Clinical trial NCT03615924
Conditions: Sickle Cell Disease
Keywords: Sickle Cell Disease Sickle Cell Anemia SCD Platelet aggregation Ticagrelor Brilinta VOC Vaso-Occlusive Crises ACS painful crisis
Sponsor: AstraZeneca
Start date: 2018-09-26; Completion date: 2020-08-13
Enrollment: 193 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to Evaluate the Effect of Ticagrelor versus Placebo in Reducing the Rate of Vaso-Occlusive Crises in Paediatric Patients with Sickle Cell Disease

Detailed description:
Hestia3 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.

* The target population are children aged ≥2 to \<18 years of age and body weight of ≥12 kg diagnosed with HbSS or HbS/β0 confirmed by high-performance liquid chromatography or hemoglobin electrophoresis. 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.
* 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 enroll only children aged 2 years or above, since VOCs become more frequent with age.
* 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 immunizations according to local guidelines and health care programmers. Study drug will be given on the background of standard treatments for SCD. 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. However, restrictions apply to some medications and interventions that may be necessary for the patient's health and well-being during the study.
* 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. The expected average follow-up is 18 months. Considering inclusion of patients with at least 2 VOC events 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.
* Due to ticagrelor mechanism of action and the potential to reduce symptoms caused by ischemia during a vaso-occlusion, a composite endpoint with painful crises and/or ACS has been selected for the primary endpoint. 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. 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).
* Patients will be treated with 15, 30 and 45 mg bd or matching placebo, depending on body weight.

Arms: arm 1: The double-blinded study drug dose will be weight dependent:

* ≥12 to ≤24kg: Ticagrelor 15 mg, twice a day
* \>24 to ≤48 kg: Ticagrelor 30 mg, twice a day
* \>48 kg: Ticagrelor 45 mg, twice a day. arm 2: The double-blinded study drug dose will be weight dependent:

* ≥12 to ≤24kg: Placebo to match ticagrelor 15 mg, twice a day
* \>24 to ≤48 kg: Placebo to match ticagrelor 30 mg, twice a day
* \>48 kg: Placebo to match ticagrelor 45 mg, twice a day.
Interventions: intervention 1: Ticagrelor intervention 2: Placebo
Intervention descriptions: intervention 1: The double-blinded study drug dose will be weight dependent:

* ≥12 to ≤24kg: Ticagrelor 15 mg, twice a day
* \>24 to ≤48 kg: Ticagrelor 30 mg, twice a day
* \>48 kg: Ticagrelor 45 mg, twice a day. intervention 2: The double-blinded study drug dose will be weight dependent:

* ≥12 to ≤24kg: Placebo to match ticagrelor 15 mg, twice a day
* \>24 to ≤48 kg: Placebo to match ticagrelor 30 mg, twice a day
* \>48 kg: Placebo to match ticagrelor 45 mg, twice a day.

Protocol documents:
SAP_002.pdf: 
Statistical Analysis Plan 
Study Code D5136C00009
Edition Number V3.0
Date 26 June 2020
CONFIDENTIAL AND PROPRIETARY
1 of 84
Statistical Analysis Plan
Study Code
D5136C00009
Edition Number
V3.0
Date
26 June 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)


Statistical Analysis Plan 
Study Code D5136C00009
Edition Number V3.0
Date 26 June 2020
CONFIDENTIAL AND PROPRIETARY
2 of 84
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)
SIGNATURE OF STUDY STATISTICIAN
Study Statistician
Date
PPD


Statistical Analysis Plan 
Study Code D5136C00009
Edition Number V3.0
Date 26 June 2020
CONFIDENTIAL AND PROPRIETARY
3 of 84
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)
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN
Global Product Statistician
Date
PPD


Statistical Analysis Plan 
Study Code D5136C00009
Edition Number V3.0
Date 26 June 2020
CONFIDENTIAL AND PROPRIETARY
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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
SIGNATURE OF STUDY STATISTICIAN......................................................................... 2
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN ................................................... 3
TABLE OF CONTENTS...................................................................................................... 4
LIST OF TABLES................................................................................................................ 7
LIST OF FIGURES .............................................................................................................. 8
LIST OF ABBREVIATIONS ............................................................................................... 9
AMENDMENT HISTORY................................................................................................. 12
1
STUDY DETAILS ........................................................................................... 14
1.1
Study Objectives............................................................................................... 14
1.1.1
Primary Objective............................................................................................. 14
1.1.2
Secondary Objectives........................................................................................ 14
1.1.3
Safety Objectives.............................................................................................. 15
1.1.4
Exploratory Objectives ..................................................................................... 15
1.2
Study Design .................................................................................................... 16
1.3
Number of Patients ........................................................................................... 18
2
ANALYSIS SETS ............................................................................................ 18
2.1
Definition of Analysis Sets ............................................................................... 18
2.2
Deviations ........................................................................................................ 21
3
PRIMARY AND SECONDARY VARIABLES ............................................... 22
3.1
General Principles............................................................................................. 22
3.1.1
Missing Data..................................................................................................... 22
3.1.2
Baseline............................................................................................................ 22
3.1.3
Change and Percentage Change from Baseline.................................................. 22
3.1.4
Treatment Period .............................................................................................. 23
3.1.4.1
End of Study Visit ............................................................................................ 23
3.1.5
Safety Follow-up Period ................................................................................... 23
3.1.6
Reference Dates (Relative Study Day) .............................................................. 23
3.1.7
On- and Off-treatment Periods.......................................................................... 24
3.1.7.1
On-treatment Period.......................................................................................... 24
3.1.7.2
Off-treatment Period......................................................................................... 24
3.1.8
Retests and Unscheduled Assessments.............................................................. 24
3.2
Primary Efficacy Variable................................................................................. 24
3.2.1
Vaso-occlusive Crises (VOCs).......................................................................... 24
3.3
Secondary Efficacy Variables ........................................................................... 25
3.3.1
Painful Crises ................................................................................................... 26


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Edition Number V3.0
Date 26 June 2020
CONFIDENTIAL AND PROPRIETARY
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3.3.2
Acute Chest Syndromes.................................................................................... 27
3.3.3
VOC Events Requiring Hospitalisation or Emergency Department Visits ......... 27
3.3.4
Acute Sickle Cell Disease Complications.......................................................... 28
3.3.5
Sickle Cell-related Red Blood Cell Transfusions............................................... 29
3.3.6
Health-related Quality of Life (HRQL) and Fatigue .......................................... 29
3.3.6.1
PedsQL SCD Module ....................................................................................... 29
3.3.6.2
Multidimensional Fatigue Scale........................................................................ 30
3.3.7
Absence from School/Work Due to SCD .......................................................... 31
3.3.8
Pain During VOC Events.................................................................................. 32
3.3.9
Type of Analgesics Use During VOC Events.................................................... 33
3.3.10
Swallowability and Palatability Data................................................................. 33
3.4
Safety Variables................................................................................................ 34
3.4.1
Adverse Events................................................................................................. 34
3.4.2
Other Significant Adverse Events (OAEs) ........................................................ 35
3.4.3
Deaths .............................................................................................................. 35
3.4.4
Bleeding Events................................................................................................ 35
3.4.5
Overdose .......................................................................................................... 35
3.4.6
Blood Product Transfusions.............................................................................. 36
3.4.7
Laboratory Variables ........................................................................................ 36
3.4.7.1
Liver Function Tests, Potential Hy’s Law and Hy’s Law................................... 38
3.4.8
ECG ................................................................................................................. 38
3.4.9
Vital Signs........................................................................................................ 39
3.4.10
Physical Examination........................................................................................ 40
3.5
Exploratory Variables ....................................................................................... 40
3.5.1
Duration of ACS............................................................................................... 40
3.5.2
Pharmacokinetic Parameters ............................................................................. 40
3.5.3
Pharmacodynamic Variables............................................................................. 41
4
ANALYSIS METHODS................................................................................... 41
4.1
General Principles............................................................................................. 41
4.1.1
General Methodology ....................................................................................... 41
4.2
Analysis Methods ............................................................................................. 43
4.2.1
Patient Disposition, Important Protocol Deviations and Analysis Sets............... 43
4.2.2
Demographic and Baseline Characteristics........................................................ 44
4.2.3
Past and Current Medical and Surgical History................................................. 46
4.2.4
Prior, Concomitant, and Post-discontinuation Medications and Therapies......... 46
4.2.5
Study Treatment Exposure and Compliance...................................................... 48
4.2.5.1
Study Treatment Exposure................................................................................ 49
4.2.5.2
Study Treatment Compliance............................................................................ 51
4.2.6
Primary Efficacy Variable................................................................................. 53
4.2.6.1
Number of VOCs.............................................................................................. 53
4.2.6.2
Testing the Fit of Negative Binomial Distribution............................................. 54
4.2.6.3
Sensitivity Analyses.......................................................................................... 54
4.2.6.4
Subgroup analyses ............................................................................................ 56
4.2.7
Time to Event Analyses.................................................................................... 57


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Edition Number V3.0
Date 26 June 2020
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4.2.8
Secondary Efficacy Variables ........................................................................... 58
4.2.8.1
Number of Painful Crises.................................................................................. 58
4.2.8.2
Number of ACSs .............................................................................................. 58
4.2.8.3
Duration of Painful Crises................................................................................. 58
4.2.8.4
Number of VOC Events Requiring Hospitalisation or Emergency Department 
Visits ................................................................................................................ 59
4.2.8.5
Number of Days Hospitalised for VOC Events ................................................. 59
4.2.8.6
Number of Acute SCD Complications .............................................................. 59
4.2.8.7
Number of Days Hospitalised for Acute SCD Complications............................ 59
4.2.8.8
Number of Sickle Cell-related Red Blood Cell Transfusions............................. 60
4.2.8.9
Health-related Quality of Life (HRQL) and Fatigue .......................................... 60
4.2.8.10
Days Absent from School/Work Due to SCD.................................................... 60
4.2.8.11
Intensity of Pain During VOC Events and Number of VOC Events by Age 
Group ............................................................................................................... 60
4.2.8.12
Type of Analgesics Used During VOC Events.................................................. 61
4.2.8.13
Swallowability and Palatability Data................................................................. 61
4.2.9
Safety ............................................................................................................... 61
4.2.9.1
Adverse Events................................................................................................. 61
4.2.9.2
Overdose .......................................................................................................... 63
4.2.9.3
Bleeding Events................................................................................................ 63
4.2.9.4
Blood Product Transfusions.............................................................................. 63
4.2.9.5
Laboratory Variables ........................................................................................ 64
4.2.9.6
ECG Variables.................................................................................................. 65
4.2.9.7
Vital Signs........................................................................................................ 65
4.2.10
Exploratory Variables ....................................................................................... 66
4.2.10.1
Duration of ACSs ............................................................................................. 66
4.2.10.2
Pharmacokinetic Data....................................................................................... 66
4.2.10.3
Pharmacodynamic Variable .............................................................................. 67
5
INDEPENDENT DATA MONITORING COMMITTEE ................................. 68
6
CHANGES/CLARIFICATIONS OF ANALYSIS FROM PROTOCOL ........... 69
7
REFERENCES................................................................................................. 69
8
APPENDIX ...................................................................................................... 71
Appendix A  Vital Signs Pre-defined Abnormality Assessment Criteria.............................. 71
Appendix B Race Mapping ................................................................................................. 72
Appendix C  Missing/Partial Start and Stop Dates for Medications/Transfusions ................ 74
Appendix D  Missing/Partial Dates for Date of Birth, Diagnosis of Sickle Cell Disease, 
Prior VOCs, and VOCs During the Study............................................................................ 75
Appendix E Accounting for Missing Data........................................................................... 77


Statistical Analysis Plan 
Study Code D5136C00009
Edition Number V3.0
Date 26 June 2020
CONFIDENTIAL AND PROPRIETARY
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LIST OF TABLES
Table 1
Analysis Sets ........................................................................................... 18
Table 2
Summary of Outcome Variables and Analysis Sets.................................. 19
Table 3
Summary of Changes/Clarifications from Protocol .................................. 69
Table 4
Vital Signs Pre-defined Abnormality Assessment Criteria....................... 71
Table 5
Reasons for patients withdrawing from the study and the corresponding 
treatment group used to calculate the imputation VOC event rate under 
MAR, pDRMI, and DRMI....................................................................... 79
Table 6
Reasons for patients discontinuing from the ticagrelor and the 
corresponding treatment group used to calculate the imputation VOC 
event rate under MAR, pDRMI and DRMI .............................................. 81
Table 7
Summary of analysis under various estimands and assumptions............... 82


Statistical Analysis Plan 
Study Code D5136C00009
Edition Number V3.0
Date 26 June 2020
CONFIDENTIAL AND PROPRIETARY
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LIST OF FIGURES
Figure 1
Study Design ........................................................................................... 17


Statistical Analysis Plan 
Study Code D5136C00009
Edition Number V3.0
Date 26 June 2020
CONFIDENTIAL AND PROPRIETARY
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LIST OF ABBREVIATIONS
Abbreviation or special 
term
Explanation
ACS
Acute Chest Syndrome
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
aMean
Arithmetic Mean
APTT
Activated Partial Thromboplastin Time
AST
Aspartate Aminotransferase
ASCD
Acute SCD Complications
ATC
Anatomic Therapeutic Chemical
AUC
Area under the plasma concentration-time curve from zero to infinity
bd
Twice Daily
β-hCG
Beta-human Chorionic Gonadotropin
BLQ
Below the Limit of Quantification
BUN
Blood Urea Nitrogen
CI
Confidence Interval
CL/F
Oral Clearance
COVID-19
Coronavirus Disease 2019
CSED
Common Study End Date
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CTMS
Clinical Trial Management System
CV
Coefficient of Variation
DBP
Diastolic Blood Pressure
DL
Direct Likelihood Approach
DRMI
Drop-out Reason Multiple Imputation
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EOS
End of Study
FAS
Full Analysis Set
FHS
Facial Hedonic Scale
FLACC
Face Legs Activity Cry Consolability Scale
FPS-R
Faces Pain Scale Revised
gCV%
% Geometric Coefficient of Variance 


Statistical Analysis Plan 
Study Code D5136C00009
Edition Number V3.0
Date 26 June 2020
CONFIDENTIAL AND PROPRIETARY
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Abbreviation or special 
term
Explanation
gMean
Geometric Mean
gSD
Geometric Standard Deviation
Hb
Haemoglobin
HbS/β0
Sickle beta-zero-thalassaemia
HBsAg
Hepatitis B Surface Antigen
HbSS
Homozygous Sickle Cell Anaemia
HCV
Hepatitis C Virus
HIV
Human Immunodeficiency Virus
HL
Hy’s Law
HRQL
Health-related Quality of Life
IDMC
Independent Data Monitoring Committee
INR
International Normalised Ratio
IP
Investigational Product
ITT
Intent to Treat
IxRS
Interactive Voice/Web Response System
LDH
Lactate Dehydrogenase
LLN
Lower Limit of Normal
LLOQ
Lower Limit of Quantification
MAR
Missing at Random
Max
Maximum
MCMC
Markov chain Monte Carlo
MedDRA
Medical Dictionary for Regulatory Activities
MI
Multiple Imputation
Min
Minimum
MNAR
Missing Not at Random
NBD
Negative Binomial Distribution
NC
Not Calculable
NQ
Non-quantifiable
NR
Not Reportable
NS
No Sample
NSAID
Non-steroidal Anti-inflammatory Drug
OAE
Other significant Adverse Events
PD
Pharmacodynamics
pDRMI
Partial Drop-out Reason Multiple Imputation


Statistical Analysis Plan 
Study Code D5136C00009
Edition Number V3.0
Date 26 June 2020
CONFIDENTIAL AND PROPRIETARY
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Abbreviation or special 
term
Explanation
PedsQL
Paediatric Quality of Life Inventory
PHL
Potential Hy’s Law
PK
Pharmacokinetics
PP
Per Protocol
PRI
Platelet Reactivity Index
PT
Preferred Term
PTT
Partial Thromboplastin Time
RBC
Red Blood Cell
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
SC
Steering Committee
SCD
Sickle Cell Disease
SD
Standard Deviation
SI
Standard International
SMPA
Study Medication Palatability Assessment
SOC
System Organ Class
TBL
Total Bilirubin
TIA
Transient Ischemic Attack
ULN
Upper Limit of Normal
VASP
Vasodilator-stimulated Phosphoprotein
VOC
Vaso-occlusive Crisis
WHODD
World Health Organisation Drug Dictionary
ZINB
Zero-inflated Negative Binomial (distribution)
ZIP
Zero-inflated Poisson


Statistical Analysis Plan 
Study Code D5136C00009
Edition Number V2.0
Date 17 March 2020
CONFIDENTIAL AND PROPRIETARY
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AMENDMENT HISTORY
Date
Description of Change
26 June 2020
Changed IQVIA study statistician from 
 to 
Updated SAP due to blind delivery review (BDR) comments review meeting 
(CRM) and due to protocol amendment related to COVID-19 such that the 
SAP is based on the clinical study protocol (CSP) V3.0 dated 20 April 2020.
Changes made throughout to reflect sponsor’s decision to terminate the study 
early.  
Minor edits that do not substantively alter the content of the document have 
been made for consistency and clarity where applicable and are not 
individually listed in this version history. 
Specifically:
Section 1.3: Clarified that the randomisation codes will be computer-
generated by Parexel and not AstraZeneca R&D
Section List of Abbreviations, 2.2, 3.4.1, 3.4.7, 4.2.1, 4.2.4, 4.2.5, 4.2.5.2, 
4.2.9.1 Appendix E: Added COVID-19
Section 3.1.4.1: Clarified EoS with the study having stopped.
Section 4.2.4: Deleted + 7 days for medications so that concomitant definition 
is different
Section 4.2.6.2: Added clarification on Wilcoxon rank sum test
Section 4.2.6.4: Added age subgroups for overall adverse events (AEs) 
summary and AEs by system organ class (SOC)/preferred term (PT)
Section 4.2.5.2: Changed compliance to be derived relative to actual exposure
days (excluding missed exposure days due to study treatment interruptions)
Section 4.2.8.3, 4.2.8.5, 4.2.10.1: Added clarification on durations (days) for 
painful crises, acute chest syndrome and hospitalisations for efficacy analysis
Appendix C,D and E: Revised imputations in appendices due to BDR1
PPD
PPD


Statistical Analysis Plan 
Study Code D5136C00009
Edition Number V2.0
Date 17 March 2020
CONFIDENTIAL AND PROPRIETARY
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16 March 
2020
Section 2.1 Table 1 Added in per protocol analysis set.  Changed “major 
protocol deviations” to “important protocol deviations”.
Section 2.1 Table 2 Updated table to include SCD-related red blood cell 
transfusion endpoint.  Footnotes added to include sensitivity analysis for 
VOC.  Added remaining secondary endpoints.  Deleted reference to PK 
parameters as this is not applicable.  Changed “major” to “important” protocol 
deviations.
Section 3.2 Added clarification for any patient who does not experience a 
VOC event.  Count of events will be assumed to be 0.
Section 3.3 Definition of on-treatment and off-treatment red blood cell 
transfusions added in.
Section 3.4 Aligned Hy’s Law with CSP, version 2.0, dated 29 August 2018.
Section 4.2 Correction to number of years since SCD diagnosis to clarify this 
is from date of randomisation (Visit 2) and not date of birth.  Updated “extent 
of disease” to “disease history”.  Added in category of < 1 VOC event 
experienced.
Section 4.2 Treatment exposure and compliance revised to include total/actual 
treatment exposure (days), missed exposure days, total exposure years (across 
patients), treatment compliance (%) and weight (kg) versus dose level 
administration disagreement by individual dose level (15 mg/30 mg/45 mg 
[per tablet count]) and overall dose level.
Section 4.2 Added in Wilcoxon rank sum test by subgroup.  Added in 
category ≤ 1 VOC event in the last 12 months.  Additional sensitivity analysis 
added including analysis based on PP analysis set and analysis based on 
baseline hydroxyurea use.  Tipping point analysis added in.
Section 4.2.8.6 Correction “worst evaluation” to “baseline to last on-treatment 
observation” for ECG summary.
Section 4.2.9.2 Reference to PK parameter analysis is not within the scope of 
this SAP and has been deleted.
Section 8 New appendices added to capture race mapping, partial or missing 
concomitant medication date imputations, missing or partial date of SCD 
diagnosis imputation and to detail sensitivity analyses of the primary efficacy 
endpoint.


