study Physician and the Investigator regarding whether to continue or 
discontinue the subject from treatment.  The AstraZeneca Study Physician or representative 
must ensure all decisions are appropriately documented. 
In those cases where continuation of study therapy is judged not to present a concern related 
to safety and disease management, the rationale for continuing study therapy must be clearly 
documented.  The patient should continue follow-up in accordance with defined study 
procedures. 
3.5 
Methods for assigning treatment groups 
The randomisation codes will be computer generated by AstraZeneca R&D and loaded into 
the IXRS database. Randomisation codes will be generated in blocks to ensure approximate 
balance (1:1) between the 2 treatment arms (ticagrelor or placebo bd). Stratification for 
baseline hydroxyurea use by country will be applied.   
For each patient randomised the IXRS will provide the Investigator with a unique kit ID 
number matching the treatment arm assigned to the patient.  Following randomisation, the first 
dose of study drug will be administered to the patient as soon as possible.  At randomisation 
and subsequent dispensing visits, the patient should always be provided medication with the 
kit ID(s) allocated by the IXRS.  If a patient receives the incorrect randomised treatment at 
any time during the study, this must be corrected as soon as discovered after discussing with 
the Study Physician. 

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3.6 
Methods for ensuring blinding 
This is a double-blind study.  Ticagrelor and matching ticagrelor placebo tablets will be 
identical in appearance and packaging.  The bottles with IPs will be labelled with unique ID 
numbers allocated from the IXRS, but it will not indicate treatment allocation. 
No member of the study team at AstraZeneca or representative, personnel at study centres or 
any contract research organisation (CRO) handling data will have access to the randomisation 
scheme during the conduct of the study, with the exception of the AstraZeneca personnel 
generating the randomisation scheme and the bioanalysis personnel analysing the 
pharmacokinetic (PK) samples as well as AstraZeneca Supply Chain, the Patient safety data 
entry site and the CRO companies providing the IXRS and carrying out the packaging and 
labelling of IPs.  This documentation will be kept in a secure location until the end of the 
study. 
There will be an independent, unblinded statistical team that will support the DMC with data 
during the study.  Personnel involved in the clinical study at AstraZeneca or representative 
will remain blinded to these analyses and will have no knowledge of the results presented to 
the DMC.  
3.7 
Methods for unblinding 
Individual treatment codes, indicating the treatment randomisation for each randomised 
patient, will be available to the Investigator(s) or pharmacists from the IXRS.  Routines for 
this will be described in the IXRS user manual that will be provided to each centre. 
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the patient requires knowledge of the treatment randomisation.  The 
Investigator documents and reports the action to AstraZeneca, without revealing the treatment 
given to patient to the AstraZeneca or representative staff.  The number of individuals at the 
study site who become aware of the treatment status should be kept to an absolute minimum 
including keeping the patient blinded if possible.  Treatment with study drug should be 
continued if considered appropriate. 
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an IP and that potentially require expedited reporting to 
regulatory authorities.  Treatment codes will not be broken for the planned analyses of data 
until all decisions on the evaluability of the data from each individual patient have been made 
and documented. 
3.8 
Restrictions 
The following restrictions will be applied for patients participating in the study: 
1. Patients may not participate in another clinical study that involves an IP (active or 
placebo) or device during this study. 

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2. Females of childbearing potential (after menarche) must not become pregnant.  Sexually 
active females of childbearing potential must use a highly effective method of 
contraception, which results in a low failure rate (ie, <1% per year) from enrolment to the 
follow-up visit.  If this cannot be secured, the patient cannot continue in this study.  
Examples of highly effective methods include implants, injectables, combined oral 
contraceptives, some intrauterine devices, or vasectomized partner.  For male study 
participants, there are no restrictions against fathering a child when treated with ticagrelor. 
3. For concomitant medications which are restricted during the study, see Appendix G. 
4. If the patient is receiving digoxin, levels should be monitored closely following initiation 
of IP and with any change in IP, see Appendix G.  
5. Intake of grapefruit juice is not allowed. 
6. Patients should participate in annual ophthalmological and TCD examinations in age 
groups according to guidelines. 
7. On visits with PK or vasodilator stimulated phosphoprotein (VASP) sampling, the 
morning dose of IP should not be taken at home.  The dose will be administered at the site.  
See Table 2 for study assessment schedule, and Sections 5.4.1 (PK) and 5.5.2 (VASP). 
3.9 
Permanent discontinuation or temporary stop of investigational 
product 
3.9.1 
Permanent discontinuation 
Patients may be permanently discontinued from IP in the following situations: 
1. The patient (or caregiver) is at any time free to discontinue treatment or advise the patient 
to discontinue treatment, without prejudice to further treatment 
2. AE, as judged by Investigator, that with continued treatment would put the patient at 
undue risk 
3. Severe non-compliance with the study protocol, as judged by Investigator and/or 
AstraZeneca 
4. Severe illness or risk to the patient as judged by the Investigator 
5. Any major bleeding, for bleeding definitions see Section 6.3.8.  
6. Repeated minor bleedings not needing medical intervention unless clearly not related to 
study drug (eg, minor trauma during playing), as judged by the Investigator 
7. For females of childbearing potential, who are sexually active and where effective 
contraception cannot be secured, the study treatment must be discontinued 
8. In the event of pregnancy, study drug should be immediately permanently discontinued.  
The patient is encouraged to continue to be followed in the study according to the study 
plan. 
9. Conditional or Abnormal TCD findings, ie, TAMMV values are ≥153 cm/sec using TCDi 
technique (corresponding to ≥170 cm/sec by the non-imaging technique), indicating an 
increased risk of stroke. 
10. Pathological findings on any imaging technique indicating increased risk of ischaemic or 
haemorrhagic stroke 
11. TIA or stroke (ischaemic or haemorrhagic) 
12. Need for chronic transfusion therapy 
13. Findings indicating impaired liver function and/or coagulopathy:  

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• ALT or aspartate aminotransferase (AST) >5 × ULN, ALT or AST >3 × ULN and 
total bilirubin level >2 × ULN (unless bilirubin increase clearly explained by 
haemolysis), INR >1.5.  For potential Hy’s Law laboratory criteria: the elevation in 
transaminases must precede or coincide with (ie, on the same day as) the elevation in 
total bilirubin, but there is no specified timeframe within which the elevations in 
transaminases and total bilirubin must occur. 
14. Renal failure requiring dialysis 
15. Patients with clinical symptoms of bradyarrhythmia as judged by the Investigator and/or 
ECG findings of significant sinus pauses or high degree atrioventricular block 
16. Development of proliferative retinopathy. 
17. Need for chronic use of NSAIDs defined as continuous intake >3 days per week 
3.9.2 
Temporary discontinuation 
Patients may be temporarily discontinued from IP in the following situations: 
1. Clinically significant thrombocytopenia (platelet count <80 x 109/L) which mandates an 
interruption of IP due to patient safety in the assessment of the Investigator.  Repeat 
laboratory studies and standard of care should be followed until resolution of laboratory 
abnormality and if deemed appropriate, the IP can be restarted when platelet counts are 
>100 x 109/L. 
2. Major or minor surgery or invasive procedures, for example, intramuscular injections.  
The IP should be temporary stopped 5 days prior to the procedure and can be restarted 
when bleeding risk is considered low, as judged by the Investigator. 
3. Temporary need of treatment with prohibited concomitant medications, see Appendix G.  
The IP may be interrupted temporarily at the discretion of the Investigator; however, such 
cases are recommended to be discussed with the IQVIA Study Physician and the Sponsor 
Physician as soon as the Investigator is aware. 
4. Novel coronavirus (COVID-19) pandemic, see Section 3.9.4. 
Discontinuation of IP does not mean discontinuation of follow-up or termination of study 
participation.  Study assessments should continue in all cases if possible. 
If patients are not willing to come back to study visits, the sites are encouraged to investigate 
patient barriers to study visit compliance and discuss with the Clinical Research Associate 
(CRA) if there is any alternative follow-up schedule which can meet patient expectations.  
Prior to implementing alternative follow-up schedules, AstraZeneca approval must be granted. 
3.9.3 
Procedures for permanent discontinuation of a subject from investigational 
product 
At any time, patients are free to discontinue IP, without prejudice to further treatment.  A 
patient that decides to discontinue IP will always be asked about the reason(s) and the 
presence of any AEs.  Adverse events (AEs) will be followed up (see Section 6) and all IPs 
should be returned by the patient.  Patients permanently discontinuing IP should always be 
asked to continue the regular visits.  It is essential to collect as much data as possible for all 
patients throughout the study and especially all potential endpoint events.  Complete 

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withdrawal from the study (withdrawal of consent) has a direct negative impact on the 
potential validity of all study data and should be avoided wherever possible. 
If patients are not willing to come back to study visits, the sites are encouraged to investigate 
patient barriers to study visit compliance and discuss with the CRA if there is any alternative 
follow-up schedule which can meet patient expectations.  Prior to implementing alternative 
follow-up schedules, AstraZeneca approval must be granted. 
If a patient is withdrawn from study, see Section 3.10.   
3.9.4 
Procedures and guidance for temporary IP discontinuation in relation to 
coronavirus disease 2019 (COVID-19) 
If a patient is diagnosed with COVID-19 or is suspected to have COVID-19 and an AE/SAE 
is reported (see Section 6.3.10), the Investigator should determine whether the patient’s IP 
administration should continue or be temporarily discontinued.  Patients who are discontinued 
from IP due to COVID-19 are to remain in the study whenever possible for safety follow-up.   
In case a patient is unable to attend on-site visits for undergoing safety-related assessments as 
detailed in the Schedule of Assessments (Table 2), due to local public health rules, patient 
inability or patient/caregiver decision, the patient must be temporarily discontinued from IP, 
unless the safety-related assessments (including vital signs, physical examination, blood 
samples for safety laboratory assessments, urine for urinalysis, eDevice review, ECGs, VOCs, 
and recording of concomitant medications and AEs) can be performed at the patient’s home 
and/or local laboratories or other local facilities by delegated site staff.   
Such temporary discontinuation of IP does not mean discontinuation of follow-up.  In case it 
is not possible to perform on-site visits, the site staff should keep in close contact with the 
patient to maintain awareness of their status and on-site visits should be replaced by telephone 
contacts following the same procedures as detailed in the Schedule of Assessments for 
telephone visits (Table 3).   
Deviations from the study schedule of assessments due to COVID-19 will be identified as 
COVID-19 related protocol deviations and recorded appropriately. 
In the event a patient is temporarily discontinued from IP, every effort should be made to have 
the patient/caregiver return all unused IP and empty bottles to the study site and study site 
staff should perform accountability as detailed in Section 7.6. 
If this is not possible: 
− 
patients should be clearly instructed that, in case of any tablets leftover in bottles already 
dispensed to them, they are not allowed to take the IP if they are not visiting the site 
− 
remaining IP should be returned during the first possible on-site visit 
− 
reasons for not returning the IP and instructions given to the patient should be thoroughly 
documented. 

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According to the local public health rules and recommendations, as soon as the patient is able 
to undergo safety-related assessments as detailed in the Schedule of Assessments (Table 2), 
then IP can be dispensed and treatment restarted. 
In the event a study site is impacted by COVID-19 in a way that results in an inability to 
perform study activities, the study monitor should be informed as soon as possible. 
If a patient is to be withdrawn from study, see Section 3.10.   
3.10 
Criteria for withdrawal 
3.10.1 
Screen failures 
Screening failures are patients who do not fulfil the eligibility criteria for the study, and 
therefore must not be randomised.  These patients should have the reason for study withdrawal 
recorded as ‘Failure to meet randomisation criteria’ (ie, patient does not meet the required 
inclusion criteria or meet any of the exclusion criteria).  This reason for study withdrawal is 
only valid for screen failures (not randomised patients). 
3.10.2 
Withdrawal of the informed consent 
Patients are free to withdraw from the study at any time (ie, permanent discontinue of IP and 
study schedule assessments), without prejudice to further treatment. 
Withdrawal of consent from the study must be documented by the Investigator in the patient 
medical records and recorded in the electronic case report form (eCRF) as well as in the 
Informed Consent Form (ICF).  The reason for permanent discontinuation of IP, the date of 
the last dose of the IP, reason for withdrawal and the presence of any AEs must be 
documented in the eCRF.  The Investigator will follow-up AEs outside of the clinical study.  
The patient will return the electronic device (eDevice).  
If a patient withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused.  Withdrawn patients will not be replaced after randomisation. 
3.11 
Discontinuation of the study 
The study may be terminated at individual centres per agreement between the Principal 
Investigator (PI) and AstraZeneca, eg, if the study procedures are not being performed 
according to Good Clinical Practice (GCP), or if recruitment is slow.  Enrolment in a country 
may be terminated in order to ensure a reasonable international distribution of patients.   
AstraZeneca may also terminate the entire study prematurely if concerns for safety arise 
within this study (see Section 1.5.2 for DMC) or in any other study with ticagrelor. 
Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation of follow-up must be recorded in the eCRF.   

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In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the patients’ interests. 
4. 
STUDY PLAN AND TIMING OF PROCEDURES 
The Schedule of Assessments is presented in Table 2.  The Schedule of Assessments for 
telephone visits is presented in Table 3.

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Table 2 
Schedule of Assessments - Physical visits at study sites 
 
Screening 
period 
Treatment perioda 
 
Follow-up 
period 
For 
details 
see 
CSP 
Section 
 
Enrol-
ment 
Random-
isation 
 
 
 
Visit Number 
1 
2 
3 
4 
6 
9 
12 
15 
18 
21 
24 
End of 
Study 
(EOS) 
 
Safety 
Follow-up 
Day/Week/Month 
-7 d 
0 d 
2 wk 
4 wk 
3 mob 
6 mob 
9 mob 12 mob 15 mob 18 mob 21 mob 
{12 to 
24 mo} 
14d after 
EOS 
Visit Window 
-28 to  
-7 d 
N/A 
±3 d 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
±14 d 
±5 d 
Signed and dated informed 
consent/assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
10.4 
Inclusion/exclusion criteria 
X 
Xa 
 
 
 
 
 
 
 
 
 
 
 
3.1 and 
3.2 
Assign E-code via IXRS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
3.3 
Relevant SCD, medical and 
surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
4.1 
SCD diagnosis (if needed) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
4.1 
Demographicsc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
4.1 
Transcranial Dopplerd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
4.1 
Ophthalmology examination (if 
not performed within previous 
12 months)d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
4.1 
Randomisation via IXRS 
 
X 
 
 
 
 
 
 
 
 
 
 
 
3.3 and 
3.5 
BP and pulse rate 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
5.2.4 
Weight and height 
X 
Xe 
 
 
 
X 
 
X 
 
X 
 
X 
 
5.2.4 
Physical examination 
(complete/brief)f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
5.2.2 
12-Lead ECG 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
5.2.3 
Malaria testing for symptomatic 
patientsg  
X 
 
 
 
 
 
 
 
 
 
 
 
 
4.1 
Virology screen (HIV, HBsAg, 
and HCV) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
5.2.1 

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Table 2 
Schedule of Assessments - Physical visits at study sites 
 
Screening 
period 
Treatment perioda 
 
Follow-up 
period 
For 
details 
see 
CSP 
Section 
 
Enrol-
ment 
Random-
isation 
 
 
 
Visit Number 
1 
2 
3 
4 
6 
9 
12 
15 
18 
21 
24 
End of 
Study 
(EOS) 
 
Safety 
Follow-up 
Day/Week/Month 
-7 d 
0 d 
2 wk 
4 wk 
3 mob 
6 mob 
9 mob 12 mob 15 mob 18 mob 21 mob 
{12 to 
24 mo} 
14d after 
EOS 
Visit Window 
-28 to  
-7 d 
N/A 
±3 d 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
±14 d 
±5 d 
Blood samples for haematology 
and clinical chemistry 
X 
Xh 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
5.2.1 
Blood samples for coagulation 
(INR, PT and APTT) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
5.2.1 
Urine pregnancy Testi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
5.2.1 
Urine for urinalysis (dipstick) 
X 
Xh 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
5.2.1 
Training and handout/collection 
of eDevice 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Review of eDevice device entries 
and reminder of usej 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
5.3.1 
HRQL (PedsQL) assessmentk 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
5.1.3 
Palatability/swallowabilityl 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
5.3.1 
Blood sampling for 
pharmacokineticsm 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
5.4 
Blood sampling for 
pharmacodynamics (VASP)m 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
5.5 
Dispense IP 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
7 
Return IP and IP accountability 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
7.5 and 
7.6 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
7.7 
Adverse event collection (AEs 
and SAEs)  
Xn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
6 
AE Adverse event; APTT Activated partial thromboplastin time; BP Blood pressure; D Day; ECG Electrocardiogram; EOS End of study; eDevice Electronic 
device; FLACC Face, Legs, Activity, Cry, Consolability Scale; FPS-R Faces Pain Scale-revised; HBsAg Hepatitis B surface antigen; HCV Hepatitis C 

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virus; HIV Human immunodeficiency virus; HRQL Health-related quality of life; INR International normalised ratio; IP Investigational product; 
IXRS Interactive Voice/Web Response System; mo Month; PedsQL Paediatric Quality of Life Inventory; PD Pharmacodynamics; PK Pharmacokinetics; 
PT Prothrombin time; SAE Serious adverse event; SCD Sickle cell disease; TCD Transcranial Doppler; VASP Vasodilator-stimulated phosphoprotein; 
VOC Vaso-occlusive crisis; wk Week.  
a 
Confirm patient still meets inclusion and exclusion criteria prior to randomising the patient in IXRS; SCD diagnostic testing not necessary if documented 
in medical records.  
b 
Interval must not be more than 100 days to ensure tablet supply for all days.  
c 
Age is required, but partial birthdate (year/month) is allowed if full data is not allowed or known.  
d 
See inclusion criteria #4 for TCD and #5 for ophthalmology exam.  Results must be available prior to randomisation and these examinations should 
thereafter be done annually during the study period.  
e 
Only weight will be measured at Visit 2.  
f 
A complete physical examination will be performed at Visit 1, EOS and Follow-up Visit and a brief examination at all other visits (see Section 5.2.2).  
g 
Local/standard tests to be used for diagnosis of malaria for patients who are symptomatic at Screening.  
h 
If the patient has had any serious illness after Visit 1 but before Visit 2, the need for repeated eligibility laboratory sampling must be evaluated before 
randomisation. If the Visit 1 laboratory results are less than 10 days old at randomisation, they can replace randomisation safety laboratory sampling to 
minimise the blood volume drawn.  
i 
For females of childbearing potential.  
j 
Electronic recording of worst pain according to FPS-R/FLACC and localisation of pain after experiencing a VOC, analgesic use and absence from 
school/work due to SCD.  
k 
The HRQL (PedsQL) instruments are patient-reported if 5-7 years, 8-12 years, or 13-18 years and reported by a caregiver if the patient is ≤4 years.   
l 
Morning dose of IP to be taken at the site.  The palatability/swallowability questionnaire assessed by an observer in children ≤4 years, and by Facial 
Hedonic Scale (FHS) for children ≥5 years.  
m 
Samples for PK and PD analysis will be taken 0 hour (predose) and 2 hours postdose at specified visits and in case of changed dose due to weight 
increase.  No predose PK sample at Visit 2.   
n 
SAEs should be collected from when the ICF is signed.  AEs should be collected from time of randomisation.  
Note: In case of modified follow-up when IP is discontinued, the study site visits can be replaced with telephone contact visits as per Table 3.  

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Table 3 
Schedule of Assessments - Telephone visits during treatment period 
 
Treatment perioda 
For details see 
Protocol Section 
Visit Number 
5 
7, 8 
10, 11 
13, 14 
16, 17 
19, 20 
22, 23 
25, 26 
Month 
2 
4, 5 
7, 8 
10, 11 
13, 14 
16, 17 
19, 20 
22, 23 
Visit Window 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
Reminder of eDevice use and 
ensure data collection of potential 
VOC eventsb 
X 
X 
X 
X 
X 
X 
X 
X 
5.1.1 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
7.7 
Adverse event collection  
(AEs and SAEs) 
X 
X 
X 
X 
X 
X 
X 
X 
6 
AE Adverse event; d Day; eDevice Electronic device; FLACC Face, Legs, Activity, Cry, Consolability Scale; FPS-R Faces Pain Scale-revised SAE Serious 
adverse event; VOC Vaso-occlusive crisis.  
a 
See Appendix E, a Guide for Scheduled Telephone Visits. 
b 
Electronic recording of pain according to FPS-R/FLACC when experiencing a VOC, analgesic use and absence from school/work due to SCD. 

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4.1 
Screening period 
Procedures will be performed according to the Schedule of Assessments (Table 2). 
Before any study-related assessments are performed, the informed consent/assent should be 
provided by the caregiver/patient, see Section 10.4.  
At Screening, consenting patients are assessed to ensure that they meet eligibility criteria.  
Patients who do not meet these criteria must not be enrolled in the study.  
If the patient has had any serious illness after Visit 1 but before Visit 2, the need for repeated 
eligibility laboratory sampling must be evaluated before randomisation.  
If the Visit 1 laboratory results are less than 10 days old at randomisation, they can replace 
randomisation safety laboratory sampling to minimise the blood volume drawn. 
Unless done within previous 12 months, the Investigator must ensure TCD and ophthalmology 
examination are performed before proceeding in the study, see Section 3.2 for exclusion 
criteria related to these examinations.  These examinations should thereafter be done annually 
during the study period. 
4.2 
Treatment period 
4.2.1 
Physical visits at study sites during the treatment period 
Descriptions of the procedures for this period are included in the Schedule of Assessments for 
physical visits at study sites (Table 2). 
At Visit 2, ensure the eligibility of the patient before continuing study-related assessments.  
The Paediatric Quality of Life Inventory (PedsQL) should be the first study assessment, ie, 
before blood sampling, electrocardiogram (ECG), etc.  The patient will be administered 
his/her first dose of the double-blind treatment at the site.  The collection of study assessments 
should be ensured before dispensing of the first dose.  After the first dose is taken, assess 
palatability/swallowability.  
For all on-site visits, remind the patient: 
• To bring the IP bottles and the electronic Device (eDevice; including unscheduled visits) 
to the study site 
• Not to take their dose at home in the morning of the visits with PK/PD sampling scheduled 
at the visit.  The patient should be reminded on how to use the eDevice including during a 
potential VOC event, regardless of primary setting of treatment (eg, in-patient 
hospitalisation, short-stay outpatient unit, emergency department or self-treated), see 
Section 5.1.1.  
Contraceptive method should be reviewed and monitored in females of childbearing potential.  

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On visits with PedsQL, the instrument should be completed before any other study 
assessments.   
Ensure that there are not more than 100 days between two planned visits containing 
dispensing of IP to ensure tablet supply for all days.   
If feasible, study visits may take place at the patient’s home or other setting if travel to the site 
is not possible due to the COVID-19 situation.   
4.2.2 
Telephone visits during treatment period 
Descriptions of the procedures for this period are included in the Schedule of Assessments for 
telephone visits during the treatment period (Table 3). 
Telephone visits should occur between the Investigator at the study site, and the caregiver for 
the patient.  The Investigator may decide to speak directly with a patient in the late teenage 
period, if judged appropriate based on the Investigator’s thorough knowledge of the patient. 
Similar to on-site visits, the telephone visit should be documented in the patient’s medical 
records.  Notes are to include: 
• Any AEs,  
• Whether an AE fulfils criteria for VOC endpoint or not,  
• Any changes of medications,  
• Any use of contraceptives (applicable to females of childbearing potential).  
See Appendix E, a Guide for Scheduled Telephone Visits for further details on conduct of the 
telephone visits. 
4.2.3 
End of study visit 
Patients are to be followed up to 24 months or until a common study end date is reached 
defined as 12 months after the last patient is randomised.  After the CSED have been 
communicated by AstraZeneca or representative, all patients still in the treatment period 
should be scheduled for the End of Study Visit (see Table 2).  The End of Study Visit should 
be done within 30 days after CSED.  The patients should return the eDevice and the IP bottles.  
The Safety Follow-up Visit should be scheduled. 
4.2.4 
Safety follow-up visit 
Descriptions of the procedures for this visit are included in the Schedule of Assessments 
(Table 2). 
4.2.5 
Unscheduled visits 
For any safety or tolerability reasons, the patients may return to the clinic for an unscheduled 
visit.  

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The Investigator’s evaluation should be documented in the source documents in the same 
manner as a regular planned visit.  Procedures performed are at the discretion of the 
Investigator.  Unscheduled visits should not affect the regular visit schedule and assessments.  
5. 
STUDY ASSESSMENTS 
The Web Based Data Capture (WBDC) system will be used for data collection and query 
handling.  The Investigator will ensure that data are recorded on the eCRF as specified in the 
Clinical Study Protocol and in accordance with the instructions provided. 
The Investigator will ensure the accuracy, completeness and timeliness of the data recorded 
and of the provision of answers to data queries according to the Clinical Study Agreement 
(CSA).  The Investigator will sign the completed eCRFs.  A copy of the completed eCRFs 
will be archived at the study site. 
An eDevice will be used by the patient/caregiver for electronic recording of pain according to 
FPS-R/FLACC when experiencing a VOC, analgesic use and absence from school/work due 
to SCD. 
5.1 
Efficacy assessments 
5.1.1 
Vaso-occlusive crisis 
A VOC is the composite of a painful crisis and/or an ACS (Howard et al 2015, 
Yawn et al 2014).  Each component is defined as:  
A painful crisis is an onset or worsening of pain that lasts at least 2 hours, for which there is 
no explanation other than vaso-occlusion and which requires therapy with oral or parenteral 
opioids, parenteral NSAIDs, or other analgesics prescribed by a health care provider in a 
medical setting (such as a hospital, clinic or emergency room visit) or at home. 
An ACS is an acute illness characterised by fever and/or respiratory symptoms, accompanied 
by a new pulmonary infiltrate on a chest X-ray.   
5.1.1.1 
Collection of VOC 
A VOC occurring during the study should be recorded by the Investigator both as a primary 
endpoint event, and also as an AE.  A potential VOC judged by the Investigator not to fulfil 
the definition of the primary endpoint should be also recorded as an AE according to standard 
AE reporting procedures (see Section 6).  
Collection of some information related to the potential VOC should be done by the 
patient/caregiver in real-time in the eDevice, and not based on recollection at the next planned 
visit.  When information related to a potential VOC is entered in the eDevice, the Investigator 
will be alerted and should, unless a contact already occurred, call the caregiver within 
72 hours from the onset of the potential event to enable a medical consultation and event data 
collection (see Appendix D, Interview Guide for VOC-triggered Telephone Calls).  Families 

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will be instructed to call the site in case of a VOC, unless already contacted by the site within 
72 hours.  
Regardless of primary setting of treatment (eg, in-patient hospitalisation, short-stay outpatient 
unit, emergency department or self-treated), some VOC-related information outlined below 
must be documented by the caregiver in the patient’s eDevice.  The Investigator only, will 
judge if the potential VOC fulfil the definition of VOC (see Section 5.1.1 for definition).  If 
needed, the Investigator should request medical records and/or other documents from other 
medical facility than the study site.  It will be the Investigators’ responsibility to document the 
VOC in medical records and ensure that the VOC data in the eCRF is correct.  
Following information will be captured in the eDevice to be reviewed by the Investigator:  
• Start and stop date/time of the VOC event 
• Assessment of worst pain intensity will be done once daily throughout the duration the 
VOC event (Patient/Observer Reported), see Section 5.1.2. 
• Report of anatomical location(s) of pain will be done once daily throughout the duration of 
the VOC event (Patient/Observer Reported).  
• If analgesics are taken during the VOC (Yes/No) and the Investigator will enter details of 
the analgesics (ie, name, type, dose, routes of administration, frequency) into the eCRF. 
The following data should be collected in the eCRF, based on review of eDevice entries, 
information from the medical consultation and copies from other medical facilities:  
• Confirmation if the event fulfils the VOC definition  
• Date of any telephone contact 
• Start and stop date/time of the event 
• Primary setting for VOC treatment (eg, in-patient hospitalisation, short-stay outpatient 
unit, emergency department or self-treated) 
• Start and stop date/time of any in-patient hospitalisation 
• Treatments administered of the event 
• Complete AE/SAE form. 
5.1.1.2 
Training in the collection of VOC events 
Patients will be supplied with a handheld eDevice for the treatment period.  Caregivers must 
be willing to learn and use the eDevice and/or supervise the use of the eDevice.  At Visit 2, all 
patients and their caregiver will be carefully instructed and trained on how to handle and 
complete the eDevice.  Written information will be supplied to each patient and caregiver in 
an age-adapted way in their local language.  Instructions for use of the eDevice will also be 
described in writing in the ICF for the caregiver, in age-adapted language in the paediatric 
assent form (if used in certain age groups), and in the ICF for any participants turning 18 years 
of age during the study period. 