Statistical Analysis Plan 
Study Code D5136C00009
Edition Number V2.0
Date 17 March 2020
CONFIDENTIAL AND PROPRIETARY
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1
STUDY DETAILS
1.1
Study Objectives
This statistical analysis plan (SAP) contains a more detailed description of the analyses 
described in the clinical study protocol (CSP), version 3.0 dated 20 April 2020.  The primary, 
secondary, safety, and exploratory objectives (apart from the population pharmacokinetics 
[PK] model) are within the scope of this SAP.  The population PK model will not be reported 
in the main clinical study report (CSR).
1.1.1
Primary Objective
Primary Objective
Outcome Measure
To compare the effect of ticagrelor vs 
placebo for the reduction of vaso-occlusive 
crises (VOCs), which is the composite of 
painful crisis and/or acute chest syndrome 
(ACS), in paediatric patients with sickle cell 
disease (SCD)
Number of VOCs
Primary endpoint as assessed throughout the treatment period which is defined from randomisation (Visit 2) to 
the end of study (EOS) visit or date of premature study discontinuation (refer to Sections 3.1.4 and 3.2.1 for 
further details).
1.1.2
Secondary Objectives
Secondary Objectives
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


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Study Code D5136C00009
Edition Number V2.0
Date 17 March 2020
CONFIDENTIAL AND PROPRIETARY
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Secondary Objectives
Outcome Measure
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 CSP Appendix I
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 recorded daily during VOC
-
For patients ≤ 4 years of age, observer-reported 
using the Face, Legs, Activity, Cry, 
Consolability Scale (FLACC)
-
For patients ≥5 years 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
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 3.3.4.
Secondary endpoints as assessed throughout the treatment period which is defined from randomisation (Visit 2) 
to the end of study (EOS) visit or date of premature study discontinuation (refer to Sections 3.1.4 and 3.1.4.1 for 
further details).
1.1.3
Safety Objectives
Safety Objective
Outcome Measure
To assess long-term safety and tolerability of 
therapy with ticagrelor vs placebo
Adverse events (AEs)/Serious adverse events 
(SAEs), including bleeding, vital signs and 
laboratory safety variables
1.1.4
Exploratory Objectives
Exploratory Objectives
Outcome Measure
To compare the effect of ticagrelor vs 
placebo for the reduction of duration of ACS
Duration of ACS
To assess the PK of ticagrelor and AR-
C124910XX in paediatric patients with SCD 
using a population PK modela
Population PK parameters such as oral clearance 
(CL/F) and ticagrelor exposure (AUC)a,b
Observed plasma concentrations of ticagrelor and 
the active metabolite AR-C124910XX
To assess the effect of ticagrelor on platelet 
aggregation
Platelet Reactivity Index (PRI) measured by 
vasodilator-stimulated phosphoprotein (VASP) 
assay
a Not within the planned scope of this SAP.
b CL/F Apparent total clearance of the drug from plasma after oral administration.  AUC Area under the plasma 
concentration-time curve.


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Study Code D5136C00009
Edition Number V2.0
Date 17 March 2020
CONFIDENTIAL AND PROPRIETARY
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1.2
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 vaso-occlusive crisis (VOC) events in paediatric patients with sickle cell 
disease (SCD).  Patients will be monitored for occurrence of VOC events and other acute SCD 
complications.
Study participants should receive standard of care for SCD. In the treatment period, 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 is children aged ≥ 2 years to < 18 years 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 two VOC events in the past 12 months prior to 
screening (Visit 1) and who fulfil the eligibility criteria will be enrolled in this study.  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.  
A schematic representation of the study design is shown in Figure 1.


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Figure 1
Study Design
bd Twice daily.  d Day.  EOS End of Study.  mo Month.  R Randomisation.  wk Week.
a
Patients randomised to ticagrelor will receive doses based on weight-band (at randomisation [Visit 2]): ≥12 kg to ≤ 24 kg=15 mg, > 24 kg to ≤ 48 kg=30mg, > 48 kg=45 mg.  
b
EOS = Patients will be followed to common study end date defined as 12 months after the last patient is randomised, or up to 24 months.  
c
See CSP Table 2 for assessments during site visits (in-clinic) and CSP Table 3 for telephone visits that will occur monthly after Week 4 between site visits (in-clinic).  
d
Interval must not be more than 100 days to ensure tablet supply for all days.  
NB.  Only in-clinic visits are shown.


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1.3
Number of Patients
The sample size was derived under the assumptions that the number of VOCs has a negative 
binomial distribution with shape parameter 0.8 and that the mean number of crises per year is 
2.0 in the placebo group with reduction of 50% in the ticagrelor group.  Considering that 
patients will be randomised in a 1:1 ratio, with minimum follow-up of 12 months and average 
follow-up of 18 months, 154 patients will 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 months, 200 patients will provide 90% power to detect a 
reduction of 50% in the ticagrelor group.
The randomisation codes will be computer-generated by Parexel Informatics and loaded into 
the Interactive Voice/Web Response System (IxRS) database.  Randomisation codes will be 
generated in blocks to ensure approximate balance (1:1) between the two randomised 
treatment groups (ticagrelor or placebo twice daily [bd]).  Stratification for baseline 
hydroxyurea use (Yes/No) by country will be applied.
2
ANALYSIS SETS
2.1
Definition of Analysis Sets
Details of the analysis sets are presented in Table 1 and
Table 2.  Criteria defining the analysis sets, as detailed below, will be expanded in a separate 
study-specific protocol deviations and reasons for exclusion specifications plan.
Table 1
Analysis Sets
Analysis Set
Definition
All patients 
All patients who provide written informed consent/assent (as relevant) 
prior to performing any specific study-related procedures.
All patients randomised/Full 
analysis set (FAS)
All randomised patients, regardless of study treatment received, will 
be included in the full analysis set.
Patients will be analysed according to their randomised study 
treatment regardless of the study treatment they actually received.  


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Analysis Set
Definition
Safety analysis set
All randomised patients who receive at least one dose of randomised 
study treatment, ticagrelor or placebo, and for whom any post-dose 
data are available, will be included in the safety analysis set.
Erroneously treated patients (e.g., those randomised to study treatment 
A but given study treatment B) will be accounted for in the actual 
study treatment received, where actual study treatment received is 
defined as:
Ticagrelor if a patient receives at least one dose of ticagrelor at any 
time during the treatment period,
Placebo, otherwise.
Per protocol (PP) analysis set 
All randomised patients considered valid for safety, who comply with 
study course requirements per CSP and who, in addition, have no 
important protocol deviations/other factors impacting the efficacy 
outcome or treatment of the patient will be included in the PP analysis 
set.
Patients will be analysed and presented by planned/actual study 
treatment.  Patients with any study treatment deviations will be 
excluded from the PP analysis set such that for patients included in the 
analysis set, their randomised study treatment assignment = actual 
study treatment received.  Refer to latest version of the study-specific 
protocol deviations and reasons for exclusion specification plan for 
further details.  
Pharmacokinetics (PK) 
analysis set
All randomised patients who receive at least one dose of ticagrelor and 
provide at least one post-dose analysable plasma sample for PK 
analysis will be included in the PK analysis set.
Patients with important 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 analysis may be 
excluded from the PK analysis set.  
Pharmacodynamics (PD) 
analysis set
All patients who receive at least one dose of randomised study 
treatment, ticagrelor or placebo, and who provide at least baseline and 
one post-baseline (pre-dose and/or post-dose) analysable sample will 
be included in the PD analysis.
Patients with important protocol deviations including changes to the 
procedures that may impact the quality of the data, or any 
circumstances that can alter the PD evaluation may be excluded from 
the PD analysis set.
Table 2
Summary of Outcome Variables and Analysis Sets
Variable
Analysis Set
Baseline data
Disposition
All patients


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Variable
Analysis Set
Important protocol deviations
Full analysis set
Analysis sets
All patients randomised
Demography and baseline characteristics, medical 
history, disease characteristics, etc.
Full analysis set
Efficacy data
Vaso-occlusive crises (VOCs)a
Full analysis set
Painful crises
Full analysis set
Acute chest syndromes (ACSs)
Full analysis set
Acute sickle cell disease (SCD) complications
Full analysis set
Health-related quality of life (HRQL)
Full analysis set
Absence from school/work due to SCD
Full analysis set
Pain intensity during VOCs
Full analysis set
Analgesics use during VOCs
Full analysis set
Duration of painful crises
Full analysis set
Duration of ACS
Full analysis set
VOCs requiring hospitalisation or emergency 
department visits
Full analysis set
Days hospitalised for VOC
Full analysis set
Days hospitalised for acute SCD complications
Full analysis set
Swallowability and palatability
Safety analysis set
SCD-related red blood cell transfusions
Full analysis set
Safety data
Adverse eventsb
Safety analysis set
Bleeding events
Safety analysis set
Concomitant medications, procedures, and 
therapies
Safety analysis set
Laboratory measurements
Safety analysis set
Physical examinations
Safety analysis set
Electrocardiograms (ECGs)
Safety analysis set
Vital signs
Safety analysis set
Overdoses
Safety analysis set
Exposure
Safety analysis set
Pharmacokinetics data


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Variable
Analysis Set
Plasma ticagrelor concentration 
PK analysis set
(Listings will be based on Safety analysis set)
Plasma active metabolite (AR-C124910XX) 
concentration
PK analysis set
(Listings will be based on Safety analysis set)
Pharmacodynamics data
Plasma concentration of P2Y12 reaction units (PRI 
[%]) measured by vasodilator-stimulated 
phosphoprotein (VASP) assay
PD analysis set
(Listings will be based on Safety analysis set)
a Refer to Section 4.2.6.3 for information on the sensitivity analyses to be performed.
b Adverse events include any deaths.
2.2
Deviations
The study team and study physician/study clinical lead will review protocol deviations as 
recorded during the conduct of the study to assess whether these deviations are considered to 
impact the completeness, accuracy, and/or reliability of the study data or to significantly affect 
a patient's rights, safety, or wellbeing thus being deemed important.  At a minimum, important 
protocol deviations may include:

Patients who entered the study even though they did not fulfil the eligibility criteria.

Patients who developed study treatment administration discontinuation criteria but 
continued with study treatment administration.  

Patients who received the wrong study treatment or incorrect dose.

Patients who received a disallowed concomitant medication.

Patients with other important protocol deviations determined in part by study design, the 
critical procedures, study data, patient protections described in the protocol, and the 
planned analyses of the study data, including those protocol deviations related to
coronavirus disease 2019 (COVID-19)
This list is not intended to be exhaustive.  Other factors/protocol deviations may be identified 
at any time and through various sources by the study team.  Based on the latest version of the 
study-specific protocol deviations management plan, identified deviations, as included in the 
cumulative clinical trial management system (CTMS) report, will be reviewed by the study 
team and study physician/study clinical lead monthly and will be considered in the final 
evaluation of patient evaluability for inclusion in the relevant analysis sets.  Details will be 
provided in a separate study-specific protocol deviations and reasons for exclusion 
specifications plan.
Prior to database lock and subsequent routine study unblinding, decisions on patient 
evaluability, assignment to the various analysis sets (with the exception of the PK analysis set 
finalised after routine study unblinding only) and identified important protocol deviations for 


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presentation purposes will be finalised in cross-functional collaboration between AstraZeneca 
and IQVIA.
3
PRIMARY AND SECONDARY VARIABLES
3.1
General Principles
3.1.1
Missing Data
In general, and unless specifically detailed in subsequent sections, variables will be analysed 
and/or summarised using available data only.  Missing data will not be imputed.  
Sensitivity analysis of the primary outcome to account for missing data will be performed.  
The data handling rules for these sensitivity analyses can be found in Appendix E Accounting 
for Missing Data.  
For the handling of missing/partial start and stop dates of medications and therapies, including 
blood product transfusions, refer to Appendix C Missing/Partial Start and Stop Dates for 
Medications/Transfusions.  
Similarly, for the handling of missing/partial date of birth, SCD diagnosis dates and for prior 
VOC events start and stop dates as captured on the VOC electronic case report form (eCRF), 
refer to Appendix D Missing/Partial Dates for Date of Birth, Diagnosis of Sickle Cell Disease, 
and Prior VOCs, and VOCs During the Study.  
3.1.2
Baseline
Baseline is the last assessment collected (scheduled or unscheduled) prior to the first dose of 
study treatment, or last assessment collected prior to or at randomisation (Visit 2), for patients 
who are randomised but do not receive any study treatment.  For in-clinic assessments with an 
assessment date equal to the first dose of study treatment, the assessment will be assumed to 
be pre-dose since all assessments are to be done prior to dispensing study treatment according 
to the protocol.  For adverse events (AEs) and concomitant medications with start date equal 
to the first dose of study treatment, the event will be considered post-baseline.  
3.1.3
Change and Percentage Change from Baseline
Change from baseline will be calculated as the post-baseline value minus the value at 
baseline:

Change from baseline (unit) = (post-baseline value – baseline value)
Percentage change from baseline will be calculated as follows when appropriate:

Percentage change from baseline (%) = (post-baseline value – baseline value)/baseline 
value × 100


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If either the post-baseline value or the baseline value is missing, then both change from
baseline and percentage change from baseline value will be set to missing and no imputation 
of missing values will be done.  If the baseline value is zero, the percentage change will be set 
to missing.
3.1.4
Treatment Period
The double-blind randomised treatment period comprises of regular scheduled in-clinic visits 
as well as regularly scheduled telephone visits.  The treatment period starts at randomisation 
(Visit 2) through the end of study (EOS) visit regardless of whether the patient prematurely 
discontinues study treatment.  Refer to Section 3.1.4.1 for details on EOS visit.  For patients 
who prematurely discontinue from study participation within this period, the double-blind 
randomised treatment period is defined through to the last available visit/assessment date or 
date of premature study discontinuation, whichever is latest.
3.1.4.1
End of Study Visit
Due to premature termination of the study by the sponsor, AstraZeneca, the end of study
(EOS) visit is defined by a common study end date (CSED) corresponding to the date of 
communication to all investigators to immediately discontinue study treatment administration 
for all patients still ongoing on study treatment.
3.1.5
Safety Follow-up Period
The safety follow-up period follows the treatment period with the final visit, per schedule of 
assessments, up to a maximum of 19 days after the EOS visit.
3.1.6
Reference Dates (Relative Study Day)
Per the aforementioned periods, study day will be calculated relative to the reference date and 
will be used to show start/stop day of assessments and events in patient data listings.
Reference date: Defined as date of randomisation (Visit 2).  

If the date of the assessment/event is on or after the reference date, then:
Relative study day = (date of event – reference date) + 1 

If the date of the assessment/event is prior to the reference date, then: 
Relative study day = (date of event – reference date)
Subsequently, randomisation as disposition event occurs on relative study Day 1 and Day 0 is 
not defined.
In the situation where the assessment/event date is partial or missing, relative study day and 
corresponding durations will appear partial or missing in the patient data listings.


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3.1.7
On- and Off-treatment Periods
For safety and limited efficacy analyses, two additional periods are defined for analysis 
purposes:
3.1.7.1
On-treatment Period
The on-treatment period is defined as the period from first dose of study treatment up to and 
including last dose of study treatment + 7 days.  
3.1.7.2
Off-treatment Period
The off-treatment period follows the end of the on-treatment period, 1 day after the “last dose 
of study treatment + 7 days” as defined in Section 3.1.7.1.  
3.1.8
Retests and Unscheduled Assessments
By-visit summaries will be presented by scheduled eCRF visit (number and name) and no 
analysis visit windowing will be applied.  Unscheduled assessments will only be listed and 
will not contribute to these by-visit summaries.  Results from unscheduled laboratory, vital 
signs and ECG assessments will, however, be included in the identification of maximum 
and/or minimum values as well as in the identification of any treatment-emergent 
abnormalities or changes.
3.2
Primary Efficacy Variable
3.2.1
Vaso-occlusive Crises (VOCs)
A VOC event occurring during the study (following randomisation at Visit 2) and, as judged 
by the investigator to fulfil the definition of the primary endpoint event, should be recorded by 
the investigator both as a primary endpoint event on the VOC1 eCRF and as an adverse event 
(AE) on the AE eCRF.  
The primary efficacy variable is the number of VOC events during the treatment period.  The 
number of VOC events is defined as the count of VOC events experienced by a patient over 
the defined treatment period (refer to Section 3.1.4), as assessed by the investigator and
collected on the VOC1 eCRF.  Any VOC event identified outside the defined treatment period 
will not be included in the primary analysis.
A VOC is the composite of a painful crisis and/or an acute chest syndrome (ACS) event.  
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 healthcare provider in a medical setting (such as a hospital, 
clinic or emergency room visit) or at home.


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
ACS is an acute illness characterised by fever and/or respiratory symptoms, accompanied 
by a new pulmonary infiltrate on a chest X-ray.
A VOC event is identified as follows:

Within each of the two separate components: Event with an onset date ≤ 7 days of the 
previous event onset date will not be counted as a new event.  It will be composed of the 
start date of the first occurrence of the component in the event to the stop date of the last 
occurrence of the component in the event.
For example: Patient 1: Counted as 2 events not 3 individual events
PAINFUL CRISIS
2019-07-24 2019-07-28
PAINFUL CRISIS
2019-10-22 2019-10-23
PAINFUL CRISIS
2019-10-28 2019-10-30

Across the two separate components: Event with an onset date ≤ 7 days of the previous 
event onset date will not be counted as a new event.  It will be composed of the start date 
of the first component in the event to the stop date of the last component in the event.
For example: Patient 2: Counted as 4 events not 5 individual events
ACUTE CHEST SYNDROME
2019-07-17 2019-07-23
PAINFUL CRISIS
2019-07-17 2019-07-23
PAINFUL CRISIS
2019-10-04 2019-10-04
PAINFUL CRISIS
2019-10-21 2019-11-05
PAINFUL CRISIS
2019-12-12 2019-12-12
3.3
Secondary Efficacy Variables
The secondary efficacy variables are: 

Number of painful crises

Duration of painful crises 


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
Number of ACS events 

Number of VOC events requiring hospitalisation or emergency department visits

Number of days hospitalised for VOC events 

Number of acute SCD complications 

Number of days hospitalised for acute SCD complications 

Number of sickle cell-related red blood cell (RBC) transfusions 

PedsQL SCD Module and PedsQL Multidimensional Fatigue Scale Scale: Total score and 
by dimension

Proportion of days absent from school or work due to SCD 

Intensity of worst daily VOC-related pain (during VOC events)

Analgesics administered for VOC events (opioids/non-opioids)

Swallowability and palatability
3.3.1
Painful Crises
Painful crisis is one of the two components of VOC events.  For the definition of painful crisis 
and identification of number of painful crises within the treatment period please refer to 
Section 3.2.1.
In addition to number of painful crises, the total duration (days) of painful crises will be 
derived as follows:
Total duration (days): Defined as the sum of the duration (days) (taking into account 
overlapping painful crisis days + 7-day onset rule as described below) of painful crises 
experienced by a patient over the defined treatment period, where:

Duration of event (days) = (stop date of event – start date of event) + 1 
Total duration (days) will be calculated as the sum of the duration (days) of each event. If 
two or more events have overlapping durations, the overlapping days will only be counted 
once.  Events with an onset date ≤7 days of the previous event onset date will not be 
counted as a new event (7-day onset rule). (refer to Section 3.2.1).  
For example: Patient 1: 2 events with total duration (taking into account overlapping days 
= 0 + 7-day onset rule) of 14 days: Derived as the sum = 5 + 2 + 3 + 4 = 14
1. PAINFUL 
CRISIS
2019-07-24
2019-07-28
5 days
2. PAINFUL 
CRISIS
2019-10-22
2019-10-23
2 days


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3. PAINFUL 
CRISIS
2019-10-28
2019-10-30
3 + 4 intermission days
For example: Patient 2: 2 events with total duration (taking into account overlapping days 
= 1 + 7-day onset rule) of 16 days: Derived as the sum = (9 + 1 + 3 + 4) – 1 (overlapping 
day) = 16
1. PAINFUL 
CRISIS
2019-10-15
2019-10-23
9 days
2. PAINFUL 
CRISIS
2019-10-23
2019-10-23
1 day (overlaps with previous 
individual event so does not 
count toward total duration)
3. PAINFUL 
CRISIS
2019-10-28
2019-10-30
3 days + 4 intermission days
For summary purposes, patients who do not experience any painful crisis during the defined 
treatment period will have their duration of painful crisis set to 0 days.
3.3.2
Acute Chest Syndromes 
Acute chest syndrome is one of the two components of VOC events.  For the definition of 
ACS and identification of number of ACS events within the treatment period refer to 
Section 3.2.  The total duration (days) of ACS events, is one the exploratory objectives of the 
present study, and will be calculated using the same rules as painful crises detailed in Section 
3.3.1.  Similarly, for summary purposes, patients who do not experience any ACS events 
during the treatment period will have their duration of ACS set to 0 days.
3.3.3
VOC Events Requiring Hospitalisation or Emergency Department 
Visits
For the definition of VOC events and identification of number of VOC events within the 
treatment period please refer to Section 3.2.1.
The number of VOC events requiring hospitalisation or emergency department visits is 
defined as the count of VOC events, experienced by a patient over the treatment period, for 
which the primary setting for VOC treatment is in-patient hospitalisation or emergency 
department as captured on the VOC1 eCRF.  
In addition to number of VOC events requiring hospitalisation or emergency department 
visits, the total duration (days) hospitalised for all individual VOC events experienced by a 
patient during the treatment period will be derived as follows:


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Total duration (days): Defined as the sum of the duration (days) of all individual 
hospitalisations (taking into account potential overlapping hospitalisation days of VOC 
components) during VOC events experienced by a patient over the treatment period for which 
the primary setting for VOC treatment is in-patient hospitalisation:

Duration (days) = (individual hospital discharge date per VOC event – individual hospital 
admission date per VOC event) + 1 
Where:
Hospital admission and discharge dates are captured on the AE eCRF.
For summary purposes, patients who do not experience any VOC event and patients who do 
not experience any VOC event requiring hospitalisation will have their number of days 
hospitalised for VOC events set to 0 days.
3.3.4
Acute Sickle Cell Disease Complications
Acute SCD complications are defined as any one or more of the following individual 
complications: Transient ischaemic attack (TIA)/ischaemic stroke, hepatic sequestration, 
splenic sequestration, priapism and dactylitis.  Data, defining acute SCD complications, are 
collected on both the acute SCD complications (ASCD) eCRF and AE eCRF.
The number of acute SCD complications is defined as the count of all individual acute SCD 
complications experienced by a patient over the treatment period as collected on the ASCD 
eCRF.
In addition, the total duration (days) hospitalised for acute SCD complications will be derived 
as follows:
Total duration (days): Defined as the sum of the duration (days) of all individual 
hospitalisations (taking into account potential overlapping hospitalisation days) due to acute 
SCD complications experienced by a patient over the treatment period, for which 
hospitalisation is reported: 

Duration (days) = (individual hospital discharge date – individual hospital admission 
date) + 1 
Where:
Hospital admission and discharge dates are captured on the ASCD eCRF.  
Patients who do not experience any acute SCD complications, as well as patients who do not 
experience any acute SCD complications requiring hospitalisation will have their number of 
days hospitalised for acute SCD complications set to 0 days.  


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The individual events comprising acute SCD complications will be assessed as exploratory 
endpoints (TIA/ischaemic stroke, hepatic sequestration, splenic sequestration, priapism, and 
dactylitis) if reported by at least 10 patients in total across the two treatment groups.
3.3.5
Sickle Cell-related Red Blood Cell Transfusions
Information about blood product transfusions during the study is captured on the TRANSF 
eCRF. ll AEs resulting in the need for red blood cell transfusions will be done prior to 
database lock to determine if the transfusion is sickle cell related or not.  The outcome of the 
medical review will be used to identify those sickle cell related red blood cell transfusions to 
be included in the subsequent efficacy analysis.
3.3.6
Health-related Quality of Life (HRQL) and Fatigue
The health-related quality of life (HRQL) will be assessed using the PedsQL SCD Module and
PedsQL Multidimensional Fatigue Scale.
3.3.6.1
PedsQL SCD Module 
The PedsQL SCD Module instrument has been developed (using a 5-point Likert scale) in 
age-specific versions and will be reported by age-specific groups accordingly (Panepinto et al 
2013).
In the present study the child self-report forms for ages ≥5 years to <8 years, ≥8 years to <13 
years, and ≥13years to ≤18 years and the caregiver proxy-report form specific for ≥2 years to 
<5 years will be used.  A child’s age at randomisation (Visit 2) defines which form should be 
completed, and this version remains the same throughout the duration of the study, regardless 
of whether the child changes age group during this period.  For summary purposes, if the 
wrong version of the age-specific questionnaire is completed based on the patient’s age at 
randomisation (Visit 2), the collected data will not be included in subsequent analyses at the 
given timepoint.
The PedsQL SCD Module consists of:

General version (child + adolescent): 43 items

Toddler version: 42 items

Young child version: 40 items
The PedsQL SCD Module measures problems in the following categories across 9 sub-scales 
with an overall total score derived:

Pain: 3 sub-scales:

Pain and hurt

Pain impact


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
Pain management/control

Worry: 2 sub-scales:

Worry I

Worry II

Emotions: 1 sub-scale

Treatment: 1 sub-scale

Communication: 2 sub-scales:

Communication I

Communication II

Total score
PedsQL SCD Module items are reverse-scored and linearly transformed to a 0 to100 scale 
(0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0) so that higher scores indicate better quality of life.  
Sub-scale scores are computed as the sum of items’ transformed scores divided by the number 
of items answered included in each sub-scale, this accounts for missing data.  However, if 
more than 50% of the items in each sub-scale are missing (ie,  >#items/2 – rounded down to 
the nearest integer) the sub-scale score is not computed.  
To create the PedsQL SCD Module total score (43/42/40 items – depending on version 
completed) the arithmetic mean of the transformed scores is computed as the sum of the 
items’ transformed scores divided by the number of items answered.  
Per the aforementioned, 50% missing items for the PedsQL SCD Module total score would 
then be:

General version (child + adolescent): 43 items: >21 items

Toddler version: 42 items: >21 items

Young child version: 40 items: >20 items    
3.3.6.2
Multidimensional Fatigue Scale
The PedsQL Multidimensional Fatigue Scale instrument has been developed (using a 5-point 
Likert scale) in age-specific versions and will be reported by age-specific groups accordingly 
(Panepinto et al 2014).
In the present study the child self-report forms for ages ≥5 years to <8 years, ≥8 years to 
<13 years, and ≥13 years to ≤18 years and the caregiver proxy-report form specific for 
≥2 years to <5 years will be used.  A child’s age at randomisation (Visit 2) defines which form 
should be completed, and this version remains the same throughout the duration of the study, 
regardless of whether the child changes age group during this period.  For summary purposes, 
if the wrong version of the age-specific questionnaire is completed based on the patient’s age 


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at randomisation (Visit 2), the collected data will not be included in subsequent analyses at the 
given timepoint.
The PedsQL Multidimensional Fatigue Scale measures problems in the following categories 
across 3 sub-scales with an overall total score derived:

General (6 items)

Sleep/rest (6 items)

Cognitive fatigue (6 items)

Total score (18 items)
PedsQL Multidimensional Fatigue Scale items are reverse-scored and linearly transformed to 
a 0 to 100 scale (0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0) so that higher scores indicate better 
quality of life.  Sub-scale scores are computed as the sum of items’ transformed scores divided 
by the number of items answered included in each sub-scale, this accounts for missing data.  
However, if more than 50% of the items in each sub-scale are missing (ie,  >3 items in each 
sub-scale) the sub-scale score is not computed.
To create the PedsQL Multidimensional Fatigue Scale total score (18 items), the arithmetic 
mean of the transformed scores is computed as the sum of the items’ transformed scores 
divided by the number of items answered.
3.3.7
Absence from School/Work Due to SCD
For patients attending school/work at randomisation (Visit 2), absence 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 proportion of days absent from school/work due to SCD in the defined treatment period 
will be calculated as follows:

Proportion of absent days = (total number of days reported)/ (total number of 
questionnaires answered × 7)
Where:

Total number of days reported: Sum of days entered as based on the question “How many 
days have you been at home from school/work during the last 7 days because of your 
disease?”.

Total questionnaires answered: Defined as the number of absent days assessments 
completed as determined by a definitive response of “Yes/No” to the question “Have you 
been at home from school/work during the last 7 days because of your disease?” in 
addition to a complete and documented weekly diary assessment date (ddMMMyyyy).


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For summary purposes, patients completing the weekly questionnaires, per the 
aforementioned definition, but who have not been absent from school/work due to SCD will 
have their number of absent days from school/work due to SCD set to 0 days.
For the handling of missing data from eDevice on absence from school/work due to SCD no 
further imputation will be done.
3.3.8
Pain During VOC Events
The Face, Legs, Activity, Cry, Consolability (FLACC) assessment tool is used to assess pain 
in children aged ≥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 is caregiver-reported and in the present study it will be used to assess pain daily 
during the VOC event for those patients <5 years of age as determined at randomisation (Visit 
2).  Each of the 5 behaviours observed are assigned a score of 0, 1 or 2.  The total FLACC 
score ranges between 0 and 10, with 0 representing “no pain” and 10 representing “very much 
pain”.
The Faces Pain Scale-revised (FPS-R) will be administered to assess pain daily during the 
VOC event by those patients aged ≥5 years as determined at randomisation (Visit 2).  The 
FPS-R has been validated and has been judged as a well-established pain assessment tool in 
patients >4 years of age (Hicks et al 2001, Cohen et al 2008).
The FPS-R consists of six faces and scoring ranges between 0 and 10 (with an increase in 
numeric value by 2), where 0 is “no pain” and 10 is “very much pain”.  A body outline 
diagram will also be presented, and the patient/caregiver will be asked to indicate the 
location(s) of the pain.  
These instruments will be assigned based on patients’ age at randomisation (Visit 2), and the 
same version should be used throughout the study to assess intensity of pain, on a daily basis, 
during a VOC event.  For summary purposes, if the wrong version of the questionnaire is 
completed as based on the patient’s age at randomisation (Visit 2) the collected data will not 
be included in subsequent analyses at the given timepoint.
Worst pain ratings will be collected once daily throughout the duration of the VOC event 
using an eDevice.  Intensity of pain during each VOC event over the defined treatment period 
will be based on the average of those available and reported worst daily pain values.  Pain 
intensity will be summarised and presented separately for each instrument for those patients 
reporting VOC events within the defined treatment period.


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For the handling of missing data from eDevice on pain during VOC events no imputation will 
be done.
3.3.9
Type of Analgesics Use During VOC Events
Analgesics use (opioid and non-opioid) during VOC events is captured by the investigator on 
the VOC1 eCRF.  
3.3.10
Swallowability and Palatability Data
Palatability will be assessed by age group.  The Facial Hedonic Scale (FHS) is a well-
established method for assessing paediatric patients’ responses to drug palatability for patients 
as young as 3 years of age (Davies and Tuleu 2008).  The FHS consists of five faces with 
descriptions ranging from “Dislike very much” to “Like very much”.  The way in which the 
study treatment is taken, ie, whether the tablet is whole or dispersed, will be captured.  No 
imputation will be done in case of missing formulation and a missing category will be 
presented, if relevant.
Patients ≥5 years of age at randomisation (Visit 2) will be asked to evaluate palatability using 
the FHS, directly after the patient has received the first dose of double-blind randomised study 
treatment at randomisation (Visit 2) and again at Visit 9 (Month 6).
For patients <5 years of age at randomisation (Visit 2) an observer’s assessment of the 
patient’s behaviour using the study medication palatability assessment (SMPA) eCRF, will be 
performed directly after the patient has received the first dose of double-blind randomised 
study treatment at randomisation (Visit 2) and again at Visit 9 (Month 6).  
Willingness to swallow will be assessed and categorised as follows:

Swallowed without a problem

Some resistance but did swallow

Spit out some/all of the medication

Vomited up the medication.
Response to palatability will be assessed through the SMPA eCRF question “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?”.  This will be 
presented as a binary outcome (ie, where “No” is no negative response and “Yes” is negative 
response).  Further breakdown includes, whether the patient turned his/her head to reject the 
intake of the double-blind randomised study treatment or not, whether the patient twisted 
his/her face or mouth as an expression of displeasure and whether the patient displayed any 
other negative behaviour, including details of this behaviour. As such, negative response to 
palatability will be presented by the following categories:


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
No (no negative response)

Yes (negative response):
o
Turn head to reject intake of study treatment
o
Twist face or mouth in an expression of displeasure
o
Other    
Questionnaire type will be assigned based on patients’ age at randomisation (Visit 2), and the 
same version should be used throughout the study.  For summary purposes, if the wrong 
version of the questionnaire is completed as based on the patient’s age at randomisation 
(Visit 2) the collected data will not be included in subsequent analyses at the given timepoint.
3.4
Safety Variables
The safety variables which address the safety of ticagrelor are AEs including serious adverse 
events (SAEs), deaths, bleeding events, overdose, blood product transfusions, laboratory 
variables, ECG and vital signs.
3.4.1
Adverse Events
Serious adverse events will be collected from signing informed consent/assent, as relevant, 
throughout the treatment period and including the safety follow-up period.  Adverse events 
will be collected from randomisation (Visit 2) throughout the treatment period and including 
the safety follow-up period.  The Medical Dictionary for Regulatory Activities (MedDRA) 
(using the latest MedDRA version) will be used to code the AEs.
Adverse events will be categorised according to their onset date as follows:

Pre-treatment: AEs occurring during screening ie, onset date < date of first dose of study 
treatment.

On-treatment: AEs with onset date ≥ the date of first dose of study treatment and ≤ the 
date of last dose of study treatment + 7 days.