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The patient and the caregiver will be instructed on how and where to request help if problems 
occur.  The Investigator is responsible to ensure that this training is performed at Visit 2 and 
any subsequent visits as needed. 
The patient/caregiver should be reminded to use the eDevice during a potential VOC event, 
regardless of primary setting of treatment (eg, in-patient hospitalisation, short-stay outpatient 
unit, emergency department or self-treated).  The patients and caregiver must bring the 
eDevice to each visit for the Investigator to review of eDevice entries.  
The patients and their caregiver should also be informed that pain during a VOC, location of 
pain and use of analgesic should be entered daily to the eDevice.  The daily questions on pain 
intensity, pain localisation and analgesic use must be responded to on the actual day; these 
data cannot be entered for other dates.  In case an already resolved VOC event was not 
registered in the eDevice, start and stop date are still possible to record retrospectively.  Pain 
intensity, pain localisation and analgesic use cannot be recorded for these events in the 
eDevice.  However, analgesic use during resolved events need to be recorded by the 
Investigator in the eCRF together with any other event details as for all VOC events. 
When information related to a potential VOC is entered in the eDevice, the Investigator will 
be alerted and should, unless a contact already occurred, call the caregiver within 72 hours 
from the onset of the potential event to enable a medical consultation and event data 
collection.  Families will be instructed to call the site in case of a VOC, unless already 
contacted by the site. 
Expectations on Investigator's documentation of endpoint events will be discussed at the 
Investigators meetings.  Before the first patient is enrolled into the study at a study site, an 
AstraZeneca representative will review and discuss the requirements of the Clinical Study 
Protocol and related documents again with the study staff in the Start-up Meeting, and train 
them in any study-specific procedures, including collection of data for the primary efficacy 
endpoint.  Study monitoring will include review of data entered for the primary efficacy 
endpoint to ensure the data are complete.  Re-training of study staff will take place as needed. 
5.1.2 
Pain during a VOC 
Pain is commonly reported in clinical trials by having patients provide a rating of their own 
pain.  In this study, pain rating will be done in the eDevice.  Different measures of numerical 
rating scales have demonstrated good psychometric properties, but are not fit for purpose for 
the youngest age groups due to their limited understanding of number concepts.  Therefore, 
pain-rating scales with a series of faces depicting different levels of pain have been developed.  
For young children (2 to ≤4 years of age), subjective observation of pain-related behaviours is 
recommended.  The Face, Legs, Activity, Cry, Consolability (FLACC) assessment tool is a 
measurement developed for and used to assess pain for children between the ages of 2 months 
and 7 years.  The FLACC behavioural pain tool has shown good reliability and validity in 
assessing pain in critically ill adults and children (Voepel-Lewis et al 2010).  The FLACC will 
be caregiver-reported for patients ≤4 years of age daily during the VOC event.  Each of the 

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5 behaviours observed are assigned a score of 0, 1 or 2.  The total FLACC score will then 
range between 0 and 10, with 0 representing no pain. 
The Faces Pain Scale - Revised (FPS-R) will be administered to all patients aged ≥5 years.  
When needed the caregiver can help the child with the assessment.  It is important to train 
caregivers not to attempt to influence child’s response in any way.  The scale consists of 
6 faces and scoring ranges between 0 and 10 (with an increase in numeric value by 2 [ie, 0, 2, 
4, 6, 8, 10]), where 0 is no pain and 10 is very much pain.  The FPS-R was validated by 
Hicks et al 2001 in 3 studies and has been judged as a well-established pain assessment tool in 
patients >4 years of age (Cohen et al 2008).  
A body outline diagram will also be presented and the patient/caregiver will be asked to 
indicate the location(s) of the pain.  See Appendix H for details of these pain assessments.  
Worst pain ratings will be collected once daily throughout the duration of the VOC event 
using an eDevice.   
All instruments will be based on patients’ age at baseline, and the same version should be used 
throughout the study. 
5.1.3 
Health-related quality of life (HRQL) 
The HRQL will be assessed using the PedsQL SCD Module and Multidimensional Fatigue 
Scale.  The SCD module consists of 43 items and measures problems with the patients’ pain 
(severity, impact, management/control), worry, emotions, treatment and communication.  The 
SCD module measures 9 sub-scales and a total score.  The Multidimensional Fatigue Scale 
consists of 18 items measuring problems with general, sleep/rest and cognitive fatigue.  The 
Multidimensional Fatigue Scale measure 3 sub-scales and a total score.  The SCD module and 
the Fatigue Scale when used in SCD have shown acceptable to excellent measurement 
properties in both the patient-reported versions for ages 5 to 18 years and the parent-reported 
version for ages 2 to 4 years (Panepinto et al 2013, Panepinto et al 2014). 
Both instruments have been developed in age-specific versions.  In this study, the 
patient-reported versions are for patients ages 5 to 7, 8 to 12, and 13 to 18 years, respectively.  
For patients 2 to 4 years of age, the parent-reported version will be reported by a caregiver.  
See Appendix I for details of HRQL.  Data will be collected using pen and paper at the site 
and will be administered at randomisation and every 6 months thereafter.  
Appropriate procedures for minimising bias and enhancing compliance will be followed 
throughout the study.  To ensure this, all study personnel will be trained to instruct the patient 
in a standardised way and further be responsible for providing all relevant instructions and 
training to the patients.  A standardised procedure for the administration of the HRQL 
questionnaires should be applied. 
Each centre must allocate responsibility for completion of the PedsQL questionnaires to a 
specific individual (eg, a Research Nurse).  It is also important that the significance and 
relevance of the data are explained carefully to participating patients/caregivers so that they 

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are motivated to comply with data collection.  The following applies to completing the 
PedsQL questionnaires: 
• The patient/caregiver must complete it in private in their own time. 
• PedsQL should preferably be completed before any investigations or discussions about the 
disease with the clinic staff and prior to any other study-related procedures. 
• The patient/caregiver should be reassured that there are no right or wrong answers and that 
the answers are strictly confidential. 
• Help should not be given from caregivers or clinical staff with the exception that the 
patient can receive help from a study nurse in understanding the instructions.  However, 
under no circumstances should help in interpreting the questions or in selecting responses 
be provided.  
• A form will be completed by the clinic staff to indicate if a questionnaire has been 
completed at each visit, and if not, the reason will be recorded. 
• On completion of the questionnaires they should be handed back to the person responsible 
for questionnaires who should check for completeness. 
• Only 1 answer should be recorded for each question. 
5.1.4 
Absence from school/work due to SCD  
For patients attending school or work at randomisation, absences from school/work due to 
SCD will be recorded weekly by the patient in the eDevice with the help of the caregiver, if 
needed.  The patients will be asked the question ‘Have you been at home from school/work 
the last 7 days because of your disease’.  If the reply is ‘Yes’, the patient will be prompted to 
answer how many days he/she has been absent.  Days off from school due to study visits will 
not be recorded. 
5.1.5 
Acute SCD complications 
The acute SCD complications will be defined as the composite of individual complications 
and be evaluated as secondary endpoint: TIA/ischaemic stroke, hepatic sequestration and 
splenic sequestration, priapism and dactylitis.  If the frequency allows, the individual 
components can be assessed as exploratory endpoints. 
5.2 
Safety assessments 
5.2.1 
Laboratory safety assessments 
Blood and urine samples for determination of clinical chemistry, haematology, virology, 
coagulation and urinalysis will be taken at the times indicated in the Schedule of 
Assessments (Table 2).  Local clinical routine procedures to reduce pain and discomfort from 
blood sampling in children will be followed, eg offering topical anaesthesia, coordinated 
sampling to avoid repeated punctures and use of in-dwelling catheters as appropriate in 
accordance with ethical and instruction guidelines for paediatric blood sampling.  Additional 
safety samples for laboratory assessment may be collected during unscheduled visits if 
clinically indicated at the discretion of the Investigator.  The date and time of collection will 
be recorded in the eCRF. 

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The clinical chemistry, haematology, virology and coagulation analyses will be performed at a 
central laboratory when possible or at an authorised/certified local laboratory as needed.  All 
sampling, handling and transporting of samples will be in accordance with IATA Guidance 
Document (Appendix B). 
Urinalysis is to be performed at the investigational site by dipstick.  Urine pregnancy test will 
be taken at all visits for females of childbearing potential.  If female patients achieve 
menarche during the study, a urine pregnancy test should be performed before any study 
procedures at the next visits. 
The laboratory variables in Table 4 will be measured. 
Table 4 
Laboratory variables 
Haematology/Haemostasis (whole blood) 
Clinical Chemistry (serum) 
B-Haemoglobin (Hb) 
S-Creatinine 
B-Haematocrit 
S-Bilirubin, total 
B-Leukocyte count 
S-Bilirubin, direct 
B-Leukocyte differential count (absolute count) 
S-Alkaline phosphatase (ALP) 
B-Platelet count 
S-Aspartate transaminase (AST) 
S-Alanine transaminase (ALT) 
Urinalysis (dipstick) 
S-Lactate dehydrogenase (LDH) 
U-Hb/Erythrocytes/Blood  
S-Uric Acid 
U-Protein/Albumin  
S-Blood Urea Nitrogen (BUN) 
U-Glucose  
S-Albumin 
U-beta-human chorionic gonadotropin (β-hCG) 
S-Potassium 
S-Chloride 
Virology Screena 
S-Sodium 
Hepatitis B surface antigen (HBsAg) 
S-Glucose 
Hepatitis C virus (HCV) 
S-Haptoglobin 
HIV 
Malaria Screen (not mandatory) 
Coagulationa 
Microscopy (blood smear evaluation) 
International normalised ratio (INR) 
Rapid diagnostic tests 
Prothrombin time (PT) 
Activated Partial Thromboplastin Time (APTT) 
B blood; S serum; U urine. 
a 
Virology screen and coagulation will be conducted at the Screening Visit only. 
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities.  The laboratory results should be signed, dated and retained at centre 

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as source data for laboratory variables. For information on how AEs based on laboratory tests 
should be recorded and reported, see Section 6.3. 
NB.  In case a patient shows an AST or ALT ≥3 × ULN and total bilirubin ≥2 × ULN, refer to 
Section 6.3.7 for further instructions. 
5.2.2 
Physical examination 
A complete physical examination will include an assessment of the following: general 
appearance, respiratory, cardiovascular, abdomen, skin, head and neck (including ears, eyes, 
nose and throat), lymph nodes, thyroid, musculo-skeletal and neurological systems. 
A brief examination of physical examination will include the following: general appearance, 
respiratory, cardiovascular and abdomen systems.  
Physical examination will be performed at timelines as specified in the Schedule of 
Assessment in Table 2.  Investigators should pay special attention to new or worsening 
abnormalities as they may qualify as AEs, see Section 6.3.6 for details. 
5.2.3 
ECG 
5.2.3.1 
Resting 12-lead ECG 
A 12-lead ECG (standard ECG with a paper speed of 25 or 50 mm/second covering at least 
6 sequential beats) will be recorded after the patient has been lying down to rest for up to 
5 minutes.  After ECG has been recorded, the Investigator or designated physician will review 
each of the ECGs and enter as ‘Normal’ or ‘Abnormal’ in the eCRF.  If the ECG is evaluated 
as “Abnormal” the Investigator should document the specific abnormality as clinically 
significant or not.   
A standardised ECG machine should be used and a paper copy of ECG tracing should be filed 
in the patient’s medical records. 
5.2.4 
Vital signs 
5.2.4.1 
Weight and height 
Weight and height assessments will be performed at the visits as shown in Table 2.  Results 
available in medical records, as taken on the visit day, will be recorded in the eCRF. 
The study site staff should use a digital precision scale if possible, and record the weight in 
kilograms or pounds to the first decimal point (eg, 95.3 kg).  The same scale should be used 
and the patient should wear a standard hospital-type gown or equivalent light clothing and no 
shoes for the body weight measurement at each visit. 
5.2.4.2 
Pulse rate and blood pressure 
Pulse rate, systolic and diastolic blood pressure will be assessed using non-invasive equipment 
after the patient has been sitting at rest for 5 minutes.  Results will be recorded in the eCRF. 