Off-treatment: AEs occurring off-treatment ie, onset date > the date of last dose of study 
treatment + 7 days.
Although AE eCRF data collection mandates complete start/stop dates (or ongoing) for AEs 
collected following randomisation (Visit 2), in the exceptional case of missing/partial dates 
(and, as relevant, no indication of ongoing), no imputation will be done, and the event will be 
assumed to be “on-treatment” (worst-case approach).  In case, for a specific event, severity or 
relationship is missing, no missing imputation will be performed, and a missing category will 
be presented in the relevant tables and listings.
Patients presenting clinical signs and symptoms consistent with COVID-19 infection will be 
managed as defined in Section 6.3.10 of the latest version of the CSP. Given the outcome of 


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the investigator’s management of such patients AE/SAEs will potentially be identified as 
COVID-19 confirmed or suspected and will be presented as such in relevant safety analyses.
3.4.2
Other Significant Adverse Events (OAEs)
Other significant adverse events (OAEs) are events of particular clinical importance as 
determined by an AstraZeneca medically qualified expert in consultation with the Global 
Safety Physician.  Based on these experts’ judgement, AEs of particular clinical importance 
may be considered as OAEs and reported as such in the CSR only.  There will be no pre-
specification of OAEs.
3.4.3
Deaths
Deaths will be recorded as SAEs on the AE eCRF, with date of death, primary and secondary 
cause of death, as well as autopsy performed (Yes/No).
3.4.4
Bleeding Events
Bleeding events will be recorded as AEs on the AE eCRF (where AE category = bleeding 
event).  In addition, the investigator will complete an assessment of the bleeding event on the 
BLEEDPED eCRF including specification of the nature of the event 
(spontaneous/trauma/procedural) and primary location.  
For patients experiencing a bleeding event that fulfils criteria in more than one category, the 
bleed will be assigned, by the investigator, to the most severe category.  The bleeding event 
categories are as follows:

Major bleeding: Defined as any fatal bleeding, clinically overt bleeding associated with a 
decrease in haemoglobin (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.
3.4.5
Overdose
Study treatment overdose at any time during the defined treatment period will be captured on 
the OVERDOSE eCRF and if associated with an AE it will be noted as such.  All cases of 
overdose will be presented in a listing for patients who have had an overdose at any time 
during the study.


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3.4.6
Blood Product Transfusions
Information about blood product transfusions during the study is captured on the TRANSF 
eCRF.
The number of blood product transfusions is defined as the count of all blood product
transfusions received by a patient at any time during the study and will be assigned, based on 
date of transfusion, to the on-treatment and off-treatment periods in accordance with the 
definitions detailed in Sections 3.1.7.1 and 3.1.7.2.
Date of transfusion should always be collected, however in case of partial/missing date, of 
transfusions refer to Appendix C Missing/Partial Start and Stop Dates for 
Medications/Transfusions for imputation rules resulting in a worst-case approach.
In addition, number of units transfused, and type of blood product will be presented for all 
patients in the safety analysis set receiving a blood product transfusion (regardless of reason
for transfusion or blood product type transfused) at any time during the study.
3.4.7
Laboratory Variables
Blood samples for safety assessments (clinical chemistry, haematology, urinalysis and 
coagulation) will be taken as per schedule of assessments (refer to Table 2 of the latest version 
of the CSP).  The list of laboratory variables to be presented in tables, listings and figures are 
included in Table 4 of the latest version of the CSP.  Laboratory tests will be presented using 
the standardised name.
Laboratory assessments will be summarised and presented for all countries combined, in 
standard international (SI) units.  Laboratory test results obtained from Egypt will be 
converted to the same SI units per central laboratory specification prior to summary and 
presentation.  Similarly, due to COVID-19, the introduction of local laboratories necessitates
the standardisation of local laboratory test results to the same SI units per central laboratory 
specification, such that data from central- and local laboratories will be combined for 
summary and presentation in relevant tables.
There will be no imputation for missing values.  However, for values recorded with a leading 
“greater than” or “less than” (>/<) symbol, the reported numeric value will be used for 
analysis and the value with the qualifier will be included in the patient data listings, unless 
otherwise specified (e.g., a value of <0.01 will be analysed as 0.01 and listed as <0.01).  
Change from baseline in haematology and clinical chemistry assessments (scheduled and 
unscheduled) will be derived as specified in Section 3.1.3.  


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Laboratory test results (scheduled and unscheduled) will be compared to the relevant 
laboratory reference range (lower limit of normal [LLN] to upper limit of normal [ULN]), 
specific to the patient’s age (years) at the time of the assessment and gender as relevant, and 
categorised as:

Low: Below lower limit of the laboratory reference range (<LLN)

Normal: Within the lower limit and upper limit of the laboratory reference range, 
inclusive (≥LLN to ≤ULN)

High: Greater than upper limit of the laboratory reference range (>ULN)
All observed values falling outside these reference ranges will be flagged.
Specifically, change from baseline to maximum/minimum values on-treatment, categorised as 
described above per laboratory reference range, will be presented, where maximum and 
minimum laboratory test results will be identified as:

Maximum on-treatment: Highest test result (scheduled or unscheduled value) observed 
within the period from date of first dose of study treatment up to and including date of last 
dose of study treatment + 7 days.

Minimum on-treatment: Lowest test result (scheduled or unscheduled value) observed 
within the period from date of first dose of study treatment up to and including date of last 
dose of study treatment + 7 days.
In addition to the aforementioned assessments, treatment-emergent change from baseline in 
observed values (scheduled and unscheduled) will be identified as compared to the relevant 
laboratory references range, where treatment-emergent is defined as follows:

Treatment-emergent = Regarded as treatment-emergent if the post-baseline assessment
on-treatment is “worse” than baseline (refer to Section 3.1.7.1 for further details).

Increase: In the identification of treatment-emergent high values, change from 
baseline categories “normal” AND “low” will be considered.

Decrease: In the identification of treatment-emergent low values, change from 
baseline categories “normal” AND “high” will be considered.
For example: Patient 1
Alkaline 
Phosphatase
Baseline
Normal
Alkaline 
Phosphatase
Visit 9
Normal


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Alkaline 
Phosphatase
Visit 15
High
Treatment-emergent
high (increase)
3.4.7.1
Liver Function Tests, Potential Hy’s Law and Hy’s Law
For the following liver function tests, the multiple of the upper limit of normal (ULN) 
(reference range) will be calculated for each data point (scheduled and unscheduled): 
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, and 
alkaline phosphatase (ALP):

Multiple = value/ULN
For example: If the ALT value is 72 IU/L and the ULN 36 IU/L, then the multiple is 
72/36 = 2.
Potential Hy’s Law (PHL)
AST or ALT ≥ 3× ULN together with total bilirubin ≥ 2× ULN at any point during the study 
following the start of study treatment irrespective of an increase in ALP.
Hy’s Law (HL)
A Hy's Law case is defined as any patient with elevations in AST or ALT ≥ 3× ULN together 
with total bilirubin level ≥ 2× ULN, where no other reason, other than the study treatment, can 
be found to explain the combination of increases, e.g., 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
To identify cases of PHL it is important to perform a comprehensive review of laboratory data 
for any patient who meets any of the following identification criteria in isolation or in 
combination:

ALT ≥ 3× ULN

AST ≥ 3× ULN

Total bilirubin level ≥ 2× ULN
3.4.8
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 performed as per schedule of assessments (refer to Table 2 of the 
latest version of the CSP) and will be recorded after the patient has been lying down to rest for 
at least 5 minutes.  After the ECG recording, the investigator or designated physician will 
review each of the ECGs and record an overall evaluation (normal, abnormal not clinically 


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significant and abnormal clinically significant).  Reasons for abnormal will be collected as 
part of a free text field.
Patients for whom the ECG assessment was not performed and/or patients with no ECG 
evaluation, as identified by a “not done” category on the ECG eCRF, will not be presented in 
subsequent summaries.
3.4.9
Vital Signs
Vital signs (blood pressure and pulse rate) will be measured after 5 minutes rest as per 
schedule of assessments (refer to Table 2 of the latest version of the CSP).  Weight and height 
assessments will be performed at the visits as shown in Table 2 of the latest version of the 
CSP.  
Change from baseline in vital signs to each post-baseline assessment (scheduled and 
unscheduled) will be calculated as described in Section 3.1.3.  
Vital signs collected at any time during the study (scheduled and unscheduled) will be 
compared to the pre-defined abnormality assessment criteria reported in Table 4 (refer to Vital 
Signs Pre-defined Abnormality Assessment Criteria).  The assessment of pre-defined 
abnormalities for systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse rate 
will be based on the upper/lower limits as relevant given the patient’s age (years) at the time 
of the assessment and categorised as:

Low: Below lower limit of the age-specific abnormality assessment criterion (< LL)

Normal: Within the lower limit and upper limit of the age-specific abnormality 
assessment criterion, limits inclusive (≥ LL to ≤ UL)

High: Greater than upper limit of the age-specific abnormality assessment criterion (> 
UL)
All observed values falling outside these criteria limits will be flagged.
Specifically, change from baseline to maximum/minimum values on-treatment (refer to 
Section 3.1.7.1), categorised as described above per abnormality assessment criteria, will be 
presented, where maximum and minimum vital signs results will be identified as:

Maximum on-treatment: Highest vital signs result (scheduled or unscheduled value) 
observed within the period from date of first dose of double-blind randomised study 
treatment up to and including date of last dose of double-blind randomised study 
treatment + 7 days.

Minimum on-treatment: Lowest vital signs result (scheduled or unscheduled value) 
observed within the period from date of first dose of double-blind randomised study 
treatment up to and including date of last dose of double-blind randomised study 
treatment + 7 days.


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In addition to the aforementioned assessments, treatment-emergent change from baseline in 
observed vital signs values (scheduled and unscheduled) will be identified as compared to the 
relevant abnormality assessment criteria, where treatment-emergent is defined as follows:

Treatment-emergent = Regarded as treatment-emergent if the post-baseline assessment 
on-treatment is “worse” than baseline (refer to Section 3.1.7.1 for further details).

Increase: In the identification of treatment-emergent high values, change from 
baseline categories “normal” AND “low” will be considered.

Decrease: In the identification of treatment-emergent low values, change from 
baseline categories “normal” AND “high” will be considered.
For example: Patient 1
3.4.10
Physical Examination
For physical examination, only information on whether the assessment was performed or not 
is recorded.  Any abnormal findings are reported as either medical history or adverse events.
3.5
Exploratory Variables
3.5.1
Duration of ACS
Refer to Section 3.3.2 for relevant details.
3.5.2
Pharmacokinetic Parameters 
The pharmacokinetic parameters which address the PK properties of ticagrelor and the active 
metabolite (AR-C124910XX) in oral dose administration are the observed plasma 
concentrations and the PK parameters, area under the plasma concentration-time curve (AUC)
and apparent total clearance of the drug from plasma after oral administration (CL/F) for 
ticagrelor and AUC for the active metabolite obtained using population PK analysis approach.
PK samples will be collected at 0 hours (pre-dose) and 2 hours post-dose (no pre-dose sample 
at randomisation [Visit 2]) as per schedule of assessments and in case of changed dose due to 
weight increase (refer to Table 2 of the latest version of the CSP).
SBP
Baseline
Normal
SBP
Visit 9
Normal
SBP
Visit 15
High
Treatment-emergent
high (increase)


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3.5.3
Pharmacodynamic Variables
The pharmacodynamic variable which addresses the PD properties of ticagrelor, as inhibitor
of platelet aggregation, is the Platelet Reactivity Index (PRI [%]) measured by vasodilator-
stimulated phosphoprotein (VASP) assay.
The PD samples will be collected at 0 hours (pre-dose) and 2 hours post-dose as per schedule 
of assessments (refer to Table 2 of the latest version of the CSP).
4
ANALYSIS METHODS
4.1
General Principles
4.1.1
General Methodology
The statistical analyses will be performed by IQVIA under the direction of Biometrics, 
BioPharmaceuticals R&D, AstraZeneca.  The data analyses will be conducted using SAS®
System (SAS Institute Inc., Cary, NC), version 9.2 or higher.  
Continuous variables will be summarised for all countries combined, by treatment group by 
means of descriptive statistics including n (number of patients with available data), arithmetic 
mean, standard deviation (SD), median, minimum value and maximum value.  Quartiles 1 and 
3 may be included for some variables where appropriate.  The mean and median will be 
presented with one more decimal place than the original data.  Standard deviation with two 
more decimal places than the original data.  Minimum and maximum values with the same 
number of decimal places as the raw data.  In case of a single observation (n=1), SD will be 
presented as not calculable (set to NC [Not Calculable]) and in case of no observations (n=0) 
descriptive statistics will be left blank.
For natural log-transformed data, the following descriptive statistics will be presented:

Number of observations (n)

Geometric mean (gMean), calculated as exp[μ], where μ is the mean of the data on a 
natural logarithmic scale

Geometric standard deviation (gSD), calculated as exp[s], where s is the SD of the data on 
a natural logarithmic scale

Geometric coefficient of variance % (gCV%), calculated as 100 √[exp(s2)-1], where s is 
the SD of the data on a natural logarithmic scale

Arithmetic mean (aMean)

SD

Median

Minimum (min)

Maximum (max)


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Categorical variables will be summarised for all countries combined in frequency tables as 
number (n) of patients and percentage (%) of patients in each category by treatment group.  
Unless otherwise stated, percentages will be calculated relative to the total number of patients 
included in the relevant analysis set, by treatment group and overall (if applicable).  
Percentages will be rounded to one decimal place.
In statistical models, patients will be analysed according to the IxRS stratification level of 
baseline hydroxyurea use by country (Yes/No) even if this stratum assignment differs to that 
identified using the CM eCRF.  This is in keeping with the intent to treat (ITT) principle.
The significance level for the primary endpoint will be 2-sided 5%; confidence intervals will 
be 95%.  2-sided p-value < 0.05 will be considered statistically significant.
No multiplicity adjustment will be included as no formal testing on secondary endpoints for 
statistical significance will be carried out.  Statistical testing of secondary efficacy endpoints 
is only for exploratory purposes.
In general, and unless otherwise specified, ticagrelor data will be pooled and analysed 
irrespective of weight-based dose (15 mg/30 mg/45 mg bd).  Therefore, all summaries will be 
presented by treatment group as follows:
Ticagrelor
15/30/45 mg bd
Placebo
Total
Study treatment exposure and compliance, as well as PK and PD data will be analysed 
according to pooled dose as well as separately per weight-band of dose, overall and/or at the 
time of assessment, as relevant.  Summaries may, therefore, be presented by treatment group 
as follows, where relevant:
Ticagrelor
15/30/45 mg bd
Ticagrelor
15 mg bd
Ticagrelor
30 mg bd
Ticagrelor
45 mg bd
Individual data (scheduled and unscheduled) will be presented in patient data listings.  Safety 
data, PK, and PD listings will be sorted by actual study treatment and E-code number.  All 
other patient data listings will be sorted by patient identifier and planned treatment group.


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4.2
Analysis Methods
4.2.1
Patient Disposition, Important Protocol Deviations and Analysis Sets
Patient disposition will be summarised for all patients providing written informed 
consent/assent (as relevant), by treatment group and overall.  The number (n) and percentage 
(%) of patients will be presented for the following categories: 

Enrolled (number of patients only)

Randomised/not randomised + reason 

Received study treatment/did not receive study treatment + reason 

Completed study treatment/did not complete study treatment + reason

Completed study/prematurely discontinued study participation + reason 
Patients prematurely discontinuing study treatment administration and/or study participation
due to COVID-19 related reasons will be presented.
Reasons for not receiving the study treatment, for not completing study treatment, and for 
premature discontinuation of study participation will also be listed.  The relative study day of 
premature discontinuation/withdrawal will also be presented. Patient disposition regards 
study participation, as well as study treatment impacted by COVID-19, will also be presented
in patient data listings.
A flow diagram of patient disposition will be presented.  
Patient enrolment will also be summarised by region, country and centre.  The denominator 
for percentage (%) will be the total number of patients in the full analysis set, by treatment 
group and overall.
Important protocol deviations, including those protocol deviations related to COVID-19, will 
be summarised using the full analysis set (refer to Sections 2.1 and 2.2).  Important protocol 
deviations will be finalised prior to database lock and routine study unblinding.  The number 
(n) and percentage (%) of randomised patients with at least one important protocol deviation 
and within standardised important protocol deviation categories will be presented by treatment 
group and overall.  Patients with important protocol deviations will also be listed.
The number (n) of patients included or excluded from each analysis set will be presented, 
including the reason(s) for exclusion from each analysis set.  Patients can have one or more 
reasons for exclusion and will be counted in each category as relevant.  Patients’ assignment 
to the various analysis sets and reasons for exclusion will be presented in patient data listings.
Patients with identified treatment deviations (where planned study treatment assignment 
differs from actual study treatment received) and patients with unplanned emergency 


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unblinding of their blinded treatment code during the treatment period, will be identified in 
patient data listings. To note, in defining the PP analysis set, patients for whom the blind was 
broken during the double-blind randomised treatment period (emergency unblinding) 
introduce potential for bias in subsequent assessments. Should such patients be identified it
will result in exclusion of the patients’ data, in any analyses based on the PP analysis set,
following the point of emergency unblinding, but will not necessarily lead to exclusion of 
such patients from the relevant analysis set, if otherwise valid.
The onset of the global COVID-19 pandemic potentially impacts a patient’s ability to 
complete the study visits as initially planned per protocol.  As such, the visit impacted by 
pandemic (VISITP) eCRF will be utilised to summarise, at a minimum, the number (n) and 
percentage (%) of patients in the full analysis set, by treatment group and overall:

Number of visits impacted:

Partially completed

Fully completed

Delayed

Not done

Reason for visit impact:

Patient decision

Pandemic-related logistic issue

Other/Specification

Visit contact mode:

Remote-audio

Remote-video

In-clinic

Other/Specification
Patient visits (scheduled and unscheduled), identifying those visits impacted by COVID-19, 
will be presented, in patient data listings.
4.2.2
Demographic and Baseline Characteristics
With reference to the general principles and definitions detailed in Sections 2.1, 3.1 and 4.1.1, 
demographic and baseline characteristics will be summarised using FAS, by treatment group 
and overall.
Demographic summary includes presentation of:

Age (years)at randomisation (Visit 2)


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
Age group at randomisation (Visit 2):

< 12 years

≥ 12 years

Sex

Race

Ethnicity

Country
In addition, summary of patient characteristics includes presentation of:

Baseline height (cm)

Baseline weight (kg)

Baseline body mass index (BMI):

Calculated as the ratio of patient’s baseline weight (kg) to the square of the patient’s 
baseline height (m): BMI (kg/m^2) = (weight [kg])/(height [m^2]) 
Where:
Height is collected in cm and will be converted to meters prior to calculating BMI by 
dividing by 100.
Similarly, summary of additional patient characteristics at baseline includes presentation of:

ECG

Seated pulse (beats/min)

Malaria

Eye examination

Transcranial doppler
Patients’ history of SCD will be characterised by summary of the following as collected on the 
SCDHIS eCRF:

SCD genotype (HbSS/HbSB Thalassaemia)

SCD history of complications

Age (years) at diagnosis of SCD: Calculated as follows: 

Age (years) at diagnosis = (date of diagnosis – date of birth + 1 )/365.25 

Number of years since SCD diagnosis: Calculated as follows:

Number of years since SCD diagnosis = (date of randomisation [Visit 2] - date of 
diagnosis + 1)/365.25
Similarly, patients’ history of VOC events will be characterised by summary of the following 
as collected on the VOC eCRF:


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
Number of VOC events in past 12 months relative to screening (Visit 1) and categorised 
as:

≤ 1 VOC event in the last 12 months relative to screening (Visit 1)

≥ 2 to ≤ 4 events in the last 12 months relative to screening (Visit 1)

> 4 VOC events in the last 12 months relative to screening (Visit 1)

Primary setting for VOC treatment

Duration (days) from start of the last prior VOC event (prior to randomisation [Visit 2]) to 
randomisation (Visit 2): Calculated as:

Duration (days) = (date of randomisation [Visit 2] – start date of last prior VOC 
event) + 1 
For the handling of missing/partial date of birth, date of SCD diagnosis and for prior VOC 
events start and stop dates as captured on the VOC eCRF, refer to Appendix D Missing/Partial 
Dates for Date of Birth, Diagnosis of Sickle Cell Disease, Prior VOCs, and VOCs During the 
Study.
Demographic and baseline characteristics will be listed for all patients, (as defined in Section 
2.1).
4.2.3
Past and Current Medical and Surgical History
Medical/relevant surgical history that occurred prior to screening (Visit 1) regardless of 
whether the condition is ongoing at the time of screening (Visit 1) will be summarised using 
FAS, by treatment group and overall (refer to Section 2.1). Medical/relevant surgical history 
will also be listed for all patients in patient data listings.
All medical/surgical history will be classified according to the latest version of the Medical 
Dictionary for Regulatory Activities (MedDRA).
Past medical history are those medical conditions/diseases which stopped prior to screening 
(Visit 1), while current medical records are those medical conditions/diseases that are still 
present or ongoing at the time of screening (Visit 1).
The number (n) and percentage (%) of FAS patients with any medical/surgical history 
(records) will be tabulated by MedDRA system organ class (SOC) and preferred term (PT).  A 
patient will only be counted once within a particular SOC/PT, even if he/she has multiple 
conditions/diseases/surgeries in the same SOC/PT.
4.2.4
Prior, Concomitant, and Post-discontinuation Medications and 
Therapies
All medications will be coded using the latest AstraZeneca Drug Dictionary at the time of 
database lock and categorised as follows:


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
Prior medication: Defined as those medications that were taken prior to the date of first 
dose of study treatment, regardless of whether medication use is ongoing.