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5.3 
Other assessments 
5.3.1 
Palatability and swallowability 
Palatability will be assessed by age groups.  The Facial Hedonic Scale (FHS) is a 
well-established method for assessing paediatric patients’ responses to drug palatability for 
patients down to 3 years of age (Davies and Luleu 2008).  The FHS consists of 5 faces with 
descriptions ranging from ‘Dislike very much’ to ‘Like very much’.  Patients ≥5 years of age 
will be asked to evaluate palatability immediately after dosing using the FHS at baseline and 
at 6 months.  For patients <5 years of age an observer’s assessment of the patient’s behaviour, 
including willingness to swallow, will be performed directly after the patient has received the 
IP at baseline and at 6 months.  See Appendix F for details.   
5.4 
Pharmacokinetics 
5.4.1 
Collection of samples 
Blood samples for determination of ticagrelor and its active metabolite (AR-C124910XX) in 
plasma will be taken at the times presented in Table 2.  Collection of PK samples should be 
time matched with PD samples.  The PK results will not be available to site.  The actual date 
and time for each sample will be collected in the eCRF.  
A PK sample will be collected 0 hours (predose) and 2 hours postdose (no predose sample at 
randomisation visit).  On visits with PK and/or VASP sampling, patients should not take IP 
(morning dose) at home prior to the visit, as this will be administered at the site.  If morning 
dose accidently was taken prior to visit, no new dose will be administered at the site and no 
predose sample will be taken.  The actual time for dosing should be noted and a postdose 
sample aiming for 2 hours should be taken.  Regardless of time in relation to actual dose 
intake the time for this postdose sample should be recorded.   
The time of last dose intake prior to any PK visits (ie, the evening dose the day before the 
visit) needs also to be precisely recorded in the eCRF to be able to relate the predose PK 
sample concentrations to time after ticagrelor dose intake.  
The predose PK sample also contains important information on the relationship of ticagrelor 
dose to exposure and platelet inhibition response and therefore, the correct time recording of 
the evening dose is equally important as the sample itself.  
In case of increased dose due to increased weight, PK sample will be collected at the next 
following visit.  The PK sample will be collected 0 hours (predose) and 2 hours postdose.   
Samples will be collected, labelled stored and shipped as detailed in the Laboratory Manual.  
A central laboratory will be used for the logistic arrangements.   
5.4.2 
Determination of drug concentration 
Samples for determination of ticagrelor and its active metabolite (AR-C124910XX) in plasma 
will be analysed by Covance on behalf of the Sponsor, using an appropriate bioanalytical 

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method.  Full details of the analytical method used will be described in a separate 
Bioanalytical Report. 
All samples still within the known stability of the analytes of interest (ie, ticagrelor and its 
active metabolite), at the time of receipt by the bioanalytical laboratory, will be analysed. 
5.4.3 
Storage and destruction of pharmacokinetic samples 
Pharmacokinetic samples will be disposed of after the Bioanalytical Report finalisation or 
6 months after issuance of the draft Bioanalytical Report (whichever is earlier), unless 
requested for future analyses. 
Pharmacokinetic samples may be disposed of or destroyed and anonymised by pooling.  
Additional analyses may be conducted on the anonymised, pooled PK samples to further 
evaluate and validate the analytical method.  Any results from such analyses may be reported 
separately from the Clinical Study Report (CSR). 
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples.  The results from the evaluation will not be reported in the CSR but 
separately in a Bioanalytical Report. 
For each placebo patient, samples will only be analysed on a ‘for cause’ basis, eg, if no 
quantifiable concentrations were observed in a patient’s samples when the drug was expected 
to be present. 
5.5 
Pharmacodynamics 
5.5.1 
Vasodilator-stimulated phosphoprotein 
Vasodilator-stimulated phosphoprotein is a critical protein that is expressed in platelets at high 
levels and plays a major role in negatively regulating secretory and adhesive events that are 
involved in platelet aggregation.  The effect of ticagrelor on inhibition of platelet aggregation 
will be assessed by the VASP assay during treatment period (Voepel-Lewis et al 2010; 
Laine et al 2013). 
5.5.2 
Collection of samples 
Blood samples for determination of platelet aggregation in whole blood will be taken at the 
time presented in Table 2.  Except for the important PD sample taken prior to first dose of 
study drug at Visit 2 randomisation where no PK sample is taken, the collection of PD 
samples are thereafter matched with PK samples.  To maintain the blinding of treatment 
allocation, the PD results will not be available to the site, and individual PD results will not be 
available to the Sponsor.  
The time of last dose intake prior to any VASP visits (ie, the evening dose the day before the 
visit) needs also to be precisely recorded in the eCRF to be able to relate the predose VASP 
inhibition to time after ticagrelor dose intake.  

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The predose VASP sample also contains important information on the relationship of 
ticagrelor dose to exposure and platelet inhibition response and therefore, the correct time 
recording of the last dose the evening before the visit is equally important as the sample itself.  
In case of increased dose due to increased weight, the PD sample will be collected at the 
following visit.  The PD sample will be collected 0 hours (predose) and 2 hours postdose.   
Samples will be collected and labelled as detailed in the Laboratory Manual. 
5.5.3 
Storage and destruction of pharmacodynamics samples 
Pharmacodynamic samples may be disposed of or destroyed and anonymised by pooling.  
Additional analyses may be conducted on the anonymised, pooled pharmacodynamic samples 
to further evaluate and validate the analytical method before finalisation of the CSR.  Any 
results from such analyses may be reported separately from the CSR. 
Samples will be stored until the study is finalised, after which they will be destroyed.  
Detailed information about samples storage can be found in the Laboratory Manual.  The 
results of any investigation will be reported either in the CSR itself or as an addendum, or 
separately in a scientific report or publication. 
5.6 
Genetics (Not applicable) 
5.7 
Biomarker analysis (Not applicable) 
5.8 
Volume of blood 
The total maximum volume of blood that will be drawn from each patient at each study visit is 
listed in Table 5 below.  
Table 5 
Volume of blood to be withdrawn from each patient 
Total maximum volume (mL) 
12 to 24 kg body weight 
>24kg body weight 
Visit 1 (Enrolment) 
9,9 
13,8 
Visit 2 (Randomisation) 
6,6 
7,7 
Visit 3 (2 weeks) 
3,4 
4,5 
Visit 4 (4 weeks) 
7,8 
8,9 
Visit 6 (3 months) 
0 
0 
Visit 9 (6 months) 
7,8 
8,9 
Visit 12 (9 months) 
0 
0 
Visit 15 (12 months) 
7,8 
8,9 
Visit 18 (15 months) 
0 
0 
Visit 21 (18 months) 
7,8 
8,9 
Visit 24 (21 months) 
0 
0 

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Table 5 
Volume of blood to be withdrawn from each patient 
Total maximum volume (mL) 
12 to 24 kg body weight 
>24kg body weight 
End of Study (EOS) 
7,8 
8,9 
Follow Up Visit 
3,4 
4,5 
Total (mL) 62,3 
75 
Note: Visits 5, 7, 8, 10, 11, 13, 14, 16, 17, 19, 20, 22, 23, 25 and 26 are telephone visits. 
Note: blood volumes are applicable to central laboratory only; local laboratory practices may vary, however the 
maximum volume should not exceed those recommended in the appropriate local guideline.   
*Maximum volume during 30 days: 19,9 mL     ** Maximum volume during 30 days: 26 mL 
6. 
SAFETY REPORTING AND MEDICAL MANAGEMENT 
The PI is responsible for ensuring that all staff involved in the study are familiar with the 
content of this section. 
6.1 
Definition of adverse events 
An AE is the development of any untoward medical occurrence in a patient or clinical study 
patient administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavourable and unintended 
sign (eg, an abnormal laboratory finding), symptom (eg, nausea, chest pain), or disease 
temporally associated with the use of a medicinal product, whether or not considered related 
to the medicinal product.  
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence.  An AE may occur at any time, including 
run-in or washout periods, even if no study treatment has been administered. 
6.2 
Definitions of serious adverse event 
A SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, follow-up), 
that fulfils 1 or more of the following criteria: 
• Results in death 
• Is immediately life-threatening 
• Requires in-patient hospitalisation or prolongation of existing hospitalisation  
• Results in persistent or significant disability or incapacity 
• Is a congenital abnormality or birth defect 
• Is an important medical event that may jeopardise the patient or may require medical 
intervention to prevent 1 of the outcomes listed above. 
For further guidance on the definition of a SAE, see Appendix A to the Clinical Study 
Protocol. 

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6.3 
Recording of adverse events 
6.3.1 
Time period for collection of adverse events 
Adverse events will be collected from the time of randomisation, and throughout the study, 
including the follow-up period.  Any SAEs should be collected from when the ICF is signed. 
6.3.2 
Follow-up of unresolved adverse events 
Any AEs that are unresolved at the patient’s last AE assessment in the study are followed up 
by the Investigator for as long as medically indicated, but without further recording in the 
electronic case report form (eCRF).  AstraZeneca retains the right to request additional 
information for any patient with ongoing AE(s)/SAE(s) at the end of the study, if judged 
necessary. 
6.3.3 
Variables 
The following variables will be collected for each AE: 
• AE (verbatim) 
• The date and time when the AE started and stopped 
• Maximum intensity 
• Whether the AE is serious or not 
• Investigator causality rating against the IP (yes or no) 
• Action taken with regard to IP 
• Outcome. 
In addition, the following variables will be collected for SAEs: 
• Date AE met criteria for serious AE 
• Date Investigator became aware of SAE 
• AE is serious due to 
• Date of hospitalisation 
• Date of discharge 
• Probable cause of death 
• Date of death 
• Autopsy performed 
• Causality assessment in relation to study procedure(s) 
• Causality assessment to other medication 
• Description of AE. 
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Section 6.2.  On the other hand, a stroke that results in only a limited degree of 

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disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Section 6.2. 
The definitions for intensity rating are: 
• Mild (awareness of sign or symptom, but easily tolerated) 
• Moderate (discomfort sufficient to cause interference with normal activities) 
• Severe (incapacitating, with inability to perform normal activities). 
6.3.4 
Causality collection 
The Investigator will assess causal relationship between IP and each AE, and answer ‘yes’ or 
‘no’ to the question ‘Do you consider that there is a reasonable possibility that the event may 
have been caused by the IP?’ 
For SAEs, causal relationship will also be assessed for other medication and study procedures.  
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’. 
A guide to the interpretation of the causality question is found in Appendix A to the Clinical 
Study Protocol. 
6.3.5 
Adverse events based on signs and symptoms 
All AEs spontaneously reported by the patient or care provider or reported in response to the 
open question from the study site staff: ‘Have you/the child had any health problems since the 
previous visit/you were last asked?’, or revealed by observation will be collected and recorded 
in the eCRF.  When collecting AEs, the recording of diagnoses is preferred (when possible) to 
recording a list of signs and symptoms.  However, if a diagnosis is known and there are other 
signs or symptoms that are not generally part of the diagnosis, the diagnosis and each sign or 
symptom will be recorded separately. 
6.3.6 
Adverse events based on examinations and tests 
The results from the Clinical Study Protocol-mandated laboratory tests and vital signs will be 
summarised in the CSR.  Deterioration as compared with baseline in protocol-mandated 
laboratory values, vital signs should therefore only be reported as AEs if they fulfil any of the 
SAE criteria or are the reason for discontinuation of treatment with the IP. 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible the reporting Investigator 
uses the clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin value).  
In the absence of clinical signs or symptoms, clinically relevant deteriorations in 
non-mandated parameters should be reported as AE(s). 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE. 

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6.3.7 
Liver biochemistry and evaluation of Hy’s Law 
Cases where a patient shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN need to be 
reported as SAEs, except if the elevation is caused by the underlying sickle cell disease, ie, 
haemolysis, as judged by the Investigator.  Please refer to Appendix C for further instruction 
on cases of increases in liver biochemistry and evaluation of Hy’s Law. 
6.3.8 
Assessment of bleeding events 
Bleeding events will be recorded as AEs.  The Investigator will do the classification of 
bleeding events.  Bleeding events will be recorded in the eCRF. 
For patients experiencing a bleeding event that fulfils criteria in more than 1 category, the 
bleed will be assigned to the most severe category.  The bleeding definitions  
(Mitchell et al 2011) are: 
• Major bleeding: defined as any fatal bleeding, clinically overt bleeding associated with a 
decrease in Hb of at least 20 g/L (2 g/dL), bleeding that is retroperitoneal, pulmonary, 
intracranial, or otherwise involves the central nervous system or bleeding that requires 
surgical intervention in an operating suite. 
• Clinically relevant non-major bleeding: defined as overt bleeding for which a blood 
product is administered and which is not directly attributable to the patient’s underlying 
medical condition, and bleeding that requires medical or surgical intervention to restore 
haemostasis, other than in an operating suite. 
• Minor bleeding: defined as any overt or macroscopic evidence of bleeding that does not 
fulfil the above criteria for either major bleeding or clinically relevant, non-major 
bleeding.  Menstrual bleeding resulting in a medical consultation and/or intervention will 
be classified as a minor bleeding event. 
6.3.9 
Vaso-occlusive crisis (VOCs) and acute SCD complications  
A VOC and acute SCD complications (TIA/ischaemic stroke, hepatic sequestration and 
splenic sequestration, priapism and dactylitis) occurring during the study should be recorded 
by the Investigator as AEs.  For a definition and collection of VOCs, see Section 5.1.1 and for 
acute SCD complication, see Section 5.1.5. 
• A VOC fulfilling the criteria should also be recorded as an adverse event with the 
diagnosis Sickle cell anaemia with crisis.  
• If the VOC event includes symptoms of other acute SCD complications, these should also 
be recorded, but separately from the VOC event in the eCRF. 
6.3.10 
Procedures in relation to COVID-19 infection 
If a patient presents with clinical signs and symptoms consistent with COVID-19 infection, 
the Investigator should request a test where possible and this should be recorded in the AE 
field of the eCRF as follows: 

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• If test is positive, record as “COVID-19 confirmed”. 
• If test is negative, record the AE/SAE signs and symptoms and/or other diagnosis. 
• If test is not available and signs and symptoms, as judged by the Investigator, are highly 
suspicious of COVID-19 infection, record as “COVID-19 suspected”. 
If other concurrent diagnoses exist, eg, pneumonia, the Investigator should record as separate 
AEs. 
If an AE/SAE is associated with COVID-19, the Investigator should determine whether the 
patient’s IP should be continued, temporarily interrupted or permanently stopped.  Refer to 
Section 3.9.4 for guidance on procedures in relation to COVID-19.  
All AE reporting instructions in this section and SAE reporting in Section 6.4 also apply to 
any AE/SAE associated with COVID-19. 
6.4 
Reporting of serious adverse events 
All SAEs have to be reported to the appropriate AstraZeneca representative, whether or not 
considered causally related to the IP, or to the study procedure(s).  All SAEs will be recorded 
in the CRF. 
If any SAE occurs in the course of the study, other than mentioned in Section 6.3.9, then 
Investigators or other site personnel inform the appropriate AstraZeneca representatives 
within 1 day, ie, immediately but no later than 24 hours  of when he or she becomes aware 
of it (see also Section 6.4.1). 
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar 
days of initial receipt for all other SAEs. 
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within 1 calendar day, ie, immediately but no later than 24 hours of when he or she becomes 
aware of it. 
Once the Investigators or other site personnel indicate an AE is serious in the WBDC system, 
an automated email alert is sent to the designated AstraZeneca representative. 
If the WBDC system is not available, then the Investigator or other study site staff reports a 
SAE to the appropriate AstraZeneca representative by telephone.  The AstraZeneca 
representative will advise the Investigator/study site staff how to proceed. 
The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 
drug. 