Concomitant medication: Defined as those medications taken at any time on or after the 
day of the first dose of study treatment up to and including the day of the last dose of 
study treatment, regardless of whether medication use is ongoing.  A medication started 
prior to the first dose of study treatment that is ongoing at the time of first dose of study 
treatment will be identified as both prior and concomitant.

Post-discontinuation medication: Defined as those medications started after the last dose 
of study treatment.
The handling of partial or missing medication dates is detailed in Appendix C Missing/Partial 
Start and Stop Dates for Medications/Transfusions.
All medications will be classified as allowed/disallowed following a physician review (prior 
to database lock) of the database and separate tables will be presented by treatment group and 
overall for patients who take allowed/disallowed concomitant medications.
Summary tables will present the number (n) and percentage (%) of patients in the safety 
analysis set, using at least one medication by generic term within anatomical therapeutic 
chemical (ATC) classification.  Patients will be counted once at each level of summarisation 
(ATC classification/generic term).
Prior, concomitant and post-discontinuation medications (allowed/disallowed) will be listed 
for all patients (as defined in Section 2.1).  Medications administered due to COVID-19 
confirmed/suspected AEs/SAEs will be identified utilising the indication variable on the CM 
eCRF, by means of the prefix “COVID-19” and will be listed in a separate patient data listing.
This study will evaluate ticagrelor efficacy and safety when added to standard of care 
treatments in SCD.  Hence, patients are not withheld from any other treatments that may be 
used in SCD (e.g., hydroxyurea) during the study conduct, which is important considering the 
use of a placebo control group.  Use of background standard of care, such as hydroxyurea, will 
be presented as follows:

Number (n) and percentage (%) of patients in the FAS with background standard of care 
(regardless of type), as captured on the CM eCRF, and confirmed as ongoing at 
randomisation (Visit 2), as relevant: This will be based on ATC codes: L01XX, A09AB, 
A05BA, A16AA and B06AX as indicated by the study physician.

Number (n) and percentage (%) of patients in the FAS with baseline hydroxyurea use 
(Yes/No) as assigned by IxRS.

Number (n) and percentage (%) of patients in the FAS with stable hydroxyurea use for 3 
months before enrolment in the study (screening [Visit 1]) and where stop date of 
hydroxyurea use is greater than randomisation (Visit 2)/date of first dose of study 


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treatment or is ongoing, as captured on the CM eCRF.  This will be based on ATC code: 
L01XX.

Number (n) and percentage (%) of patients in the FAS with hydroxyurea use started after 
randomisation (Visit 2)/date of first dose of study treatment and a duration of at least 
6 months.  Duration (months) will be derived as follows:

Duration (months) = (latest stop date of hydroxyurea use - earliest start date of 
hydroxyurea use [AFTER randomisation {Visit 2}]) + 1 (converted to months)
Where: 
In case of ongoing medication use, study completion date or date of premature study 
discontinuation will be used to impute the latest stop date of hydroxyurea use in order 
to derive duration (months) within the context of the study course.
4.2.5
Study Treatment Exposure and Compliance
The following will be summarised by individual dose level (15 mg/30 mg/45 mg [per tablet 
count] bd) and overall dose level, by actual treatment group and overall, using the safety 
analysis set (refer to Section 2.1):

Total study treatment exposure (days)

Actual study treatment exposure (days)

Number of study treatment interruptions, as reported by the investigator on the EX eCRF 
where action taken with study drug is indicated as “drug interrupted”

Main reason for study treatment interruption, as judged by the investigator, will be 
presented differentiating between COVID-19 related reasons and non-COVID-19 
related reasons

Total missed exposure days due to study treatment interruptions, as reported by the 
investigator on the EX eCRF where action taken with study drug is indicated as “drug 
interrupted”

Total missed exposure days due to COVID-19 related study treatment interruptions, 
as reported by the investigator on the EX eCRF where action taken with study drug is 
indicated as “drug interrupted”

Total exposure years (across patients) based on total study treatment exposure (days)

Study treatment compliance (%)

Study treatment compliance (%) category:

< 80 %

≥80 % to ≤120 %

>120 %

Missing


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o
COVID-19 related reason
o
Non-COVID-19 related reason

Weight (kg) versus dose level administration disagreement
Study treatment exposure and compliance will be based on the CSP weight-based 
specifications:

≥12 to ≤24 kg body weight: 15 mg dose level: 1 tablet of ticagrelor 15 mg or 1 tablet of 
placebo to match ticagrelor 15 mg twice daily

> 24 to ≤48 kg body weight: 30 mg dose level: 2 tablets of ticagrelor 15 mg or 2 tablets 
of placebo to match ticagrelor 15 mg twice daily

> 48 kg body weight: 45 mg dose level: 3 tablets of ticagrelor 15 mg or 3 tablets of 
placebo to match ticagrelor 15 mg twice daily
For patients with a weight increase exceeding 12.5% of the upper weight limit of the weight-
band (≥27 kg and ≥54 kg, respectively), the dose will need to be increased according to the 
next weight-band. Decrease in dose level is not allowed and there will be no dose adjustments 
for decreasing weight. 
The double-blind randomised treatment period comprises the following scheduled 
dispense/return visit intervals:

Visit 2 (Week 0 ) to Visit 6 (3 Months)

Visit 6 (3 Months) to Visit 9 (6 Months)

Visit 9 (6 Months) to Visit 12 (9 Months)

Visit 12 (9 Months) to Visit 15 (12 Months)

Visit 15 (12 Months) to Next Scheduled In-clinic Visit/EOSa
a Only for patients completing the 24-month double-blind randomised treatment period or who are still ongoing within 
the double-blind randomised treatment period at the time of the CSED.
Study treatment dispense/return can, however, occur at any unscheduled timepoint within each 
of the scheduled dispense/return visit intervals and may also be impacted by COVID-19 with 
related reasons as captured on the drug accountability pandemic (DAP) eCRF.
Considering the aforementioned specifications, the following data handling conventions will 
therefore apply:
4.2.5.1
Study Treatment Exposure
Total duration of study treatment exposure (days) by dose level and overall dose level 
(includes missed exposure days due to study treatment interruptions):


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
Exposure (days) = (date of last dose of double-blind randomised study treatment – date of 
first dose of double-blind randomised study treatment) + 1 
Where: 
Date of first dose of double-blind randomised study treatment equals:

Variable: Start date of study drug administration: Based on the EX eCRF, earliest 
administration date, at or after randomisation (Visit 2), at a given dose level and for 
each dose level received.

By overall dose level: Overall earliest of the aforementioned first dose of study 
treatment administration dates, over all dose levels received.
Date of last dose of double-blind randomised study treatment equals:

Variable: End date of study drug administration: As captured on the EX eCRF and is 
the latest administration date, on or after randomisation (Visit 2), at a given dose 
level and for each dose level received regardless of temporary study treatment 
administration discontinuation (study treatment interruptions).

By overall dose level: Overall latest of the aforementioned last dose of study 
treatment administration dates, over all dose levels received. Patients may 
prematurely discontinue study treatment administration whilst continuing with 
scheduled assessments in the double-blind randomised treatment period. DOSDISC 
eCRF collects the variable, date subject discontinued IP. This date should equal the 
overall date of last dose of study treatment as captured on the EX eCRF but can be 
used in conjunction with EX data to accurately identify the overall date of last study 
treatment administration over all dose levels received in the double-blind randomised 
treatment period.
Total exposure years (across patients in a given treatment group) is defined as the sum of total 
double-blind randomised study treatment exposure (days) by overall dose level, including 
missed exposure days due to study treatment interruptions, for all patients in a given treatment 
group and is expressed in years as follows:

Total exposure years (across patients) = Sum of (total study treatment exposure [days] by 
overall dose level)/360 
Where:
Year = 360 days. .
Actual study treatment exposure (days) by dose level and overall dose level follows the same 
approach, however excludes all missed exposure days due to study treatment interruptions.
For example, Patient 1: 30 mg dose level:


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Total study treatment exposure (days) = 238 days (from 18 Apr 2019 to 11 Dec 2019)
Missed exposure days = 9 days (from 17 Nov 2019 to 25 Nov 2019) considering only the total 
number of missing exposure days due to study treatment interruptions (action taken with study 
drug on EX eCRF indicated as “drug interrupted”)
Actual study treatment exposure (days) = 238 – 9 = 229 days
Dose
Unit
Formulation Freq
Reason for 
Action
Start Date
End Date
Action 
Taken with 
Study Drug
1 30
mg
TABLET
BID
Adverse 
Event
2019-04-18
2019-11-16 Drug 
Interrupted
2 30
mg
TABLET
BID
Other
2019-11-26
2019-12-11 Dose 
Increased 
due to 
Weight Gain
3 45
mg
TABLET
BID
2019-12-12
ONGOING
4.2.5.2
Study Treatment Compliance
Study treatment compliance (%) by dose level and overall dose level as based on actual study 
treatment exposure (days) (refer to Section 4.2.5.1):

Compliance (%) = (actual tablets taken/expected tablets taken) × 100
Where:

Actual tablets taken equals:
o
Per kit IDs for a given dose level: Difference between total tablets dispensed and 
total tablets returned, regardless of temporary study treatment administration 
discontinuation (study treatment interruptions) and noting that tablets may be 
returned after the end of the dose level administration.
o
By overall dose level: Sum of actual tablets taken over all dose levels received. 
If tablets returned amount is missing for any/all kit IDs dispensed, both dose level and 
overall dose level actual tablets taken will be missing, ie, no imputation assumptions of 
tablets taken will be applied and as such study treatment compliance will be missing.

Expected tablets taken equals:
o
Expected tablets to be taken per last available weight (kg) at the time of study 
treatment administration (planned) is based on actual study treatment exposure 


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(days) excluding missed exposure days due to study treatment interruptions, by 
each dose level received:

15 mg (>12 kg to ≤24 kg body weight): 1× 15 mg tablet bd: 2× actual study 
treatment exposure (days) 

30 mg (>24 kg to ≤48 kg body weight): 2× 15 mg tablets bd: 4× actual study 
treatment exposure (days)

45 mg (>48 kg body weight): 3× 15 mg tablets bd: 6× actual study treatment 
exposure (days)
o
By overall dose level: Sum of expected tablets taken over all dose levels received
In addition, study treatment compliance (%), as derived per the aforementioned, will be 
categorised as follows:

< 80 %

≥80 % to ≤120 %

>120 %

Missing
Number (n) and percentage (%) of patients in the safety analysis set, per compliance category 
will be presented, by actual treatment group and overall.  Percentage will be calculated 
relative to the total number of patients in the safety analysis set, by actual treatment group and 
overall.  If, for at least 10 patients in total across the two treatment groups, compliance (%) 
cannot be calculated, the reason for missing compliance will be presented, if relevant, as:

COVID-19 related reason

Non-COVID-19 related reason
In addition to the aforementioned, weight (kg) versus dose level administration disagreement 
will be determined as follows:
Weight (kg) will be assessed every 6 months per the planned schedule of assessments.  
Weight (kg) (whether scheduled or unscheduled), as available at the start of study treatment 
administration at a given dose level, will be assessed in accordance with the CSP weight-
based specifications and categorised as follows:

Weight-based dose level agreement

Weight-based dose level disagreement
The number (n) and percentage (%) of patients in the safety analysis set with weight-based 
dose level disagreement at any time over the course of the double-blind randomised treatment 
period and over all dose levels received will be presented.  Percentage will be calculated 


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relative to the total number of patients in the safety analysis set, by actual treatment group and 
overall.
Details related to the administration of investigational product during the double-blind 
randomised treatment period will be presented in patient data listings.
4.2.6
Primary Efficacy Variable
4.2.6.1
Number of VOCs
The primary efficacy variable is the number of VOC events during the defined treatment 
period (refer to Section 3.1.4) and the primary analysis is to compare the VOC event rate of 
ticagrelor with placebo based on the intent to treat (ITT) principle.  The primary efficacy 
analysis will be performed using FAS (refer to Section 2.1).  
The null hypothesis is that the VOC event rate on ticagrelor is equal to the VOC event rate on 
placebo.  The alternative hypothesis is that the VOC event rate on ticagrelor is not equal to the 
VOC event rate on the placebo, ie,
H0: Rate ratio (ticagrelor vs placebo) = 1  
Ha: Rate ratio (ticagrelor vs placebo) ≠1
The VOC event rate on ticagrelor will be compared to the VOC event rate on placebo using a 
negative binomial model for the primary analysis.  The response variable in the model will be 
the number of VOC events experienced by a patient during the defined treatment period, 
regardless of premature discontinuation of study treatment.  The model will include covariates 
of treatment group and baseline hydroxyurea use (Yes/No) as covariates.
The logarithm of the patient’s observed follow-up time per defined treatment period expressed 
in years (where a year = 360 days) will be used as an offset term in the model to adjust for 
patients having different follow-up times.
The estimated treatment effect (ie, the rate ratio of ticagrelor versus placebo), the 
corresponding Wald 95% confidence interval (CI) and the p-value for the rate ratio will be 
presented.  In addition, the VOC event rate and the corresponding 95% CI within each 
treatment group will be presented.  The VOC event rate will be computed using the OM 
option in the LSMEANS statement of PROC GENMOD.
An estimated value of the rate ratio < 1 will favour ticagrelor.  The estimated dispersion 
parameter will also be noted.


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4.2.6.2
Testing the Fit of Negative Binomial Distribution
The fit of the negative binomial distribution to the data will be tested by means of the Pearson 
goodness of fit test after estimating the parameters of the distribution and checking whether 
there are no convergence issues with the maximum likelihood estimation of the coefficients.  
The negative binomial model will be tested against the Poisson model in a likelihood ratio test 
to test the robustness of the model.
If the negative binomial distribution is not appropriate, a stratified Wilcoxon rank sum test 
will be used.  As the stratified Wilcoxon rank sum test cannot be adjusted for the patient’s 
follow-up time, the annualised number of VOC events will be used for the analysis rather than 
the number of VOCs as analysed for the primary efficacy.  .  By using annualised number of 
VOC events, it scales it allowing a comparison of VOC rates across patients with varying time 
in the study.  Baseline hydroxyurea use (Yes/No) will be used as a stratification factor.  
Number of annualised VOC events is the count of VOC events experienced by a patient 
over the defined treatment period (refer to Section 3.1.5) as assessed by the investigator 
and collected on the VOC1 eCRF, multiplied by 360 days, and divided by the number of days 
in the defined treatment period.
 	
 
 =
  
( !" #$#"# %! "  $#&$" !$#!"  $#)( ) * 360
A Wilcoxon rank sum test for each subgroup defined in Section 4.2.6.4 will also be presented.  
No stratification factor will be included in this analysis.
Median, median difference and 95% confidence interval for the median difference will be 
estimated using Hodges-Lehmann method.  Summary statistics of the annualised VOC rate 
will also be presented.
4.2.6.3
Sensitivity Analyses
Sensitivity analyses to assess the robustness of the primary analysis results to missing data as 
outlined in Appendix E Accounting for Missing Data, may be conducted utilising the FAS, 
unless otherwise specified, depending on the amount of missing data due to patients who 
prematurely discontinue study treatment and/or study participation.
In addition to the sensitivity analyses outlined in Appendix E Accounting for Missing Data, 
the following analyses will also be performed: 
1
The primary analysis will be repeated including only data from patients whilst being on 
study treatment ie, excluding data once patients discontinue from study treatment. For 
this analysis the patient’s observed follow-up time will correspond to their actual “on-
treatment” period defined as the period from first dose of study treatment (ticagrelor or 


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placebo) up to and including last dose of study treatment + 7 days.  Refer to 
Section 3.1.7.1.
2
The primary analysis will be repeated where the response variable is the number of VOC 
events that occur during the defined treatment period, irrespective of the number of days 
between the onset of events.
3
The analysis will be repeated by replacing the factor for IxRS baseline hydroxyurea use 
(Yes/No) with a more inclusive indicator for hydroxyurea use defined as a combination of 
(a. and/or b.): 
(a) IxRS baseline hydroxyurea use (Yes/No) AND/OR
(b) Hydroxyurea use:
(i)
Start date after randomisation (Visit 2) AND
(ii) Duration of hydroxyurea use of at least 6 months during the study (latest stop 
date of hydroxyurea use record – earliest start date of hydroxyurea use record 
AFTER randomisation [Visit 2] + 1 [converted to months] ≥ 6 months).  
Where: 
In case of ongoing medication use, study completion date, as collected on the 
disposition eCRF, or date of premature study discontinuation will be used to 
impute the latest stop date of hydroxyurea use in order to derive duration 
(months) within the context of the study.
If both these criteria (i) and (ii) are met the value will be “Yes”, otherwise it will be 
“No”.
4
The primary analysis will be repeated using the PP analysis set.
5
The primary analysis will be repeated for the following combination of covariates, if there 
are at least 5 patients within each stratum:
(a) Treatment group, baseline hydroxyurea use (Yes/No), age group at randomisation 
(Visit 2) (≥ 2 years to < 12 years, ≥ 12 years to < 18 years)
(b) Treatment group, baseline hydroxyurea use (Yes/No), prior VOC events in previous 
12 months prior to study enrolment at screening (Visit 1) (≥ 2 to ≤4, > 4), as 
collected on the VOC eCRF
(c) Treatment group, baseline hydroxyurea use (Yes/No), and geographic region
(d) Where geographic region is defined as: 
o
North and South America (USA, Canada, Brazil)
o
Europe (UK, Turkey, Spain, Italy, Greece, Belgium)
o
Africa and Asia (Egypt, Ghana, India, Kenya, Lebanon, South Africa, Tanzania, 
Uganda)


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(e) Treatment group, baseline hydroxyurea use (Yes/No), age group at randomisation
(Visit 2) (≥ 2 years to < 12 years, ≥ 12 years to < 18 years), prior VOC events in 
previous 12 months prior to study enrolment at screening (Visit 1) (≥ 2 to ≤4, > 4), 
as collected on the VOC eCRF, and geographic region 
6
Zero-inflated Poisson and zero-inflated negative binomial models will be run on the same 
data as used for the primary analysis to allow for over dispersion seen in the negative 
binomial and Poisson models.  The models allow for the excessive zero counts in the data.  
The zero-inflated Poisson and negative binomial models split the data into two separate 
distributions where one distribution (either Poisson or negative binomial) that generate 
both zero and non-zero counts, the second distribution is a constant distribution that 
generates only zero counts.  When a zero count is observed, there is some probability, 
called the zero-inflation probability, that the observation came from the always-zero 
distribution; the probability that the zero came from the Poisson/negative binomial 
distribution is 1 minus the zero-inflation probability.  When the underlying count 
distribution is a Poisson distribution, the mixture is called a zero-inflated Poisson (ZIP) 
distribution; when the underlying count distribution is a negative binomial distribution, 
the mixture is called a zero-inflated negative binomial (ZINB) distribution (Hilbe 2007).
4.2.6.4
Subgroup analyses 
To explore the uniformity of the detected overall treatment effect on the primary efficacy 
variable, subgroup analyses and statistical modelling including testing for interaction between 
treatment and covariates will be performed on the full analysis set for the factors below.
If there are issues with model convergence, only descriptive statistics by subgroup will be 
presented.  Descriptive statistics by subgroup will be presented for all cases regardless of the 
model convergence. These analyses are exploratory and the results from these analyses will 
not affect the choice of terms used in the model for the primary analysis.
The following subgroups will be reported:

Age by category: 
-
≥2 years to <12 years at randomisation (Visit 2)
-
≥12 years to <18 years at randomisation (Visit 2)

Number of VOC events within the previous 12 months prior to study enrolment at 
screening (Visit 1): 
-
≥2 to ≤4 
-
>4

Baseline hydroxyurea use: Based on IxRS

Yes

No


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
Sickle cell genotype: HbSS and HbSB0 Thalassaemia

Geographic region:

North and South America (USA, Canada, Brazil)

Europe (UK, Turkey, Spain, Italy, Greece, Belgium)

Africa and Asia (Egypt, Ghana, India, Kenya, Lebanon, South Africa, Tanzania, 
Uganda)

Gender: Male and Female

Race as reported in Appendix B Race Mapping:
-
White 
-
Black or African-American 
-
Asian 
-
Other
If the negative binomial regression model is judged to be appropriate, then for each subgroup 
analysis separately, where sufficient data allows, a negative binomial regression model will be 
fitted including as covariates treatment group, subgroup main effect and the treatment-by-
subgroup interaction. The p-value for the treatment-by-subgroup interaction will be presented.
The logarithm of the patient’s observed follow-up time per defined treatment period expressed 
in years (where a year = 360 days) will be used as an offset term in the model to adjust for 
patients having different follow-up times.
4.2.7
Time to Event Analyses
Pending number of events (as defined below), a time to event analysis may be considered 
utilising Kaplan-Meier methodology.  Kaplan-Meier figures will be presented for the 
following:

Time to first VOC event (days) in the defined treatment period: Based on the earliest start 
date of all VOC events, as collected on the VOC1 eCRF, experienced by a patient during 
the defined treatment period.  Time (days) will be derived as the difference in days from 
randomisation (Visit 2) to the earliest start date of the VOC events. Patients not 
experiencing a VOC event will be censored at the end of their defined treatment period, 
derived as the latest of:  Date of EOS visit, date of last available assessment within the 
defined treatment period or date of premature study discontinuation (regardless of the 
reason for premature study discontinuation)(refer to Section 3.1.4).

Time to discontinuation of study treatment (days) (overall and by study treatment 
related/not study treatment related reason for discontinuation, as defined in Appendix E
Accounting for Missing Data): Patients may prematurely discontinue study treatment 
administration whilst continuing with scheduled assessments.  DOSDISC eCRF collects 
the variable, date subject discontinued IP.  Time (days) will be derived as the difference 
in days from date of first dose of double-blind randomised study treatment to the date of 


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premature study treatment discontinuation.  Patients randomised but not treated will be 
censored at date of randomisation (Visit 2) = Day 1. Patients completing double-blind
randomised study treatment administration will be censored at the date of last dose of 
double-blind randomised study treatment administration.
4.2.8
Secondary Efficacy Variables
In general, and unless otherwise specified, the secondary efficacy analyses will be performed 
using the FAS (refer to Section 2.1) by planned treatment group. Palatability and 
swallowability will be performed using the safety analysis set by actual double-blind 
randomised study treatment received.
4.2.8.1
Number of Painful Crises
Descriptive statistics will be presented for the number of painful crises experienced by a 
patient over the treatment period by planned treatment group using the FAS.  Descriptive 
statistics will also be presented for the number of individual painful crises irrespective of the 
number of days between the onset of painful crises.  
The number of painful crises will be analysed using the negative binomial regression model, 
as described in Section 4.2.6.1 for the primary endpoint.  Similarly, as sensitivity analysis, the 
same negative binomial regression model will be used on the number of individual painful 
crises irrespective of the number of days between the onset of painful crises.
4.2.8.2
Number of ACSs
Descriptive statistics will be presented for the number of ACSs experienced by a patient over 
the defined treatment period by planned treatment group.  Descriptive statistics will also be 
presented for the number of individual ACSs irrespective of the number of days between the 
onset of ACSs.  
If numbers allow, the number of ACSs will be analysed using the negative binomial 
regression model as described in Section 4.2.6.1 for the primary endpoint.  Similarly, as 
sensitivity analysis, the same negative binomial regression model will be used on the number 
of individual ACSs irrespective of the number of days between the onset of ACSs.
4.2.8.3
Duration of Painful Crises
Descriptive statistics will be presented for the total duration (days) (taking into account 
overlapping painful crisis days + 7-day onset rule) of painful crises experienced by a patient 
over the defined treatment period by planned treatment group.  Patients who do not experience 
any painful crisis will have their duration of painful crises set to 0.
If numbers allow, the total duration (days) (taking into account overlapping painful crisis days 
+ 7-day onset rule) of painful crises will be analysed using the negative binomial regression 
model, as described in Section 4.2.6.1.


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4.2.8.4
Number of VOC Events Requiring Hospitalisation or Emergency Department 
Visits
Descriptive statistics will be presented for the number of VOC events requiring hospitalisation 
or emergency department visits experienced by a patient over the treatment period by planned 
treatment group.  
If numbers allow, the number of VOC events requiring hospitalisation or emergency 
department visits will be analysed using the negative binomial regression model, as described 
in Section 4.2.6.1.
4.2.8.5
Number of Days Hospitalised for VOC Events
Descriptive statistics will be presented for the total number of days hospitalised (taking into 
account potential overlapping hospitalisation days of VOC components) for VOC events 
experienced by a patient over the defined treatment period by planned treatment group.  
Patients who do not experience any VOC event as well as patients who do not experience any 
VOC events requiring hospitalisation due to VOC will have their number of days hospitalised 
for VOC set to 0.
If numbers allow, the total number of days hospitalised for VOCs (taking into account 
potential overlapping hospitalisation days of VOC components) will be analysed using the 
negative binomial regression model, as described in Section 4.2.6.1.
4.2.8.6
Number of Acute SCD Complications
Descriptive statistics will be presented for the number of acute SCD complications 
experienced by a patient over the treatment period by planned treatment group.
If numbers allow, the number of acute SCD complications will be analysed using the negative 
binomial regression model, as described in Section 4.2.6.1.
If reported by at least 10 patients in total across the two treatment groups, the individual 
events comprising acute SCD complications will be assessed descriptively as exploratory 
endpoints (TIA/ischaemic stroke, hepatic sequestration, splenic sequestration, priapism, and 
dactylitis).
4.2.8.7
Number of Days Hospitalised for Acute SCD Complications
Descriptive statistics will be presented for the total number of days hospitalised (taking into 
account potential overlapping hospitalisation days) for acute SCD complications experienced 
by a patient over the defined treatment period by planned treatment group.  Patients who do 
not experience any acute SCD complication as well as patients who do not experience any 
acute SCD complications requiring hospitalisation will have their number of days hospitalised 
for SCD complications set to 0.


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If numbers allow, the total number of days hospitalised (taking into account potential 
overlapping hospitalisation days) for acute SCD complications will be analysed using the 
negative binomial regression model as described in Section 4.2.6.1.
4.2.8.8
Number of Sickle Cell-related Red Blood Cell Transfusions
Descriptive statistics, including arithmetic mean, SD, median, min and max, will be presented 
for the number of sickle cell-related red blood cell transfusions received by a patient over the 
defined treatment period by planned treatment group.
If numbers allow, the number of sickle cell-related red blood cell transfusions will be analysed 
using the negative binomial regression model as described in Section 4.2.6.1.
4.2.8.9
Health-related Quality of Life (HRQL) and Fatigue
Descriptive statistics will be presented for patients in FAS, by planned treatment group and 
visit, for the PedsQL SCD Module considering the 9 sub-scales (refer to Section 3.3.6.1 for 
details) and the derived total score as well as the change from baseline in these scores to each 
post-baseline visit, based on scheduled eCRF visit (number and name).
Similarly, for the Multidimensional Fatigue Scale considering the 3 sub-scales (refer Section 
3.3.6.2 for details) and the derived total score as well as the change from baseline in these 
scores to each post-baseline visit, based on scheduled eCRF visit (number and name)..
All descriptive statistics will be presented by age-specific category only. Individual patient 
data will be listed. It should be noted that child self-reported or caregiver-reported cannot be 
ascertained from the data collected and as such is not presented in relevant tables and listings.
4.2.8.10
Days Absent from School/Work Due to SCD
Descriptive statistics will be presented for the proportion of days absent from school/work due 
to SCD by planned treatment group, only for those patients who were going to school or work 
at randomisation (Visit 2).
4.2.8.11
Intensity of Pain During VOC Events and Number of VOC Events by Age 
Group
The number (n) and percentage (%) of patients experiencing at least one individual VOC 
event will be calculated based on FAS and will be presented by age group (<5 years and ≥5 
years) and planned treatment group.  Similarly, the total number of individual VOCs will be 
presented by age group (<5 years and ≥5 years) and planned treatment group. 
Descriptive statistics of the average intensity of pain during VOCs will be presented by age 
group (<5 years by means of FLACC and for patients ≥5 years by means of FPS-R).


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4.2.8.12
Type of Analgesics Used During VOC Events
Analgesics use during VOC events as well as the type of analgesics (opioid/non-opioid) will 
be summarised and presented, by planned treatment group, on both event and patient level:

Number of (individual) VOC events occurring during the defined treatment period

Analgesics use (during individual VOC events)

Type of analgesics:

Opioid

Non-opioid
At event level, only the number of observations (n) in each category will be presented.
At patient level, the percentage (%) of patients reporting at least one VOC event will be 
calculated based on FAS.  Percentage of analgesics use will be calculated based on the total 
number of patients in FAS with at least one VOC event reported in the defined treatment 
period.  Patients with multiple analgesics used during VOC events will be counted only once 
in that category.  Patients who used both types of analgesics (opioid/non-opioid) will be 
counted once in both categories.
4.2.8.13
Swallowability and Palatability Data
Swallowability and palatability data will be summarised taking into consideration the 
administration formulation.  A summary table will be produced showing the number (n) and 
percentage (%) of patients with ease/difficulty of swallow based on the categories defined in 
Section 3.3.10.
In addition, the number (n) and percentage (%) of patients with a negative response to 
palatability will be presented.  Percentage will be based on the total number of patients in the 
safety analysis set, per age group as determined at randomisation (Visit 2), who completed the 
correct age-specific assessment for study treatment palatability per formulation, by actual 
treatment group. Number of patients reporting a negative response will be also presented 
based on the categories defined in Section 3.3.10.
4.2.9
Safety
Safety summaries will be presented using the safety analysis set (refer to Section 2.1), unless 
otherwise specified, by actual study treatment received.  No formal statistical analyses will be 
performed on safety data.
4.2.9.1
Adverse Events
Summary tables will include on-treatment/off-treatment AEs (refer to Section 3.4.1) only, 
unless otherwise specified.  That is, pre-treatment AEs will be included in the patient data 
listings only.  


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Separate overall summary tables will be produced for AEs on-treatment and off-treatment 
showing the number (n) and percentage (%) of patients with at least one AE in each of the 
following AE categories: Any AE, any AE causally related to study treatment, maximum AE 
intensity, any AE with an outcome of death, any SAE and discontinuation of study treatment 
due to AEs.  The overall summary tables will be repeated by age group as follows:

≥2 years to <12 years at randomisation (Visit 2)

≥12 years to <18 years at randomisation (Visit 2)
AEs/SAEs will be summarised by MedDRA SOC and MedDRA PT by actual study treatment 
received and by the same age group as previously defined.  Events will be sorted by 
international order for system organ class (SOC) and alphabetically for PTs within each SOC.  
For each SOC/PT, the number (n) and percentage (%) of patients reporting at least one event 
at each level of summarisation (SOC/PT) will be presented ie, for a patient with multiple 
occurrences of the same AE, the event will only be counted once per PT/SOC.  Patients with 
events in more than one SOC/PT are counted once per individual SOC/PT. 
Most common AEs will be summarised separately by MedDRA PT, where most common is 
defined as a frequency > 5% in either of the two treatment groups and sorted by decreasing 
frequency based on the ticagrelor treatment group. Similarly, for presentation of non-serious 
AEs.  In addition, AEs will be summarised by MedDRA PT and causality/relatedness.  If a 
patient reports multiple occurrences of the same AE, the patient will be summarised only for 
the most related.  Similarly, by MedDRA PT and maximum reported intensity.  If a patient 
reports multiple occurrences of the same AE, the patient will be summarised only for the 
maximum reported intensity.  In case of missing causality/relatedness and/or intensity, a 
missing category will be presented per relevant PT.
The event rate per 100 patient years will be presented by treatment group, where:
Event rate per 100 patient years = (number of patients with AEs/total exposure years) × 100 
(refer to Section 4.2.5). 
Where:
Year = 360 days.
Patient data listings of AEs leading to death, SAEs, SAEs causally related to study treatment 
and discontinuation of study treatment due to AEs will be presented. In addition, COVID-19 
suspected AEs/SAEs and COVID-19 confirmed AEs/SAEs will be presented in a separate 
patient data listing.  Dose level at onset of AEs/SAEs will also be presented in patient data 
listings.


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4.2.9.2
Overdose
A listing will be provided of patients who experience at least one overdose over the study 
period.  The listing will be sorted by actual study treatment taken and patient ID. Dose level 
at time of overdose and time to onset of overdose will also be presented.
4.2.9.3
Bleeding Events
For the safety analysis set, summary tables will include on-treatment/off-treatment bleeding 
events (refer to Sections 3.4.4) only.  Pre-treatment bleeding events will be included in the 
patient data listings only.  Any bleeding events occurring after premature study treatment 
discontinuation regardless of initiation of alternative therapy for SCD will be flagged in the 
patient data listings.
Total number of bleeding events (n only), frequency (n and %) of patients who have 
experienced at least one bleeding event on-treatment/off-treatment will be presented by actual 
study treatment received.  Percentage of patients experiencing at least one bleeding event will 
be based on the safety analysis set, by actual treatment group.
Event-level and patient-level summary of bleeding characteristics: Severity of bleed, nature of 
the bleed and primary location of the bleed will also be presented.  Percentage of bleeding 
events reported in each category will be based on the total number of bleeding events 
experienced by patients in the safety analysis set.  Percentage of patients in each category will 
be based on the total number of patients in the safety analysis set who experienced at least one 
bleeding event, by actual treatment group.
All bleeding events at any time during the study will be presented in patient data listings.  
Dose level at onset of the bleeding event will also be presented.
4.2.9.4
Blood Product Transfusions
For the safety analysis set, summary tables will include on-treatment/off-treatment blood
product transfusions (refer to Sections 3.1.7.1 and 3.1.7.2), unless otherwise specified. 
Transfusions (as defined in Section 3.4.6) including the number of patients who have had any 
AE leading to the need for a transfusion, the number of transfusions for each patient, and the 
number of units transfused along with the type of blood product transfused will be presented 
by actual study treatment received.
All blood product transfusions at any time during the study will be presented in patient data 
listings. Dose level at onset of the blood product transfusion will also be presented.