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6.4.1 
Reporting of SAEs that are also endpoints in the study 
Efficacy endpoints in the study (VOCs and acute SCD complications [TIA/ischaemic stroke, 
hepatic sequestration and splenic sequestration, priapism and dactylitis]) fulfilling the criteria 
for SAE will not be reported by AstraZeneca to health authorities to avoid unnecessary 
unblinding of efficacy endpoints that are also SAEs.  
6.5 
Overdose 
An overdose is considered any dose greater than that specified in the protocol. 
There is currently no known antidote to reverse the effects of ticagrelor, and ticagrelor is not 
expected to be dialysable.  Treatment of overdose should follow local standard medical 
practice.  The expected effect of excessive ticagrelor dosing is prolonged duration of bleeding 
risk associated with platelet inhibition.  If bleeding occurs appropriate supportive measures 
should be taken. 
In healthy adults, ticagrelor is well tolerated in single doses up to 900 mg.  Gastrointestinal 
toxicity (nausea, vomiting, diarrhoea) was dose-limiting in healthy adults following ascending 
single doses.  Other clinically meaningful adverse effects, which may occur with overdose, 
include dyspnoea and ventricular pauses.  In the event of overdose, observe for these potential 
adverse effects, and consider ECG monitoring.  Measure platelet inhibition to determine the 
extent and duration of excessive platelet inhibition. 
• An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the CRF and on the Overdose CRF module. 
• An overdose without associated symptoms is only reported on the Overdose CRF module. 
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient safety data entry site. 
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 6.4.  
For overdoses not fulfilling SAE criteria, AstraZenceca will ensure that the overdose is 
reported to the AstraZeneca data entry site within 30 calendar days of awareness. 
6.6 
Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca 
representatives. 
6.6.1 
Maternal exposure 
If a patient becomes pregnant during the course of the study IP should be discontinued 
immediately. 

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Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study 
may have interfered with the effectiveness of a contraceptive medication.  Congenital 
abnormalities/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs.  Elective abortions without complications should not be handled as AEs.  The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital abnormality) should be followed up and documented even if the patient 
was discontinued from the study. 
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1 day, ie, immediately but no 
later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient safety data entry site within 1 or 
5 calendar days for SAEs (see Section 6.4) and within 30 days for all other pregnancies. 
The same timelines apply when outcome information is available. 
The eCRF is used to report the pregnancy.  The outcome of the pregnancy is reported on a 
separate form outside the eCRF.  
6.6.2 
Paternal exposure 
There is no restriction on fathering children or donating sperm during the study.  Pregnancies 
in partners are not to be reported. 
6.7 
Medication error 
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study drug that either causes harm to the subject or 
has the potential to cause harm to the subject.  
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or subject. 
Medication error includes situations where an error:  
• Occurred 
• Was identified and intercepted before the patient received the drug 
• Did not occur, but circumstances were recognised that could have led to an error. 
Examples of events to be reported in clinical studies as medication errors: 
• Drug name confusion 
• Dispensing error, eg, medication prepared incorrectly, even if it was not actually given to 
the patient 

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• Drug not administered as indicated, for example, wrong route or wrong site of 
administration 
• Drug not taken as indicated, eg, tablet dissolved in water when it should be taken as a solid 
tablet  
• Drug not stored as instructed, eg, kept in the fridge when it should be at room temperature  
• Wrong patient received the medication (excluding IXRS errors) 
• Wrong drug administered to patient (excluding IXRS errors). 
Examples of events that do not require reporting as medication errors in clinical studies: 
• Errors related to or resulting from IXRS - including those which lead to 1 of the above 
listed events that would otherwise have been a medication error  
• Patient accidentally missed drug dose(s), eg, forgot to take medication 
• Accidental overdose (will be captured as an overdose) 
• Patient failed to return unused medication or empty packaging 
• Errors related to background and rescue medication, or standard of care medication in 
open-label studies, even if an AstraZeneca product. 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.   
If a medication error occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day, ie, immediately 
but no later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is completed within 1 or 5 calendar days if there is an SAE associated 
with the medication error (see Section 6.4) and within 30 days for all other medication errors. 
6.8 
Management of IP-related toxicities 
See Section 3.9. 
7. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS 
7.1 
Identity of investigational product(s) 
Investigational product 
Dosage form and strength 
Manufacturer 
Ticagrelor 15 mg tablet 
Oral, plain, round, biconvex, white/off-white, 
uncoated, 15 mg 
AstraZeneca 
Placebo for ticagrelor 15 mg 
tablet 
Oral, plain, round, biconvex, white/off-white, 
uncoated, containing no active ingredient 
AstraZeneca 
 

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Ticagrelor tablets of 15 mg and its matching placebo (approximately 6 mm in diameter) will 
be packed in high-density polyethylene bottles containing 100 tablets. Subsequent intervals 
between dispensing visits should not be more than 100 days.   
7.2 
Dose and treatment regimens 
Allocation of IP bottles will be managed via the IXRS and at Visit 2, first dose of the IP will 
be administered at the clinic by site staff.  Subsequent doses should be taken morning and 
evening, at approximately 12-hour intervals.  The IP can be taken with or without food.  
7.2.1 
Treatment during double-blind randomisation period 
Randomisation to twice daily double-blind treatment with ticagrelor or placebo will occur at 
Visit 2 via the IXRS.  Eligible patients will be randomly assigned to 1 of 2 treatment 
regimens, based on body weight at Visit 2: 
• ≥12 to ≤24 kg body weight: 15 mg - 1 tablet of ticagrelor 15mg or 1 tablet of placebo to 
match ticagrelor 15 mg twice daily 
• >24 to ≤48 kg body weight: 30 mg - 2 tablets of ticagrelor 15mg or 2 tablets of placebo to 
match ticagrelor 15mg twice daily 
• >48 kg body weight: 45 mg - 3 tablets of ticagrelor 15mg or 3 tablets of placebo to match 
ticagrelor 15mg twice daily 
At Visit 2, the first dose of IP will be administered at the clinic by site staff as soon as possible 
after randomisation and after all baseline assessments have been completed.  Subsequent 
doses should be taken morning and evening, at approximately 12-hour intervals.  Missed 
doses of ticagrelor or placebo blinded IP should not be compensated (ie, if a dose is missed 
the next regularly scheduled dose should be taken and should not be doubled). 
The study drug will be administered orally either swallowed whole or dispersed in water, 
other suitable liquids or vehicles based on age and/or ability to swallow study drugs.  Refer to 
handling instructions for further details.  
7.2.2 
Dose increase during study  
For any patient having a weight gain during the study period clearly exceeding the upper 
weight limit of the band (≥27 kg and ≥54 kg, respectively), the dose will need to be increased 
according to the next weight band. 
In case of a dose increase: 
• IXRS will generate correct dose based on body weight range entered 
• Stop date for the old dose and start date for the new dose should be recorded in the eCRF 
• The patient should return all unused IP and empty bottles and new IP bottles should be 
dispensed  
• PK and PD samples should be taken at the following visit after the adjusted dose has been 
dispensed, see Sections 5.4 and 5.5. 

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7.3 
Labelling 
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines.  The labels will fulfil GMP Annex 13 requirements for labelling.  Label 
text will be translated into local language. 
7.4 
Storage 
All study drugs should be kept in a secure place under appropriate storage conditions.  The IP 
label on the bottle specifies the appropriate storage. 
7.5 
Compliance 
The administration of IP (ticagrelor or placebo) should be recorded in the appropriate sections 
of the eCRF. 
Each time IP is dispensed, compliance will be reinforced.  The caregiver will be asked to 
bring all unused IP and empty bottles to the study site at each on-site visit.  When IP is 
returned, compliance will be assessed based upon an interview with the caregiver and a count 
of the tablets returned.   
7.6 
Accountability 
The IP provided for this study will be used only as directed in the Clinical Study Protocol. 
The study site staff will account for all IPs dispensed to and returned from the patient. 
The caregiver will be asked to bring all unused IP and empty bottles to the study site at each 
on-site visit.  The Investigator or delegate will enter the amount of returned tablets in the 
eCRF. 
Study site personnel or the AstraZeneca delegated monitor will account for all IPs received at 
the site, empty bottles, unused study drugs and for appropriate destruction, according to local 
procedures at an authorised site.  Certificates of delivery, destruction and return must be 
signed by an AstraZeneca representative. 
7.7 
Concomitant medication and other treatments 
See Appendix G for a complete list of restricted medications.  All concomitant medications 
and any changes during the study should be recorded by the Investigator in the eCRF.   
Use of anti-platelet aggregation drugs like ADP receptor blockers (eg, cangrelor, clopidogrel, 
prasugrel, ticlopidine) or aspirin, or phosphodiesterase inhibitors (eg, dipyridamole and 
cilostazol) is not allowed in the study. 
Treatment with oral or parenteral anticoagulants (except for heparins for flushing of catheters) 
is not allowed in the study.  Chronic non-steroidal anti-inflammatory agents (requiring 
treatment >3 days/week) is not allowed in the study (see exclusion criteria in Section 3.2). 

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CYP3A inhibitors 
Concomitant use of strong inhibitors of CYP3A (eg, boceprevir, clarithromycin, conivaptan, 
indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, 
posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole) is not allowed.  
When macrolide antibiotics is indicated azithromycin is allowed.  
CYP3A substrates or inducers 
Co-administration of CYP3A substrates with a narrow therapeutic index is not allowed.  
Co-administration of strong inducers of CYP3A (eg, rifampin/rifampicin, rifabutin, phenytoin, 
carbamazepine, phenobarbital, avasimibe, St. John’s wort) is not allowed. 
P-glycoprotein interactions 
Ticagrelor is a weak inhibitor of P-glycoprotein (P-gp), a drug efflux transporter.  Digoxin is a 
substrate of P-gp and concurrent treatment with ticagrelor modestly increases digoxin levels.  
If the patient is receiving digoxin, levels should be monitored closely following initiation of IP 
and with any change in IP. 
7.7.1 
Blood transfusions 
If a patient requires any blood transfusion during the study, this information will be captured 
in the eCRF. 
7.7.2 
Other concomitant treatment 
If a patient is treated with hydroxyurea, the weight-adjusted dose must be stable for 3 months 
before enrolment.  
Other medication other than that described above, which is considered necessary for the 
patient’s safety and well-being, like L-glutamine may be given at the discretion of the 
Investigator and recorded in the appropriate sections of the eCRF.  The entry must include the 
dose, regimen, route, indication and dates of use. 
Patients may not participate in any other interventional drug study for at least 30 days prior to 
starting this study and may not participate in any other interventional drug study throughout 
the study period. 
7.8 
Post study access to study treatment (Not applicable) 

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8. 
STATISTICAL ANALYSES BY ASTRAZENECA OR 
DELEGATE 
Statistical analyses are summarised below.  Further details will be provided in the Statistical 
Analysis Plan (SAP).  
8.1 
Statistical considerations 
Statistical analyses will be performed by IQVIA under the direction of Biometrics & 
Information Sciences, AstraZeneca using SAS® version 9.2 or higher and, where appropriate, 
additional validated software. 
IQVIA will finalise the SAP according to any required regulatory timelines but before review 
of any potential treatment revealing data is undertaken (this includes Blind Deliverable 
Reviews and Data Monitoring Committee reviews). 
8.2 
Sample size estimate 
The number of VOCs is assumed to have a negative binomial distribution with shape 
parameter 0.8.  The mean number of crises per year is assumed to be 2.0 in the placebo group 
with reduction of 50% in the ticagrelor group.  Patients will be randomised to 1:1 ratio and 
with minimum follow-up of 12 months and average follow-up of 18 months, 154 patients 
provide about 90% power for a 2-sided test of the mean number of crises for ticagrelor versus 
placebo, at significance level 5%.  Allowing for dropouts, the sample size is increased to 182.  
The calculations were based on simulation with 5,000 repetitions. 
Scenarios and simulations were evaluated to assess the risk with shorter and longer mean 
follow-up time.  To ensure that the study is adequately powered the recruitment rate will be 
monitored and the sample size may be adjusted to a maximum of 200 patients.  With a mean 
follow-up time of 13 month, 200 patients will provide 90% power to detect a reduction of 
50% in the ticagrelor group. 
8.3 
Definitions of analysis sets 
8.3.1 
Full analysis set 
All randomised patients, regardless of treatment received, will be included in the Full Analysis 
Set.  The primary statistical analysis of the efficacy of ticagrelor will be carried out on the Full 
Analysis Set.  Patients will be analysed according to their randomised IP. 
8.3.2 
Safety analysis set 
All patients who receive at least 1 single dose of randomised IP, ticagrelor or placebo, and for 
whom any postdose data are available, will be included in the safety analysis set.  Erroneously 
treated patients (eg, those randomised to treatment A but actually given treatment B) will be 
accounted for in the actual treatment group, where actual treatment is defined as: ticagrelor if 
a patient receives at least 1 dose of ticagrelor, otherwise actual treatment is placebo. 