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4.2.9.5
Laboratory Variables
With reference to the general principles and definitions detailed in Sections 2.1, 3.1 and 4.1.1, 
laboratory variables will be summarised using the safety analysis set, by actual treatment 
group.  Relevant data will be presented in patient data listings.
For continuous variables, observed values and change from baseline will be summarised for 
each clinical chemistry, haematology, and urinalysis variable at each scheduled time point 
(per planned eCRF visit [number and name]).  For categorical variables, shift tables will be 
presented for the change from baseline by actual treatment group.
Box plots of observed values and change from baseline will also be presented for each clinical 
chemistry, and haematology laboratory variable.
For each laboratory variable, a shift table will be produced presenting the baseline value 
classification according to laboratory reference range versus the minimum and maximum on-
treatment value.
Descriptive statistics, summarising patients with at least one treatment-emergent change (high
[increase]/low [decrease]) per laboratory variable, based on laboratory reference ranges, will 
be presented by actual treatment group (refer to Section 3.4.7).  Where:

n = Number of patients with at least one treatment-emergent change occurring on-
treatment (patients with multiple occurrences on-treatment will only be counted once).

% = Percentage of patients in the safety analysis set with at least one treatment-emergent 
change occurring on-treatment relative to the total number of patients in the safety
analysis set, with a baseline and at least one post-baseline assessment on-treatment
available.
4.2.9.5.1
Liver Enzyme Elevations and Hy’s Law
The following summaries will include the number (n) and percentage (%) of patients in the 
safety analysis set with at least one post-baseline liver function assessment available in the 
defined double-blind randomised treatment period and identified as on-treatment or off-
treatment (refer to Section 3.1.7.1 and 3.1.7.2), who have:

Elevated ALT, AST, and total bilirubin over the defined treatment period

ALT <3, ≥3× to <5×, ≥5× to <10×, ≥10× ULN

AST <3×, ≥3× to <5×, ≥5× to <10×, ≥10× ULN

Total bilirubin <2×, ≥2× ULN

ALT or AST <3×, ≥3× to <5×, ≥5× to <10×, ≥10× ULN 


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
ALT or AST ≥3× ULN and total bilirubin ≥2× ULN (Potential Hy’s law): The onset 
date of ALT or AST elevation should be prior to or on the date of total bilirubin 
elevation.
To identify potential Hy’s Law cases, a listing of patients in the safety analysis set who have 
ALT or AST ≥3× ULN and total bilirubin ≥2× ULN at any time during the study (ie, not 
necessarily at the same time) following first dose of double-blind randomised study treatment 
administration will be provided.  This listing will include all assessments (scheduled and 
unscheduled) for this subset of patients over the entire study course.  Dose level at the time of 
liver function assessments will also be presented.
A shift plot will also present maximum on-treatment (refer to Section 3.4.7) ALT observed 
value by maximum on-treatment total bilirubin observed value, expressed as multiples of 
ULN.  A similar plot will be presented for maximum on-treatment AST observed value.  
Reference lines will be included at 2× ULN for total bilirubin and 3× ULN for ALT/AST.
Additionally, a figure presenting the individual liver biochemistry test results over time for
patients with elevated ALT or AST, and elevated total bilirubin at any time following first 
dose of double-blind randomised study treatment administration will be provided. Results 
will be expressed as multiples of ULN.
4.2.9.6
ECG Variables
Overall evaluation of ECG will be summarised at each timepoint/visit reporting the number 
(n) and percentage (%) of patients in the safety analysis set presenting with a normal, 
abnormal not clinically significant or abnormal clinically significant evaluation.  A shift table 
from baseline to last on-treatment ECG evaluation (scheduled or unscheduled) will also be 
presented.  Percentage will be based on the total number of patients in the safety analysis set, 
by actual treatment group, with a baseline and at least one post-baseline evaluable ECG 
assessment on-treatment available.
4.2.9.7
Vital Signs
For the safety analysis set, observed values and change from baseline to each scheduled visit 
(per planned eCRF visit [number and name]) will be summarised for each vital sign by actual 
treatment group.  
For SBP, DBP and pulse rate, a shift table will be produced presenting the baseline value 
classification according to abnormality assessment criteria versus the minimum and maximum 
on-treatment value.
Descriptive statistics, summarising patients with at least one treatment-emergent change (high 
[increase]/low [decrease]), based on the abnormality assessment criteria, will be presented by 
actual treatment group. Where:


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
n = Number of patients with at least one treatment-emergent change occurring on-
treatment (patients with multiple occurrences on-treatment will only be counted once).

% = Percentage of patients in the safety analysis set with at least one treatment-emergent 
change occurring on-treatment relative to the total number of patients in the safety 
analysis set, with a baseline and at least one post-baseline assessment on-treatment 
available.
4.2.10
Exploratory Variables
4.2.10.1
Duration of ACSs
Descriptive statistics will be presented for the total duration (days) (taking into account 
overlapping ACS days + 7-day onset rule) of ACSs experienced by a patient over the defined 
treatment period by planned treatment group.  Patients who do not experience any ACS will 
have their duration of ACS set to 0 (see Section 3.3.2).
4.2.10.2
Pharmacokinetic Data
4.2.10.2.1
Statistical Analysis of Pharmacokinetic Data
The PK analysis set is defined in Table 1.
All available plasma concentration-time data for ticagrelor and active metabolite 
(AR-C124910XX) will be listed for the safety analysis set with any data to be excluded from 
the summary tables and figures for the PK analysis set indicated.  Any PK data excluded from 
the summary tables (either individual time points or entire treatment period) will also be 
excluded from the associated figures.
For those patients eligible for inclusion in the PK analysis set the plasma concentration-time 
data will be summarised by protocol-scheduled timepoint for each dosing regimen.
The levels of precision for reporting PK concentration data in the listings and for each 
descriptive statistic in the summary tables are detailed in the PK Order Form provided by the 
PK Scientist on which the tables, figures and listings shells are based.
Descriptive statistics used for summarising the PK data, ie, plasma concentrations of 
ticagrelor and active metabolite (AR-C124910XX), at each timepoint for each visit will follow 
from general methodology (refer to Section 4.1.1).
Plasma concentrations that are below the limit of quantification (BLQ) will be reported as 
follows:
Individual concentrations below the lower limit of quantification (LLOQ) of the bioanalytical 
assay will be reported as non-quantifiable (NQ) in the listings with the LLOQ defined in the 
footnotes of the relevant tables, figures, and listings.  Individual plasma concentrations that 
are not reportable will be reported as not reportable (NR) and those that are missing will be 


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reported as no sample (NS) in the listings.  Plasma concentrations that are NQ, NR or NS will 
be handled as follows in the presentation of descriptive statistics: 

Any values reported as NR or NS will be excluded from the summary tables and figures.  
At a timepoint where less than or equal to 50% of the concentration values are NQ, all 
NQ values will be substituted with the LLOQ concentration, and all descriptive statistics 
will be calculated accordingly.

At a timepoint where more than half (but not all) of the values are NQ, the gMean, gCV% 
and SD will be reported as not calculable (NC).  The maximum value will be reported 
from the individual data and the minimum and median will be set to NQ.

If all concentrations are NQ at a timepoint, the gMean, min, median and max will be 
reported as NQ and the SD and gCV% will be reported as NC.
The number of values above LLOQ (n >LLOQ) will be reported for each timepoint together 
with the total number of collected values.
Three observations > LLOQ will be required as a minimum for PK plasma concentrations to 
be summarised.  For consistency, the same plasma concentration values will be used in the 
mean data graphs as those given in the descriptive statistics summary table for each timepoint.
The plasma PK concentration data for ticagrelor and active metabolite (AR-C124910XX) will 
be displayed graphically.  Displays will include:
1
Individual patient plasma concentration-time profiles on the linear scale showing 
ticagrelor and active metabolite (AR-C124910XX) on the same plot.
2
Individual patient plasma concentration-time spaghetti plots of ticagrelor on the linear 
scale for each dose level showing all patients on the same plot.  This will be repeated for 
active metabolite (AR-C124910XX).
3
Geometric mean (gMean) pre-dose plasma concentrations of ticagrelor (with gSD error 
bars) and active metabolite (AR-C124910XX) on the same plot versus visit (visit number 
as X-axis) for the pooled weight-bands/doses and for each weight-band/dose level.
4
Geometric mean (gMean) 2-hour plasma concentrations (with gSD error bars) of 
ticagrelor and active metabolite (AR-C124910XX) on the same plot versus visit (visit 
number as X-axis) for the pooled weight-bands/doses and for each weight-band/dose 
level.
4.2.10.3
Pharmacodynamic Variable
Pharmacodynamic analysis, by actual treatment group, will be performed utilising patients 
considered evaluable for inclusion in the PD analysis set and who provide at least baseline and 
one post-baseline (pre-dose and/or post-dose) analysable sample (refer to Section 2.1).
All available data will be listed for the safety analysis set with any PD data to be excluded 
from the summary tables and figures indicated by means of a flag.


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PRI (%) values will be presented by actual study treatment received for each week/month and 
timepoints (pre-dose and 2 hours post-dose).  Descriptive statistics will be presented for each 
observed result including:

gMean: Calculated as exp[μ], where μ is the mean of the data on a natural logarithmic 
scale

gSD: Calculated as exp[s], where s is the SD of the data on a natural logarithmic scale

gCV%: Calculated as 100 √[exp(s2)-1], where s is the SD of the data on a natural 
logarithmic scale

aMean

SD

Median

Minimum (min)

Maximum (max)
and for change from baseline (refer to Section 3.1.3) by means of:

aMean

SD

Median

Minimum (min)

Maximum (max)
In addition, PRI (%) will be presented graphically as follows:

Individual patient PRI-time spaghetti plots for the pooled weight-bands/doses and for 
each weight-band/dose level.  Pre-dose and 2-hours post-dose PRI values will not be 
averaged and will be presented separately.

Mean (geometric and arithmetic) pre-dose PRI values versus visit (visit number as X-
axis) for the pooled weight-bands/dose level and for each weight-band/dose level.

Mean (geometric and arithmetic) 2-hours post-dose PRI values versus visit (visit number 
as X-axis) for the pooled weight-bands/dose level and for each weight-band/dose level.
If considered relevant, the same data handling conventions detailed for the PK analyses will 
be applied for those PRI (%) values that are NQ, NR or NS.
5
INDEPENDENT DATA MONITORING COMMITTEE
An independent data monitoring committee (IDMC) composed of independent SCD paediatric 
experts and including a platelet expert and statistician, will be appointed for this study and 
will report to the Steering Committee (SC).  The IDMC 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 IDMC will make 


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recommendations on the progression of the study based on the totality of unblinded data or 
other findings putting patients at undue risk.  Please refer to Section 1.5.2 of the CSP for 
further details.
Additionally, the IDMC 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-hour post-dose PRI (%) values at 4 weeks will be calculated for each 
individual patient 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 for not achieving the targeted inhibition level of 35 to 80% in the study, the first 
task of the IDMC would be to investigate the PK values and that 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 IDMC not to 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 study treatment compliance and potentially escalate the issue to the SC 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.
6
CHANGES/CLARIFICATIONS OF ANALYSIS FROM 
PROTOCOL
Table 3
Summary of Changes/Clarifications from Protocol
Reference
Protocol
Change
Justification
Sec 2.1
V2.0 29AUG2018
Added PP analysis set
Missing from protocol 
but needed for outputs
Appendix E and 
Sec 4.2.6.1
V2.0 29AUG2018
Added tipping point 
and other sensitivity 
analysis
Needed to explore 
more end points than 
protocol specified
7
REFERENCES
Cohen et al 2008
Cohen LL, Lemanek K, Blount RL, Dahlquist LM, Lim CS, Palermo TM, et al. Evidence-
based assessment of pediatric pain. J Pediatr Psychol 2008;33(9):939-55; discussion 956-7.
Davies and Tuleu 2008
Davies EH and Tuleu C. Medicines for children: a matter of taste. J Pediatr 2008;153:599-
604.
Hicks et al 2001
Hicks CL, von Baeyer CL, Spafford PA, van Korlaar I, Goodenough B. The Faces Pain Scale-
Revised: toward a common metric in pediatric pain measurement. Pain 2001;93(2):173-83.


Statistical Analysis Plan 
Study Code D5136C00009
Edition Number V2.0
Date 17 March 2020
CONFIDENTIAL AND PROPRIETARY
70 of 84
Hilbe 2007
Hilbe JM.  Negative binomial regression.  Cambridge University Press 2007.
Keene et al 2014
Keene ON, Roger JH, Hartley BF, Kenward MG.  Missing data sensitivity analysis for 
recurrent event data using controlled imputation.  Pharmaceut.  Statist.  2014, 13 258–264.
Kliegman 2015
Kliegman RM, Stanton BMD, St. Geme J, Schor NF. Nelson textbook of pediatrics, 20th
edition. Elsevier Health Sciences 2015. 
Panepinto et al 2013
Panepinto JA, Torres S, Bendo CB, McCavit TL, Dinu B, Sherman-Bien S, Bemrich-Stolz C,
Varni JV.  PedsQL™ sickle cell disease module: Feasibility, reliability, and validity.  Pediatr 
Blood Cancer 2013;60:1338-44.
Panepinto et al 2014
Panepinto JA, Torres S, Bendo CB, McCavit TL, Dinu B, Sherman-Bien S, Bemrich-Stolz C,
Varni JV.  PedsQLTM Multidimensional fatigue scale in sickle cell disease: Feasibility,
reliability, and validity.  Pediatr Blood Cancer 2014;6:171-77.
Rubin 1987
Rubin D. Multiple Imputation for Nonresponse in Surveys. Wiley.
Varni et al 2011
Varni JW, Limbers CA, Neighbors K, Schulz K, Lieu JE, Heffer RW, et al. The PedsQL™ 
Infant Scales: feasibility, internal consistency reliability, and validity in healthy and ill infants. 
Qual Life Res 2011;20(1):45-5.
Voepel-Lewis et al 2010
Voepel-Lewis T, Zanotti J, Dammeyer JA, Merkel S. Reliability and validity of the face, legs, 
activity, cry, consolability behavioral tool in assessing acute pain in critically ill patients. Am 
J Crit Care 2010;19(1):55-61.


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8
APPENDIX
Appendix A  Vital Signs Pre-defined Abnormality Assessment Criteria
As far as vital signs are concerned, the following pre-defined abnormality assessment criteria
will be considered:
Table 4
Vital Signs Pre-defined Abnormality Assessment Criteria
Years
Systolic Blood 
Pressure
Diastolic Blood 
Pressure
Pulse
Lower
Upper
Lower
Upper
Lower
Upper
≥ 2 to < 4
80
110
55
75
70
130
≥ 4 to < 6
80
115
55
75
70
120
≥ 6 to < 8
85
115
55
75
65
115
≥ 8 to < 12
90
120
60
80
60
110
≥ 12 to < 14
95
125
65
85
60
110
≥ 14 to < 16
95
130
65
85
55
100
≥ 16 to < 18
95
135
70
85
50
90


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Appendix B Race Mapping 
Analysis Race
Race as Collected 
AMERICAN INDIAN OR ALASKA 
NATIVE
AMERICAN INDIAN OR ALASKA 
NATIVE
ASIAN
ASIAN
ASIAN
ASIAN AMERICAN
BLACK OR AFRICAN AMERICAN
AFRICAN
BLACK OR AFRICAN AMERICAN
AFRICAN CARIBBEAN
BLACK OR AFRICAN AMERICAN
BAHAMIAN
BLACK OR AFRICAN AMERICAN
BARBADIAN
BLACK OR AFRICAN AMERICAN
BLACK CENTRAL AMERICAN
BLACK OR AFRICAN AMERICAN
BLACK OR AFRICAN AMERICAN
BLACK OR AFRICAN AMERICAN
BLACK SOUTH AMERICAN
BLACK OR AFRICAN AMERICAN
BOTSWANAN
BLACK OR AFRICAN AMERICAN
DOMINICA ISLANDER
BLACK OR AFRICAN AMERICAN
DOMINICAN
BLACK OR AFRICAN AMERICAN
ETHIOPIAN
BLACK OR AFRICAN AMERICAN
HAITIAN
BLACK OR AFRICAN AMERICAN
JAMAICAN
BLACK OR AFRICAN AMERICAN
LIBERIAN
BLACK OR AFRICAN AMERICAN
NAMIBIAN
BLACK OR AFRICAN AMERICAN
NIGERIAN
BLACK OR AFRICAN AMERICAN
TOBAGOAN
BLACK OR AFRICAN AMERICAN
TRINIDADIAN


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BLACK OR AFRICAN AMERICAN
WEST INDIAN
BLACK OR AFRICAN AMERICAN
ZAIREAN
NATIVE HAWAIIAN OR OTHER 
PACIFIC ISLANDER
NATIVE HAWAIIAN OR OTHER 
PACIFIC ISLANDER
WHITE
ARAB
WHITE
EASTERN EUROPEAN
WHITE
EUROPEAN
WHITE
MEDITERRANEAN
WHITE
MIDDLE EASTERN
WHITE
NORTH AFRICAN
WHITE
NORTHERN EUROPEAN
WHITE
RUSSIAN
WHITE
WESTERN EUROPEAN
WHITE
WHITE
WHITE
WHITE CARIBBEAN
WHITE
WHITE CENTRAL AMERICAN
WHITE
WHITE SOUTH AMERICAN
OTHER
OTHER


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Appendix C  Missing/Partial Start and Stop Dates for 
Medications/Transfusions
Partial start dates are allowed for medications per the CM eCRF design. 
Start dates missing the day or both the day and month of the year will adhere to the following 
conventions to classify prior/concomitant medications:

The missing start day of a medication will be set to the first day of the month that the 
medication was taken.