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8.3.3 
PK analysis set 
All patients who receive at least 1 dose of IP and provide at least 1 post dose analysable 
plasma sample for PK analysis will be included in the PK analysis set. 
Patients with major protocol deviations including changes to the procedures that may impact 
the quality of the data, or any circumstances that can alter the evaluation of the PK may be 
excluded from the PK analysis set. 
8.3.4 
PD analysis set 
All patients who have receive at least 1 dose of IP and provide at least 1 postdose analysable 
sample for PD analysis will be included in the PD analysis set. 
Patients with major protocol deviations including changes to the procedures that may impact 
the quality of the data, or any circumstances that can alter the evaluation of the PD may be 
excluded from the PD analysis set. 
8.4 
Outcome measure for analyses 
See Section 2 for outcome measures.  
8.5 
Methods for statistical analyses 
In general;   
• Ticagrelor data will be pooled and analysed irrespective of dose. 
• Safety, plasma concentrations of ticagrelor and active metabolite, HRQL variables will be 
presented using descriptive statistics and graphed as appropriate.  
• Categorical variables will be summarised in frequency tables (number of patients and 
percentage), by treatment group.   
• Continuous variables will be presented with descriptive statistics (n, arithmetic mean, 
standard deviation [SD], median, min, max), within treatment group.  If appropriate, 
geometric mean and coefficient of variation (CV) will be used instead of arithmetic mean 
and SD, with CV (%) calculated as:  
( )
(
)1
exp
100
2 −

s
 where s is the SD of the data on a log scale. 
• Data will also be presented in individual patient listings. 
• Baseline values will be the closest observation prior to and including the randomisation 
visit. 
8.5.1 
Analysis of the primary variable 
The primary analysis will be based on the intent-to-treat principle.  Ticagrelor data will be 
pooled and analysed irrespective of dose. 
The number of VOCs will be analysed using negative binomial regression.  Any VOC event 
with an onset date within 7 days from a prior event onset date will not be counted as a new 

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episode.  The response variable is the number of VOCs experienced by a patient over the 
treatment period.  Patient follow-up time (log-transformed) will be included as an offset in the 
linear predictor to adjust for patients having different exposure times.  Additional covariates to 
be adjusted for in the linear predictor will be treatment group (placebo as reference group) and 
baseline hydroxyurea therapy (Yes/No).  The treatment effect will be tested at a 5% 
significance level.   
If the negative binomial distribution is not appropriate, a Wilcoxon rank sum test will be used.  
As the Wilcoxon rank sum test cannot be adjusted for the patients follow-up time, sensitivity 
analyses will be performed to ensure robustness of the results. 
The primary analysis (under the treatment policy estimand) includes all data until patients 
withdraw from the study regardless of if they discontinue from randomised treatment.  The 
primary analysis uses the negative binomial regression model with logarithm of the 
observation period as an offset term and assumes that missing data is missing at random.  
Hence, the model assumes that the frequency-of-events during an unobserved period is the 
same as the frequency estimated using observed data. 
To examine the sensitivity of the results and the robustness of this assumption analyses will be 
performed using controlled multiple imputation method.  For this method, an underlying 
negative binomial stochastic process for the number of VOCs is assumed and post study 
withdrawal counts will be imputed based on the observed number of events prior to the 
withdrawal.  
The following, but not limited to, missing data analysis will be performed: 
• Missing counts in each arm are imputed assuming the expected event rate within that arm.  
This method corresponds closely to the original model and the results are expected to 
correspond closely to the primary analysis.  This analysis is included to allow for 
comparison with the partial-DRMI method. 
• Multiple imputation based on dropout reason (partial-DRMI); Missing counts will be 
imputed differently depending on the reason for dropout; meaning that counts for patients 
in the ticagrelor arm who withdraw consent for a potential treatment related reason are 
imputed based on the expected event rate in the placebo arm, whereas the remaining 
patients who have withdrawn consent are imputed assuming missing at random.  Potential 
treatment related reasons include but are not limited to AEs, deaths and development of 
study specified reasons.  
8.5.2 
Analysis of the secondary variables 
If numbers allow, the following will be analysed using the same analysis method as the 
primary endpoint: number of painful crises, number of ACSs, duration of painful crises, 
number of VOCs requiring hospitalisation or emergency department visits, number of days 
hospitalised for VOC, number of acute SCD complications, number of days hospitalised for 
acute SCD complications, and number of sickle cell-related red cell transfusions.  

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Number (%) of patients per type of analgesic use will be summarised.  Number (%) of patients 
per palatability and swallowability category will be summarised.  Descriptive statistics will be 
presented for the intensity of VOC-related pain, proportion of day’s absence from school or 
work due to SCD and HRQL score; no statistical testing will be performed for these 
endpoints.  The descriptive statistics will include n, arithmetic mean, SD, median, minimum and 
maximum.  
8.5.3 
Analysis of the exploratory variables 
For categorical variables, the population size (N for sample size and n for available data) and 
the percentage (of available data) for each class of the variable will be presented.  Continuous 
variables will be summarised using descriptive statistics, including n, arithmetic mean, SD, 
median, minimum and maximum values.  If appropriate, geometric mean and CV will be used 
instead of arithmetic mean and SD.  
A population PK and PK/PD analysis may be performed and include an investigation of the 
impact of (or lack of) relevant demographic and disease-related covariates.  This analysis will 
be reported separate from the CSR. 
8.5.4 
Analysis of the safety variables 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Number of patients with events and percentages will be tabulated by preferred 
term and system organ class.  An event that occurred once or more times during the treatment 
period will contribute 1 observation to the numerator of the proportion.  The denominator of 
the proportion will comprise all patients in the safety set.  Adverse events will also be 
summarised by intensity/severity and separately, by causality/relatedness (as determined by 
the Investigator).  Should a patient report the same preferred term/system organ class within 
multiple intensity/severity or causality/relatedness categories, the patient’s worst occurrence 
(most severe/most related) will be tabulated.  Serious AEs, AEs leading to discontinuation of 
IP, and commonly occurring AEs will be summarised in a generally similar manner.  Adverse 
events, SAEs, AEs leading to death, and AEs leading to discontinuation of IP will be 
summarised for each treatment group as applicable. 
Laboratory data will be summarised by presenting shift tables from baseline to end of study 
using normal ranges and by presenting summary statistics of observed and change from 
baseline values (means, medians, quartiles, ranges).  The incidence of clinically notable 
laboratory abnormalities will be summarised. 
Vital sign data will be summarised by presenting summary statistics of observed and change 
from baseline values.  The incidence of clinically notable vital sign abnormalities will be 
summarised. 
For summarising of bleeding event, the number and percent of patients who experience (1) at 
least 1 bleeding event; (2) at least 1 major bleeding event; (3) at least 1 major or clinically 
relevant non-major bleeding event; (4) at least 1 minor bleeding event, will be presented by 
treatment group.  The total number of events will also be provided. 

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9. 
STUDY AND DATA MANAGEMENT BY ASTRAZENECA 
9.1 
Training of study site staff 
Before the first patient is entered into the study, an AstraZeneca representative will review and 
discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational site staff and also train them in any study specific procedures, such as the 
eDevice for reporting of some VOC-related information, the HRQL assessments and the 
WBDC system(s) utilised.  
The PI will ensure that appropriate training relevant to the study is given to all staff at the site 
involved in the study, and that any new information relevant to the performance of this study 
is forwarded to the staff involved. 
The PI will maintain a record of all individuals involved in the study (medical, nursing and 
other staff). 
9.2 
Monitoring of the study 
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to: 
• Provide information and support to the Investigator(s) 
• Confirm that facilities remain acceptable 
• Confirm that the investigational team is adhering to the Clinical Study Protocol, that data 
are being accurately and timely recorded in the CRFs, that biological samples are handled 
in accordance with the Laboratory Manual and that study drug accountability checks are 
being performed 
• Perform source data verification (a comparison of the data in the CRFs with the patient’s 
medical records at the hospital or practice, and other records relevant to the study) 
including verification of informed consent of participating patients.  This will require 
direct access to all original records for each patient (eg, clinic charts) 
• Ensure withdrawal of informed consent to the use of the patient’s biological samples is 
reported and biological samples are identified and disposed of/destroyed accordingly, and 
the action is documented, and reported to the patient. 
The AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the centre needs information and advice about the study conduct. 
9.2.1 
Source data 
Refer to the CSA for location of source data. 
9.2.2 
Study agreements 
The PI at each centre should comply with all the terms, conditions and obligations of the CSA, 
or equivalent, for this study.  In the event of any inconsistency between this Clinical Study 
Protocol and the CSA, the terms of Clinical Study Protocol shall prevail with respect to the 

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conduct of the study and the treatment of patients and in all other respects, not relating to 
study conduct or treatment of patients, the terms of the CSA shall prevail. 
Agreements between AstraZeneca and the PI should be in place before any study-related 
procedures can take place, or patients are enrolled. 
9.2.3 
Archiving of study documents 
The Investigator follows the principles outlined in the CSA. 
9.3 
Study timetable and end of study 
The end of the study is defined as ‘the last visit of the last patient undergoing the study’. 
The study is expected to start in Q2 2018 and to end by Q4 2020. 
The Sponsor will notify the PI(s) when recruitment is complete. 
9.4 
Data management by AstraZeneca or delegate 
Data management will be performed by IQVIA.  
Data will be entered into the WBDC (Inform) system at the study site.  Trained site staff will 
be entering the data as specified in the protocol and according to the eCRF instructions.  Data 
entered into the WBDC system will be immediately saved to a central database and changes 
tracked to provide an audit trail.  The data will then be Source Data Verified, reviewed, 
queried and updated as needed.   
Adverse events and medical/surgical history will be classified according to the terminology of 
the latest version the MedDRA.  Medications will be classified according to the World Health 
Organisation Drug Dictionary.  All coding will be performed by IQVIA. 
The PI is responsible for signing the eCRF and this may be delegated to a trained Investigator. 
The data will be validated as defined in the Data Management Plan.  Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly.  The Data Management Plan will also clarify the roles and 
responsibilities of the various functions and personnel involved in the data management 
process. 
When all data have been coded, validated, signed and locked, clean file will be declared.  Any 
treatment revealing data may thereafter be added and the final database will be locked.  
A copy of the eCRF will be archived at the study site when the study is completed. 
Serious adverse event (SAE) reconciliation 
SAE reconciliation reports are produced and reconciled with the AstraZeneca Global safety 
database.  

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Data associated with human biological samples 
Data associated with biological samples will be transferred from laboratory(ies) internal or 
external to AstraZeneca. 
Management of external data 
Data Management determines the format of the data to be received from external vendors and 
coordinates the flow of data to the clinical database.  External data reconciliation will be done 
with the clinical database as defined in the Data Management Plan. 
10. 
ETHICAL AND REGULATORY REQUIREMENTS 
10.1 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Council for Harmonisation/GCP, 
applicable regulatory requirements and the AstraZeneca policy on Bioethics and Human 
Biological Samples. 
10.2 
Subject data protection 
The ICF will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that complies with relevant data protection and privacy legislation. 
10.3 
Ethics and regulatory review 
An Ethics Committee (EC)/Institutional Review Board (IRB) should approve the final Clinical 
Study Protocol, including the final version of the ICF and any other written information and/or 
materials to be provided to the patients.  The Investigator will ensure the distribution of these 
documents to the applicable EC/IRB, and to the study site staff. 
The opinion of the EC/IRB should be given in writing.  The Investigator should submit the 
written approval to AstraZeneca before enrolment of any patient into the study.  
The EC/IRB should approve all advertising used to recruit patients for the study. 
AstraZeneca should approve any modifications to the ICF that are needed to meet local 
requirements. 
If required by local regulations, the Clinical Study Protocol should be re-approved by the 
EC/IRB annually. 
Before enrolment of any patient into the study, the final Clinical Study Protocol, including the 
final version of the ICF, is approved by the national regulatory authority or a notification to 
the national regulatory authority is done, according to local regulations. 

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AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities. 
AstraZeneca will provide regulatory authorities, EC/IRB and PI with safety updates/reports 
according to local requirements. 
Each PI is responsible for providing the EC/IRB with reports of any serious and unexpected 
adverse drug reactions from any other study conducted with the IP.  AstraZeneca or its 
representatives will provide this information to the PI so that he/she can meet these reporting 
requirements. 
10.4 
Informed consent 
This study consists of the main caregiver ICF that allows the patient to participate in the study 
and possibly multiple assent forms based on age group and country-specific requirements.  
Enrolment code must be obtained from IXRS.   
If the patient turns 18 years of age during the study, the patient will sign a new ICF. 
The PI(s) at each centre will ensure that: 
• Each patient and caregiver is given full and adequate oral and written information about 
the nature, purpose, possible risk and benefit of the study 
• Each patient and legal caregiver is notified that they are free to discontinue from the study 
at any time 
• Each patient and legal caregiver is given the opportunity to ask questions and allowed time 
to consider the information provided 
• Each patient and legal caregiver provides signed and dated informed consent before 
conducting any procedure specifically for the study 
• Ensure the original, signed ICF(s) is/are stored in the Investigator’s Study File 
• Ensure a copy of the signed ICF is given to the patient and caregiver 
• Ensure that any incentives for patients who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described in the 
ICF that is approved by an EC/IRB. 
10.5 
Changes to the Clinical Study Protocol and Informed Consent 
Form 
Study procedures will not be changed without the mutual agreement of the SC and 
AstraZeneca or AstraZeneca delegate. 
If there are any substantial changes to the Clinical Study Protocol, then these changes will be 
documented in a new version of the study protocol. 
The new version of the Clinical Study Protocol is to be approved by the relevant Ethics 
Committee and if applicable, also the national regulatory authority approval, before 

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implementation.  Local requirements are to be followed for new versions of Clinical Study 
Protocols. 
AstraZeneca or AstraZeneca delegate will distribute any new versions of the Clinical Study 
Protocol to each PI.  For distribution to EC/IRB see Section 10.3. 
If a change to a Clinical Study Protocol requires a change to a centre’s ICF, AstraZeneca and 
the centre’s EC/IRB are to approve the revised ICF before the revised form is used.  
If local regulations require, any administrative change will be communicated to or approved 
by each EC/IRB. 
10.6 
Audits and inspections 
Authorised representatives of AstraZeneca, a regulatory authority or an EC may perform 
audits or inspections at the centre, including source data verification.  The purpose of an audit 
or inspection is to systematically and independently examine all study-related activities and 
documents, to determine whether these activities were conducted, and data were recorded, 
analysed, and accurately reported according to the Clinical Study Protocol, GCP, guidelines of 
the ICH, and any applicable regulatory requirements.  The Investigator will contact 
AstraZeneca or AstraZeneca delegate immediately if contacted by a regulatory agency about 
an inspection at the centre. 

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11. 
LIST OF REFERENCES 
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Ataga KI, Brittain JE, Desai P, et al. Association of coagulation activation with clinical 
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Blann AD, Mohan JS, Bareford D, Lip GY. Soluble P-selectin and vascular endothelial 
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Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful 
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Cohen LL, Lemanek K, Blount RL, et al. Evidence-based assessment of pediatric pain.  
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Davies EH, Tuleu C. Medicines for children: a matter of taste.  
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Gill FM, Sleeper LA, Weiner SJ, et al. Clinical events in the first decade in a cohort of infants 
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Heeney et al 2016 
Heeney MM, M.D., Hoppe CC, Abboud MR, et al.  A multinational trial of prasugrel for 
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platelet reactivity testing in a double-blind study of prasugrel in children with sickle cell 
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Laine M, Toesca R, Berbis J, et al. Platelet reactivity evaluated with the VASP assay 
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Nylander S, Femia EA, Scavone M, Berntsson P, Asztély AK, Nelander K, et al. Ticagrelor 
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Panepinto et al 2014 
Panepinto JA, Torres S, Bendo CB, McCavit TL, Dinu B, Sherman-Bien S, Bemrich-Stolz C, 
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Wessel et al 2013 
Wessel DL, Berger F, Li JS, Dähnert I, Rakhit A, Fontecave S, et al. Clopidogrel in infants 
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Wittfeldt A, Emanuelsson H, Brandrup-Wognsen G, et al. Ticagrelor enhances 
adenosine-induced coronary vasodilatory responses in humans.  
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Wun T, Soulieres D, Frelinger AL, Krishnamurti L, Novelli EM, Kutlar A, et al. A 
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Appendix A 
Additional Safety Information 
Further Guidance on the Definition of a Serious Adverse Event (SAE)  
Life-threatening 
‘Life-threatening’ means that the subject was at immediate risk of death from the adverse 
event (AE) as it occurred or it is suspected that use or continued use of the product would 
result in the subject’s death.  ‘Life-threatening’ does not mean that had an AE occurred in a 
more severe form it might have caused death (eg, hepatitis that resolved without hepatic 
failure). 
Hospitalisation 
Out subject treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the patient was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study. 
Important medical event or medical intervention 
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life-threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardise the patient or may require 
medical intervention to prevent 1 or more outcomes listed in the definition of serious.  These 
should usually be considered as serious. 
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used. 
• Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment 
• Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine 
• Intensive treatment in an emergency room or at home for allergic bronchospasm 
• Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation 
• Development of drug dependency or drug abuse 
A Guide to Interpreting the Causality Question 
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug. 
• Time Course.  Exposure to suspect drug.  Has the patient actually received the suspect 
drug?  Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug? 

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• Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class?  Or could the AE be anticipated from its pharmacological 
properties? 
• De-challenge experience.  Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug? 
• No alternative cause.  The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors. 
• Re-challenge experience.  Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped?  AstraZeneca would not normally recommend or support a re-
challenge. 
• Laboratory tests.  A specific laboratory investigation (if performed) has confirmed the 
relationship. 
In difficult cases, other factors could be considered such as: 
• Is this a recognised feature of overdose of the drug? 
• Is there a known mechanism? 
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship. 
The causality assessment is performed based on the available data including enough 
information to make an informed judgement.  With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’. 
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility. 

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Appendix B 
International Airline Transportation Association (IATA) 6.2 
Guidance Document 
Labelling and shipment of biohazard samples 
International Airline Transportation Association (IATA) classifies biohazardous agents into 
3 categories.  For transport purposes the classification of infectious substances according to 
risk groups was removed from the Dangerous Goods Regulations in the 46th edition (2005).  
Infectious substances are now classified either as Category A, Category B or Exempt.  There 
is no direct relationship between risk groups and categories A and B. 
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  Category A pathogens are, eg, Ebola, Lassa fever 
virus: 
• are to be packed and shipped in accordance with IATA Instruction 602. 
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are, eg, hepatitis A, B, C, D and E viruses, 
human immunodeficiency viruses types 1 and 2.  They are assigned the following UN number 
and proper shipping name: 
• UN 3373 - Biological Substance, Category B 
• Are to be packed in accordance with UN3373 and IATA 650 
Exempt - all other materials with minimal risk of containing pathogens 
• Clinical trial samples will fall into Category B or exempt under IATA regulations 
• Clinical trial samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging  
• Biological samples transported in dry ice require additional dangerous goods specification 
for the dry ice content 
• IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable 
• Samples routinely transported by road or rail are subject to local regulations which require 
that they are also packed and transported in a safe and appropriate way to contain any risk 
of infection or contamination by using approved couriers and packaging/containment 
materials at all times.  The IATA 650 biological sample containment standards are 
encouraged wherever possible when road or rail transport is used. 

Clinical Study Protocol Appendix C 
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Study Code D5136C00009 
Version 3.0 
Date 20 April 2020 
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Appendix C 
Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law 
Introduction 
This appendix describes the process to be followed in order to identify and appropriately 
report cases of Hy’s Law (HL).  It is not intended to be a comprehensive guide to the 
management of elevated liver biochemistries.   
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The Investigator is responsible for determining whether a subject meets 
potential Hy’s Law (PHL) criteria at any point during the study. 
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met.  
HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than Drug Induced Liver Injury (DILI) caused by the Investigational 
Medicinal Product (IMP).  
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting Adverse Events (AEs) and SAEs according to the outcome of the review and 
assessment in line with standard safety reporting processes. 
Definitions 
Potential Hy’s Law  
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥3 × upper limit of 
normal (ULN) together with total bilirubin ≥2 × ULN at any point during the study following 
the start of IP irrespective of an increase in alkaline phosphatase (ALP).  
Hy’s Law (HL) 
AST or ALT ≥3 × ULN together with total bilirubin level ≥2 × ULN, where no other reason, 
other than the IMP, can be found to explain the combination of increases, eg, elevated ALP 
indicating cholestasis, viral hepatitis, another drug.   
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in total bilirubin level, but there is no specified timeframe within 
which the elevations in transaminases and total bilirubin level must occur. 
Identification of Potential Hy’s Law Cases 
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any subject who meets any of the following identification criteria in 
isolation or in combination: 
• ALT ≥3 × ULN 
• AST ≥3 × ULN 

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• Total bilirubin level ≥2 × ULN 
When a patient meets any of the identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the Investigator (also sent to AstraZeneca 
representative).  
The Investigator will also remain vigilant for any local laboratory reports where the 
identification criteria are met, where this is the case the Investigator will: 
• Notify the AstraZeneca representative 
• Request a repeat of the test (new blood draw) by the central or local laboratory 
• Complete the appropriate unscheduled laboratory case report form (CRF) module(s) with 
the original local laboratory test result. 
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay: 
• Determine whether the subject meets PHL criteria (see Section 2 Definitions within this 
appendix for definition) by reviewing laboratory reports from all previous visits (including 
both central and local laboratory results) 
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will: 
• Notify the AstraZeneca representative 
• Determine whether the subject meets PHL criteria (see Section 2 Definitions within this 
Appendix for definition) by reviewing laboratory reports from all previous visits 
• Promptly enter the laboratory data into the laboratory CRF. 
Follow-up 
Potential Hy’s Law Criteria not met 
If the subject does not meet PHL criteria the Investigator will: 
• Inform the AstraZeneca representative that the subject has not met PHL criteria. 
• Perform follow-up on subsequent laboratory results according to the guidance provided in 
the Clinical Study Protocol. 
Potential Hy’s Law Criteria met 
If the subject does meet PHL criteria the Investigator will: 
• Notify the AstraZeneca representative who will then inform the central Study Team.  
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study subjects’ follow-up and the continuous review of data.  Subsequent to 
this contact the Investigator will: 

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• Monitor the subject until liver biochemistry parameters and appropriate clinical symptoms 
and signs return to normal or baseline levels, or as long as medically indicated  
• Investigate the aetiology of the event and perform diagnostic investigations as discussed 
with the Study Physician.  This includes deciding which tests available in the HL lab kit 
should be used.  
• Complete the 3 Liver CRF Modules as information becomes available  
If at any time (in consultation with the Study Physician) the PHL case meets serious criteria, 
report it as an SAE using standard reporting procedures. 
Review and Assessment of Potential Hy’s Law Cases 
The instructions in this section should be followed for all cases where PHL criteria are met. 
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
IMP.  The AstraZeneca Global Clinical Lead or equivalent and Global Safety Physician will 
also be involved in this review together with other subject matter experts as appropriate.   
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below. 
If there is an agreed alternative explanation for the ALT or AST and total bilirubin level 
elevations, a determination of whether the alternative explanation is an AE will be made and 
subsequently whether the AE meets the criteria for a SAE: 
• If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF. 
• If the alternative explanation is an AE/SAE, record the AE/SAE in the CRF accordingly 
and follow the AstraZeneca standard processes. 
If it is agreed that there is no explanation that would explain the ALT or AST and total 
bilirubin level elevations other than the IMP: 
• Report an SAE (report term ‘Hy’s Law’) according to AstraZeneca Standard processes.  
The ‘Medically Important’ serious criterion should be used if no other serious criteria apply. 
As there is no alternative explanation for the HL case, a causality assessment of ‘related’ 
should be assigned. 
If there is an unavoidable delay of over 3 weeks in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made. 

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• Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and causality 
assessment as per above. 
• Continue follow-up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are met.  Update the SAE report according to the outcome of the 
review amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined. 
References 
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf  

Clinical Study Appendix D 
Drug Substance Ticagrelor  
Study Code D5136C00009 
Version 3.0 
Date 20 April 2020 
83(123) 
Appendix D 
Interview Guide for VOC-triggered Telephone Calls 
Instructions:   
• Establish telephone contact with parent/caregiver when a potential VOC event is reported 
in the eDevice. 
• Check the StudyWorks data reported from the eDevice either before or during the call. 
• Document the call that is triggered by a potential VOC event in patient’s medical records.  
• Note the event details and whether or not event is considered to be fulfilling criteria for 
VOC endpoint or not. 
• Also note any other AEs that come up during the conversation. 
• Also note any change of medications that come up during the conversation. 
 
When calling the parent/caregiver, the Investigator should introduce him/herself in an 
appropriate way and make sure he/she is speaking to the appropriate person.  
In general, the parent/caregiver will be the appropriate person. The 
Investigator may decide to speak directly with a patient in late teenage age 
period, if judged more appropriate based on Investigator’s thorough 
knowledge about the patient. 
 
Cover the discussion items below during the normal doctor-parent/caregiver conversation in 
the phone call. Depending on the situation and the responses, additional questions may be 
needed for the Investigator to complete the required information in the eCRF. 
 

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Discussion item 
Specific question (as applicable) 
1. Collection of any VOC 
endpoints 
 
Purpose: To ensure any VOC events not yet 
reported to Investigator are captured. 
 
Questions should be tailored to ensure all 
the relevant data are collected for events 
meeting criteria for a VOC endpoint (painful 
crisis or ACS) so the eCRF can be 
completed*, examples:  
• Judge if event meets VOC 
definitions for this study 
• Start/stop  
• Treatment setting 
• Pain localisation  
• Type of analgesics taken 
(opioid/non-opioid) 
• Any other treatments given 
 
*Note that depending on where the event 
was treated, copies of medical records from 
other clinic or hospital may be needed. 
“Has <<patient name>> experienced any 
painful episodes or had any episodes with 
chest problems, fever, and often also 
breathing symptoms, since the last time we 
talked?” 
2. AE collection 
 
Purpose: To collect any AEs other than the 
VOC event with onset since last contact and 
check status of ongoing AEs. 
 
Use follow-up questions as needed to cover 
start/stop, outcome, any treatments 
provided, seriousness, severity, relationship 
to study drug or study procedures, and any 
changes to study drug treatment as outlined 
in the corresponding eCRF modules. 
“Has<<patient name>> had any new health 
issues since the last time we talked?” 
 
If this patient has any ongoing AEs recorded 
in the eCRF, ask about the status of those 
events:  
 
“What about the <<ongoing event (e.g. cold, 
ankle sprain, etc.) we talked about last time? 
What happened with that?” 

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Study Code D5136C00009 
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Discussion item 
Specific question (as applicable) 
 
Update information as needed on any 
ongoing AEs in the eCRF. 
3. Concomitant medications 
 
Purpose: To ensure concomitant 
medications are correctly captured. 
 
Any changes to concomitant medications, 
both regularly taken and per needed, are to 
be further explored to ensure updated 
information is recorded in the eCRF. 
 
Depending on what information on 
medications that came out from Discussion 
item 1 on the VOC event, any changes to 
medications may need to be further 
explored. 
  “Please can you tell me about all the 
medications that <<patient name>> has 
taken since the last time we talked?”  
  
Then continue to prompt with  
“Anything else?”  until you have everything 
4. eDevice functionality and usage 
 
Purpose: To ensure eDevice is working OK 
and identify any need for re-training. 
 
“Have you and <<patient name>> 
experienced any issues with using the 
eDevice?” 
 
If any expected data in StudyWorks is 
missing: 

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Discussion item 
Specific question (as applicable) 
Any issues reported for the eDevice should 
be identified, further explored and resolved.  
 
Remind parent/caregiver of the self-training 
availability in the eDevice. 
 
Extra visits to site should be offered for 
hands-on re-training as needed. 
 
 
“Is there anything more relating to << pain 
intensity / absence from school/work>> that 
you haven’t included?” 
 
“Is there anything else you haven’t 
included?  
 
“Please can you tell me, if there is 
something we can do to help the eDevice 
recordings work better for you?” 
 
5. Adherence to visit schedules and 
study procedures 
 
Purpose: To reinforce adherence to study 
visits and procedures. 
 
Provide reminder for the date and time for 
next visit to site or telephone visit. 
 
Remind to not administer study drug at 
home in the morning of visits with PK/PD 
sampling. 
 
Remind to bring all study drug bottles 
(including empty ones) to study visits. 
 
 
 

Clinical Study Appendix E 
Drug Substance Ticagrelor  
Study Code D5136C00009 
Version 3.0 
Date 20 April 2020 
87(123) 
 
Appendix E 
Guide for Scheduled Telephone Visits 
Instructions:   
• Schedule Telephone Visits monthly between On-site Visits. 
• Have the appropriate information on the patient before the call.  Check the StudyWorks 
entries made by the parent/caregiver/patient from their eDevice before the call. 
 