If the start date of a medication is missing both the day and month, the start date will be 
set to January 1 of the year of onset of medication use.
If the start date of a medication is unknown, but the medication was known to have been 
started more than 1 month prior to screening (Visit 1) , sites can select “treatment started more 
than 1 month prior to study start” in the CM eCRF in lieu of entering a start date (implies prior 
medication for patients in the safety analysis set at a minimum). 
If the start date of a medication is not recorded and has not been checked in the CM eCRF as 
having started “more than 1 month prior to study start”, and the stop date is a complete date: 

in case the stop date is after the date of first dose of double-blind randomised study
treatment then the start date will be set to the date of the first dose of double-blind 
randomised study treatment.

otherwise the start date will be set to the stop date of the medication.
Partial stop dates for concomitant medications are not allowed per CM eCRF design. Fully 
missing concomitant medication stop dates will not be imputed and such medications will be 
regarded as ongoing, implies concomitant medication for patients in the safety analysis set.
Date of blood product transfusion is required per TRANSF eCRF design and 
partial/completely missing blood product transfusion dates will not be imputed. In case of 
partial/completely missing blood product transfusion date then the transfusion date will be 
regarded as the start date of the relevant adverse event as identified by AEID (AE Number)
captured on the TRANSF eCRF. Otherwise if it is not possible to link the blood product 
transfusion to an adverse event, the blood product transfusion will be reported as follows:

For patients with at least one double-blind randomised study treatment administration, the 
transfusion will be assumed to be “on-treatment” (worst-case approach) when considering 
the safety analysis set.


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Appendix D  Missing/Partial Dates for Date of Birth, Diagnosis of Sickle 
Cell Disease, Prior VOCs, and VOCs During the Study
Date of birth is required, however a partial date is allowed and as such the complete date will 
be imputed as:

the 15th day of the month if only the day is missing

1st January if both day and month are missing
In case of completely missing date of birth no imputation will be done, and any age derivation 
will be set to missing.
A partial date is allowed for the diagnosis date of sickle cell disease. The complete date will 
be imputed as:

the 15th day of the month if only the day is missing

1st January if both day and month are missing
If the imputed date is prior to the date of birth, it will instead be set to the date of birth.  In 
case of completely missing date, SCD diagnosis date will be set to the date of birth. 
A partial date is allowed for prior VOCs as collected on the VOC eCRF. The complete date 
will be imputed as:

the 15th day of the month if only the day is missing
In case of completely missing date or if only a year is reported, prior VOC event date will be 
set to the day before screening (Visit 1).
Those VOCs occurring during the study will be collected on the VOC1 eCRF. Data collection
pe the VOC1 eCRF mandates complete start/stop dates for VOC events collected during the 
study, in the exceptional case of missing/partial dates, no imputation will be done.  The 
following conventions will apply:

VOC events collected on the VOC1 eCRF during the double-blind randomised treatment 
period with missing/partial dates will be assumed to be on-treatment (worst-case).  

VOC events collected during the double-blind randomised treatment period cannot be 
pooled if there is no complete start/stop date to link it to another VOC event within 7 days, 
but these events will be counted as individual VOC events.

Similarly, for the handling of missing/partial dates when calculating the total duration 
(days) of VOC events and total duration (days) of hospitalisation, no imputation will be 


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done.  Example of such an exceptional case may be events with a fatal outcome and hence 
no stop date of event.


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Appendix E Accounting for Missing Data
Accounting for missing data for recurrent events (VOC event rate endpoint)
In this study some patients dropping out of the study potentially leads to unobserved events. 
The amount of missing data is minimised in this study as patients are encouraged to remain in 
the study after premature discontinuation of double-blind randomised study treatment and 
complete visits according to the protocol schedule of assessments.
This section describes the plan to account for missing data in the sensitivity analyses to assess 
the robustness of the treatment effect under different underlying assumptions to account for 
missing data. 
Missing data descriptions
Tabular summaries for the percentage of patients by the reason for premature discontinuation 
of double-blind randomised study treatment as well as for early withdrawal from the study
will be presented by double-blind randomised treatment group to describe why patients 
prematurely discontinue from double-blind randomised treatment or withdraw prematurely 
from the study.
Primary analysis under the Treatment Policy Estimands using the Missing at Random (MAR) 
assumption
The primary analysis is under the treatment policy estimand which allows for differences in 
outcomes over the entire defined double-blind randomised treatment period to reflect the 
effect of initially assigned randomised study treatment as well as if subsequent alternative 
treatments for SCD are taken. This primary analysis includes all data until patients withdraw 
from the study regardless of whether they prematurely discontinue from double-blind 
randomised study 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 (MAR) and is a direct likelihood approach (DL). 
Sensitivity analyses under the Treatment Policy Estimands using both MAR and MNAR 
assumptions
To examine the sensitivity of the results of the primary analysis to departures from the 
underlying assumptions, additional analyses will be performed using controlled multiple 
imputation (MI) methods which allow for different underlying assumptions to be used. As 
with the primary analysis the sensitivity analyses include all data until patients withdraw from 
the study regardless of whether they prematurely discontinue from double-blind randomised 
study treatment.


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For this method an underlying negative binomial stochastic process for the rate of VOCs is 
assumed and post-withdrawal counts will be imputed conditional upon the observed number 
of events prior to the withdrawal.  This allows various assumptions about the missing data to 
be analysed by modifying the post-withdrawal model assumption.
The method involves first fitting the primary analysis (in addition to each analysis described 
in Section 4.2.6.3, bullet numbers 5 [if there are at least 5 patients in each strata]) ie, negative 
binomial regression model to the observed data and then imputing post-withdrawal counts by 
sampling from the conditional negative binomial probability relating post-withdrawal counts 
and observed prior-withdrawal counts based on various assumptions;
Pr,-!.,0 = 10| -!.,) = 1)3 =
4(5(67(68)
4(68())4(5(67) 9.
68(1 −9. )<(68            (1)
Here 
is number of counts prior to withdrawal from the study, 
is number of counts after 
withdrawal from the study, 
is the dispersion parameter and is assumed to be the same for 
the different double-blind randomised treatment groups, j denotes the treatment group and i
denotes the patient identifier. Furthermore,  9. =
%=,8&%=,7%=,8
)& %=,7%=,8    (2)  where 
is the negative 
binomial distribution (NBD) rate parameter prior to withdrawal from the study, and 
is the 
rate parameter after withdrawal from the study as determined based on various assumptions.       
The imputed number of VOC events that would have been seen is then combined with the 
observed VOC events and data is analysed using the primary analysis methodology (DL). 
This analysis is repeated 1000 times and the results combined using Rubin’s formulae (Rubin 
1987).
The following default assumptions that will be used to impute the missing data for patients 
who prematurely discontinue from the study are as follows:
1
MAR: Missing counts in each double-blind randomised treatment group are imputed 
assuming the expected event rate within that treatment group. 
2
Partial Dropout Reason-based Multiple Imputation (pDRMI): Missing counts will be 
imputed differently depending on the reason for dropout; counts for patients in the 
Ticagrelor groups who dropped out for a study treatment-related reasons are imputed 
based on the expected VOC event rate in the placebo treatment group, whereas the 
remaining patients who have dropped out are imputed assuming MAR. Study treatment-
related reasons may include (1) AEs, (2) Death and (3) Development of study-specified 
reasons.
3
Dropout Reason-based Multiple Imputation (DRMI): As for pDRMI with study 
treatment-related reasons and including “severe non-compliance with the protocol”.
A review of each patient who withdraws from the study will be carried out prior to database 
lock and routine study unblinding. The review will include assessment of the reason for 


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discontinuation of double-blind randomised study treatment for those patients who 
discontinued the double-blind randomised study treatment and then withdrew from the study 
and free text for when the reason for withdrawal or discontinuation of double-blind 
randomised study treatment is “subject decision” or “other”. Based on this review the default 
assumptions for pDRMI and DRMI may be changed. A list of these patients and the 
assumptions made under pDRMI and DRMI will be documented prior to database lock and 
routine study unblinding. 
A summary of reasons for patients withdrawing from the study and the corresponding 
treatment group used to calculate the imputation VOC event rate under MAR, pDRMI, and 
DRMI is given in Table 5.
Table 5
Reasons for patients withdrawing from the study and the 
corresponding treatment group used to calculate the imputation VOC 
event rate under MAR, pDRMI, and DRMI
Reason for 
withdrawala
MAR
pDRMI
DRMI
Death
Ticagrelor
Placebo
Placebo
Severe non-
compliance to protocol
Ticagrelor
Based on review of 
important protocol 
deviations prior to 
study unblinding
Based on review of 
important protocol 
deviations prior to 
study unblinding
Patient lost to follow-
up
Ticagrelor
Based on review prior 
to study unblinding
Based on review prior 
to study unblinding
Withdrawal by patient
Ticagrelor
Based on review prior 
to study unblinding
Based on review prior 
to study unblinding
Otherb
Ticagrelor
Based on review prior 
to study unblinding
Based on review prior 
to study unblinding
aAll patients withdrawing from placebo have VOC event rate imputed using the placebo treatment group rate.
bAll patients withdrawing for a COVID-19 related reason, regardless of which category of reason is collected for 
them, will be reviewed prior to study unblinding
In addition, a tipping point analysis will be performed (if appropriate, ie, the primary efficacy 
was a favourable result) using the same model as above and where:

Missing counts for a patient will be imputed, according to the rate of the double-blind 
randomised treatment group that the patient belongs to multiplied by a factor delta (δ).

A series of analyses will be performed with a range of increasing deltas for the two 
treatment groups (δP and δT for placebo and ticagrelor groups respectively) so that one 
can assess at which point the study conclusions would change from favourable to 
unfavourable; ie, to identify a tipping point.


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In this assessment, the ticagrelor group is assumed to worsen after withdrawal. Therefore, 
deltas will be increased starting from 1 in increments of 0.025, until a favourable primary 
efficacy result is no longer favourable. If statistical significance is maintained among the 
matrix of possible δ combinations, the comparison is deemed robust to missing data. 
Together with the primary analysis the sensitivity analyses are considered to cover the range 
from realistic to plausible worst-case assumptions about missing data.  The MAR multiple 
imputation approach is expected to correspond closely to the primary analysis and is included 
to allow for comparisons with MNAR assumptions using the same multiple imputation 
methodology.
The pDRMI/DRMI approach was selected as the most conservative approach because placebo 
patients are potentially receiving standard of care and are not expected to change to a 
substantially more effective treatment after withdrawing from study or double-blind 
randomised study treatment. For patients receiving ticagrelor who withdraw from the study 
due to study treatment-related reasons it is assumed that at worst they would be on the 
standard of care treatment ie, the placebo group.  
On-treatment Analyses (Efficacy and Effectiveness estimands) 
In addition, primary and sensitivity analyses described previously, two alternative estimands 
will be estimated using only the initial randomised study treatment data:

Efficacy estimand: What would the outcome have been if all patients had stayed on study 
treatment: This will be estimated using the primary analysis method but including only 
data from patients whilst being on initial randomised study treatment, and assuming MAR 
subsequently.

Effectiveness estimand with assumed loss of effect post-discontinuation of ticagrelor: 
This will be estimated using the pDRMI and DRMI controlled imputation approaches 
including only data from patients whilst on study treatment.
Therefore, the primary analyses and sensitivity analyses will be repeated including only data 
from patients whilst being on initial randomised study treatment ie, excluding data once 
patients discontinue from randomised study treatment.
A summary of reasons for patients withdrawing from the ticagrelor and the corresponding 
treatment group used to calculate the imputation VOC event rate under MAR, DRMI and 
pDRMI are presented in Table 6. As for patients who withdraw from the study, a review of 
each patient who discontinued double-blind randomised study treatment will be carried out 
prior to database lock and routine study unblinding, where the default assumptions for pDRMI 
and DRMI as described in Table 5 may be changed. Again, a list of these patients and the 
assumptions made under pDRMI and DRMI will be documented prior to database lock and 
routine study unblinding.


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Table 6
Reasons for patients discontinuing from the ticagrelor and the 
corresponding treatment group used to calculate the imputation VOC 
event rate under MAR, pDRMI and DRMI
Reason for discontinuation of 
treatmenta
MAR
pDRMI
DRMI
Subject decision 
Ticagrelor
Based on review 
prior to study 
unblinding
Based on review 
prior to study 
unblinding
Adverse event
Ticagrelor
Placebo
Placebo
Severe non-compliance to protocol
Ticagrelor
Ticagrelor
Placebo
Condition under investigation worsened
Ticagrelor
Placebo
Placebo
Development of study-specific 
discontinuation criteria
Ticagrelor
Placebo
Placebo
Subject lost to follow-up
Ticagrelor
Ticagrelor
Ticagrelor
Otherb
Ticagrelor
Based on review 
prior to study 
unblinding
Based on review 
prior to study 
unblinding
aAll patients withdrawing from placebo have VOC event rate imputed using the placebo treatment group rate.
bAll patients withdrawing for a COVID-19 related reason, regardless of which category of reason is collected for 
them, will be reviewed prior to study unblinding
Using on-treatment data is easier to interpret as it is not impacted by any subsequent pattern of 
alternative therapies for SCD once patients discontinue from double-blind randomised study 
treatment. The efficacy estimand together with the reason for and timing of why a patient 
might not tolerate the study treatment allows for the simplest interpretation as it describes the 
treatment effect for patients who adhere to study treatment together with why and when they 
might not adhere to study treatment.  Sensitivity analyses using the effectiveness estimands 
under the pDRMI and DRMI allow for alternative assumptions to be made based on reasons 
for discontinuation. 
Overall summary of analyses to account for missing data
A summary of the different analyses to be carried out under different estimands and 
assumptions are described in Table 7.


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Table 7
Summary of analysis under various estimands and assumptions
Treatment Policy Estimand
On-treatment Analyses 
(Efficacy and Effectiveness Estimands)
DL
MAR
pDRMI
DRMI
DL
MAR
pDRMI
DRMI
Double-blind randomised treatment period
On-treatment
Estimand
Treatment policy 
(MAR)
Treatment policy 
(MNAR)
Efficacy 
(MAR)
Effectiveness 
(MNAR)
VOC 
event rate 
for 
imputation 
in 
Ticagrelor
arm**
No 
explicit 
imputation 
*
Ticagrelor 
rate 
assumed 
for all 
reasons for 
withdrawal
Ticagrelor 
rate assumed 
for all 
reasons for 
withdrawal
Placebo rate 
assumed for 
AEs, Death 
and 
development 
of study 
specified
reasons to 
withdraw 
from study , 
otherwise 
Ticagrelor 
rate 
assumed. 
Reasons are 
subject to 
review prior 
to study 
unblinding
Placebo rate 
assumed for 
AEs, Death, 
development 
of study 
specified 
reasons to 
withdraw 
from study 
and Severe 
non-
compliance 
to protocol, 
otherwise 
Ticagrelor 
rate 
assumed. 
Reasons are 
subject to 
review prior 
to study 
unblinding
No 
explicit 
imputation 
*
Ticagrelor 
rate 
assumed for 
all reasons 
for 
discontinued 
study 
treatment 
Placebo rate 
assumed for 
AEs, and 
development 
of study 
specified 
reasons to 
stop study 
treatment, 
otherwise 
Ticagrelor 
rate 
assumed. 
Reasons are 
subject to 
review prior 
to study 
unblinding
Placebo rate 
assumed for 
AEs, 
development 
of study 
specified 
reasons to 
stop study 
treatment and 
Severe non-
compliance to 
protocol, 
otherwise 
Ticagrelor 
rate assumed. 
Reasons are 
subject to 
review prior 
to study 
unblinding


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Default 
definition 
for
and
based 
on 
formula 
(2).
***
For all 
treatment 
groups j=T 
and P
For all 
treatment 
groups j=T 
and P
with δ 
multiplied 
by imputed 
values. 
incrementing 
δ by 0.025 at 
each 
iteration
for reasons 
above 
otherwise
for reasons 
above 
otherwise
For all 
treatment 
groups j=T 
and P
for reasons 
above 
otherwise
for 
reasons above 
otherwise
P Placebo. T Ticagrelor.
*  Implicitly assumes unobserved rate is the same as observed. 
** All patients withdrawing from placebo have VOC event rate imputed using the placebo treatment group rate. (i.e. 
).
*** Note can be over written by review prior to database lock and routine study unblinding.


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Forest plots will be used to show the primary analysis results along with the missing data 
sensitivity and alternative estimand analysis results.
It is noted that if the primary analysis is statistically significant, it is not necessarily expected 
that all sensitivity analyses will also give statistically significant results. If the results of the 
sensitivity analyses provide reasonably similar estimates of the treatment effect to the primary 
analysis, this will be interpreted as providing assurance that neither the lost information nor 
the mechanisms which cause the data to be missing have an important effect on primary 
analysis conclusions. Based on these outputs and the study treatment’s mechanism of action, 
the plausibility of the assumptions made about missing data in the different analyses will be 
considered and described in the CSR.


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Prot_001.pdf: 
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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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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(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 
Drug Substance Ticagrelor  
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 
Drug Substance Ticagrelor  
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 
Drug Substance Ticagrelor  
Study Code D5136C00009 
Version 3.0 
Date 20 April 2020 
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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 


Clinical Study Protocol 
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Study Code D5136C00009 
Version 3.0 
Date 20 April 2020 
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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 et al 2012 
Ataga KI, Brittain JE, Desai P, et al. Association of coagulation activation with clinical 
complications in sickle cell disease. PLoS One 2012;7(1):e29786.  
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Blann AD, Mohan JS, Bareford D, Lip GY. Soluble P-selectin and vascular endothelial 
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Cabannes R, Lonsdorfer J, Castaigne JP, et al. Clinical and biological double-blind-study of 
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Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful 
crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle 
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Cohen et al 2008 
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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Heeney et al 2016 
Heeney MM, M.D., Hoppe CC, Abboud MR, et al.  A multinational trial of prasugrel for 
sickle cell vaso-occlusive events.  
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platelet reactivity testing in a double-blind study of prasugrel in children with sickle cell 
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Laine et al 2013 
Laine M, Toesca R, Berbis J, et al. Platelet reactivity evaluated with the VASP assay 
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Li JS, Yow E, Berezny KY, Bokesch PM, Takahashi M, Graham TP Jr, et al. Dosing of 
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Mitchell LG, Goldenberg NA, Male C, Kenet G, Monagle P, Nowak-Göttl U. Definition of 
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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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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. 


Clinical Study Protocol Appendix B 
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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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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 
Version 3.0 
Date 20 April 2020 
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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 
Date 20 April 2020 
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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?” 


Clinical Study Appendix E 
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Study Code D5136C00009 
Version 3.0 
Date 20 April 2020 
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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. 
 


Clinical Study Appendix E 
Drug Substance Ticagrelor  
Study Code D5136C00009 
Version 3.0 
Date 20 April 2020 
91(123) 
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 
Date 20 April 2020 
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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 
Drug Substance Ticagrelor  
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 
Drug Substance Ticagrelor  
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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