Similar to On-site Visits, document the Telephone Visits in patient’s medical records. Notes 
are to include: 
• Any adverse events,  
• Whether the event fulfils criteria for VOC endpoint or not,  
• Any changes of medications,  
• And any use of contraceptives (applicable to females of childbearing potential and  
• Consider if appropriate to discuss in telephone visits). 
 
When calling the parent/caregiver, the Investigator should introduce him/herself in an 
appropriate way and make sure he/she is speaking to the appropriate person.  
In general, the parent/caregiver will be the appropriate person. The Investigator may 
decide to speak directly with a patient in late teenage period, if judged more 
appropriate based on Investigator’s thorough knowledge about the patient. 
 
Cover the discussion items below during the normal doctor-parent/caregiver conversation in 
the phone call. Depending on the situation and the responses, additional questions may be 
needed for the Investigator to complete the required information in the eCRF. 
 
Discussion item 
Specific question (as applicable) 
6. AE collection 
 
Purpose: To ensure AEs are captured 
during study. 
 
“Has <<patient name>> had any new health 
issues since the last time we talked?” 
 
If this patient has any ongoing AEs recorded 
in the eCRF, ask about the status of those 
events:  

Clinical Study Appendix E 
Drug Substance Ticagrelor  
Study Code D5136C00009 
Version 3.0 
Date 20 April 2020 
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Discussion item 
Specific question (as applicable) 
Collect any AEs with onset since last 
contact, and check status of ongoing AEs. 
 
As outlined in the corresponding eCRF 
modules, use follow-up questions as needed 
to cover: 
• Start/stop,  
• Outcome,  
• Any treatments provided,  
• Seriousness,  
• Severity,  
• Relationship to study drug or study 
procedures,  
• And any changes to study drug 
treatment  
 
 
“What about the <<ongoing event (eg, cold, 
ankle sprain, etc.) >> we talked about last 
time? What happened with that?” 
 
7. Collection of any VOC endpoints 
 
Purpose: To ensure any VOC events not yet 
reported to Investigator are captured. 
 
Questions should be tailored to ensure all 
the relevant data are collected for events 
meeting criteria for a VOC endpoint (painful 
crisis or ACS) so the eCRF can be 
completed*, examples:  
• Judge if event meets VOC definitions 
for this study 
• Start/stop  
• Treatment setting 
• Pain localisation  
• Type of analgesics taken 
(opioid/non-opioid) 
• Any other treatments given 
 
Unless already sorted out during the AE 
Discussion Item above, ask specifically 
about VOC events:  
 
“Has <<patient name>> experienced any 
painful episodes or had any episodes with 
chest problems, fever, and often also 
breathing symptoms, since the last time we 
talked?” 
 
 

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Version 3.0 
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Discussion item 
Specific question (as applicable) 
*Note that depending on where the event 
was treated, copies of medical records from 
other clinic or hospital may be needed. 
 
8. eDevice functionality and usage 
 
Purpose: To ensure that the eDevice is 
working OK and identify any need for re-
training. 
 
Questions should be tailored based on 
entries made in StudyWorks, eg, if perfect 
compliance to weekly assessments of 
school/work absence but no VOC events, 
question could focus on ensuring no 
potential VOC events have been missed.  
 
Potential problems with using the eDevice 
should be further explored and resolved.  
 
Remind parent/caregiver of the self-training 
availability in the eDevice. 
 
Offer extra visits to site for hands-on re-
training as needed. 
 
“Have you and <<patient name>> 
experienced any issues with using the 
eDevice?” 
 
If any expected data in StudyWorks is 
missing: 
 
“I can see that you have not recorded much 
about <<pain intensity / absence from 
school/work>> in your eDevice.” 
 
“Is there anything more relating to << pain 
intensity / absence from school/work>> that 
you haven’t included?” 
 
“Is there anything else you haven’t 
included?”  
 
“Please can you tell me if there is something 
we can do to help the eDevice recordings 
work better for you?” 

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Discussion item 
Specific question (as applicable) 
9. Some VOC event details need to be 
recorded in the eDevice  
 
Purpose: To ensure the VOC details to be 
reported by the parent/caregiver/patient for 
any VOC events are captured in the 
eDevice. 
 
Provide reminder to record any painful 
crises and ACS events, and to do a daily 
VOC pain rating while the event is ongoing, 
regardless of where such events are treated.   
 
Also provide reminder to bring the eDevice 
with them in case they seek medical care. 
 
10. Parents/caregivers to contact the 
study site in case a suspected VOC 
 
Purpose: To ensure a timely collection of 
event-related information to have high-
quality VOC endpoint data. 
 
Provide reminder to call site within 72 hours 
in the event of any painful crises and/or 
ACS. 
 
Also check that parent/caregiver knows 
contact details to the site. 
 

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Study Code D5136C00009 
Version 3.0 
Date 20 April 2020 
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Discussion item 
Specific question (as applicable) 
11. Concomitant medications 
 
Purpose: To ensure concomitant 
medications are captured during study. 
 
Any change to concomitant medications is 
to be further explored to ensure updated 
information is recorded in the eCRF. 
“Please can you tell me about all the 
medications that <<patient name>> has 
taken since the last time we talked?” 
 
Then continue to prompt with 
“Anything else?”  
until you have everything. 
12. Use of contraceptive methods (when 
applicable) 
 
Purpose: To reduce risk for pregnancies 
during study in fertile female participants. 
 
Remind parent/caregiver/patients that 
female, fertile participants should not get 
pregnant during study. An individually 
appropriate contraceptive method should be 
discussed (See study protocol section 3.8) 
and the importance of use re-enforced. 
 
Consider if appropriate to discuss contraceptives in 
Telephone Visits or only at On-site Visits. 
“You know that young girls should not get 
pregnant while in this study. Is there a need 
for <<patient name>> to use any 
contraceptive method to not get pregnant? 
What is she using?” 
13. Adherence to visit schedules and study 
procedures 
Purpose: To reinforce adherence to study 
visits and procedures. 
 
Remind patient about the date and time for 
next visit to site or telephone visit. 
 
 

Clinical Study Appendix E 
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Study Code D5136C00009 
Version 3.0 
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Discussion item 
Specific question (as applicable) 
Remind to not administer study drug at 
home in the morning of visits with PK/PD 
sampling. 
 
Remind to bring all study drug bottles 
(including empty ones) to study visits. 
 
 
 

Clinical Study Appendix F 
Drug Substance Ticagrelor  
Study Code D5136C00009 
Version 3.0 
Date 20 April 2020 
93(123) 
Appendix F 
Palatability and Swallowability Assessment 
Study Medication Palatability Assessment for patients 5 years of age or 
older 
Facial Hedonic Scale (FHS) 
Instructions to Study Staff 
Immediately after administration of investigational product (IP) on Visit 2 and Visit 9, capture 
the patients’ assessment of the taste of the medication.  Use this question for all patients taking 
the study drug who are 5 years of age or older. 
Read to patient: 
I have a question about the medication you have just taken.  I would like you to tell me how 
you feel about the taste of the medicine you have just swallowed.  You can give your answer 
by making a mark (“X”) on the box below the faces to show how much you like or dislike the 
taste of the medicine.  You can choose from ‘Dislike very much’ to Like very much’ [If child 
cannot read, point at 1 face at a time and read the descriptive text below]. 
 
 
 
Dislike very much 
 
Dislike a little 
 
Not sure 
 
Like a little 
 
Like very much 
 
Patient ID: ____________________________  
Assessment Date: ______________________  
Assessment Time: ______________________  
Initials of person administering the assessment: ______ 
 
 
 

Clinical Study Appendix F 
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Study Code D5136C00009 
Version 3.0 
Date 20 April 2020 
94(123) 
Study Medication Palatability Assessment 
Observer Assessment for Patients 2 - 4 Years of Age 
Instructions to Study Staff  
Immediately after administration of Brilinta at Visit 2 and Visit 9, capture the patient’s 
reaction of the taste of the medication. Use this case report form (CRF) for all patients taking 
the study drug who are 2 to 4 years of age. 
1. Choose the response that best matches a description of what you observe of the patient’s 
willingness to swallow the study drug. 
Willingness to swallow 
 
 Swallowed without problem 
 
 Some resistance but did swallow 
 
 Spit out some / all of medication 
 
 Vomited up medication 
 
2. Was any behaviour observed when the study medication was given to this patient that 
would be indicative of a negative response to the palatability of the study medication? 
 
 NO 
 
YES 
 
If answered YES, please answer the following questions: 
2a. 
Did the patient turn his/her head to reject intake of the medication?  
 
 NO 
 
YES 
 
2b. 
Did the patient twist his/her face or mouth in an expression of displeasure?  
 
 NO 
 
YES 
 
2c. 
Did the patient display any other negative behaviour?  
 
 NO 
 
YES 

Clinical Study Appendix F 
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Study Code D5136C00009 
Version 3.0 
Date 20 April 2020 
95(123) 
If YES, please describe: _______________________________________________________  
Patient ID: ____________________________  
Assessment Date: ______________________  
Assessment Time: ______________________  
Initials of person administering the assessment: ______ 

Clinical Study Appendix G 
Drug Substance Ticagrelor  
Study Code D5136C00009 
Version 3.0 
Date 20 April 2020 
96(123) 
Appendix G 
Drug Interactions 
1. 
Platelet aggregation inhibitors: NOT ALLOWED 
• Other adenosine diphosphate (ADP) receptor blockers - cangrelor, clopidogrel, prasugrel, 
ticlopidine 
• Dipyridamole 
• Cilostazol 
• Aspirin. 
2. 
Anticoagulants: NOT ALLOWED  
• Coumarins - warfarin 
• Heparins (except for flushing venous catheters prior to sampling)  
• Factor Xa inhibitors - fondaparinux, apixaban, rivaroxaban, edoxaban 
• Thrombin inhibitors - bivalirudin, dabigatran, argatroban, desirudin, lepirudin. 
3. 
Non-steroidal anti-inflammatory agents: NOT ALLOWED if chronically used, 
requiring treatment >3 days/week. 
• Propionic acid derivates - ibuprofen, dexibuprofen, naproxen, ketoprofen 
• Acetic acid derivates - indomethacin, ketorolac, tolmetin, sulindac, diclofenac 
• Enolic acid derivates - piroxicam, meloxicam, tenoxicam  
• Selective COX-2 inhibitors - celecoxib, parecoxib, etoricoxib 
• Others - clonixin.  
4. 
CYP3A inhibitors: NOT ALLOWED as they substantially increase ticagrelor 
exposure. 
• Strong inhibitors - boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, 
ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, 
ritonavir, saquinavir, telaprevir, telithromycin, voriconazole 
• Intake of grapefruit juice. 
5. 
CYP3A substrates or inducers: NOT ALLOWED as they reduce ticagrelor 
exposure and may result in reduced efficacy.  
• Rifampin/rifampicin  
• Rifabutin 
• Rifapentine 
• Phenytoin  
• Carbamazepine  
• Phenobarbital  
• Avasimibe  
• St. John’s wort 
• Simvastatin/lovastatin (metabolised by CYP3A- increases their concentration - avoid 
doses greater than 40 mg) 

Clinical Study Appendix G 
Drug Substance Ticagrelor  
Study Code D5136C00009 
Version 3.0 
Date 20 April 2020 
97(123) 
6. 
P-glycoprotein interactions 
• Digoxin - If the patient is receiving digoxin, levels should be monitored closely following 
initiation of investigational product (IP) and with any change in IP. 
• Cyclosporine - NOT ALLOWED as it increases ticagrelor exposure.  
 

Clinical Study Appendix H 
Drug Substance Ticagrelor  
Study Code D5136C00009 
Version 3.0 
Date 20 April 2020 
98(123) 
Appendix H 
Pain Assessment 
Faces Pain Scale - Revised (FPS-R) 
For patients aged ≥5 years 
NB - this will be administered via an electronic device 
Instructions 
These faces show how much something can hurt. The face to the left shows no pain. The faces 
show more and more pain up to the right face - it shows very much pain. Please choose the 
face that shows the worst pain you had. 
 
 
 
    0 
    2 
    4 
    6 
    8 
    10  
 
Patient ID: ____________________________  
Assessment Date: ______________________  
Assessment Time: ______________________  
Initials of person administering the assessment: ______ 
 
 

Clinical Study Appendix H 
Drug Substance Ticagrelor  
Study Code D5136C00009 
Version 3.0 
Date 20 April 2020 
99(123) 
Marking of localisation of pain 
 
 
 

Clinical Study Appendix H 
Drug Substance Ticagrelor  
Study Code D5136C00009 
Version 3.0 
Date 20 April 2020 
100(123) 
The Face, Legs, Activity, Cry, Consolability (FLACC) 
For patients ages 2-4 years 
 
NB - this will be administered via an electronic device 
 
Patient ID/E-code : ________________ 
Assessment Date : _____________________ 
 
Please describe how your child behaved because of the pain.  
FACE 
No particular 
expression or smile 
Occasional grimace or frown, 
withdrawn, disinterested 
Frequent to constant frown, 
clenched jaw, quivering 
chin 
0 
1 
2 
LEGS 
Normal position or relaxed 
Uneasy, restless, tense 
Kicking, or legs drawn up 
0 
1 
2 
ACTIVITY 
Lying quietly, normal 
position, moves easily 
Squirming, shifting back and 
forth, tense 
Arched, rigid, or jerking 
0 
1 
2 
CRY 
No cry (awake or asleep) 
Moans or whimpers, occasional 
complaint 
Crying steadily, screams or 
sobs, frequent complaints 
0 
1 
2 
CONSOLABILITY 
Content, relaxed 
Reassured by occasional 
touching, hugging, or being 
talked to, distractable 
Difficult to console or 
comfort 
0 
1 
2 
References: 
English for USA 
Merkel, S., Voepel-Lewis, T., Shayevitz, J., & Malviya, S. The FLACC: A behavioral scale for scoring 
postoperative pain in young children. Pediatric Nursing 1997 23(3),293-297.   
© 2002, The Regents of the University of Michigan. All Rights Reserved.

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