Clinical trial NCT02214121
Conditions: Investigation of Platelet Aggregation in Paediatric Patients With Sickle Cell Disease
Keywords: sickle cell anemia paediatric
Sponsor: AstraZeneca
Start date: 2014-09-11; Completion date: 2017-02-27
Enrollment: 46 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this Phase II dose-ranging study is to investigate pharmacokinetic (PK) and pharmacodynamic (PD) properties of various doses of ticagrelor followed by 4 weeks of twice-daily treatment in paediatric patients with sickle cell disease

Detailed description:
This is a multicenter, open-label, dose-ranging study of ticagrelor followed by a double blind, placebo-controlled extension phase in paediatric patients with sickle cell disease (SCD).

Part A: Patients will be randomised 1:1 to receive one of two dosing schedules consisting of two single weight-adjusted doses of ticagrelor. Pharmacokinetic (PK) parameters and pharmacodynamic (PD) measurements will be determined following each dose. Platelet aggregation will be measured using the VerifyNow™ P2Y12 assay.

Following these 2 single doses, all patients will receive open-label one-week treatment with ticagrelor twice daily to determine tolerability prior to randomisation into Part B.

Part B: In this part patients will be randomised (2:1 ratio) to ticagrelor twice daily or placebo for a 4-week treatment phase.

During the study, patients will be followed for the occurrence of vaso-occlusive crisis (VOC) and for other disease manifestations such as daily pain, analgesic use and complications of SCD.

Arms: arm 1: Part A: Ticagrelor Dose 1a and ticagrelor Dose 2a single doses + 1 week repeated dosing Part B: Ticagrelor or placebo 4 weeks repeated dosing. arm 2: Part A: Ticagrelor Dose 1b and ticagrelor Dose 2b single doses + 1 week repeated dosing. Part B: Ticagrelor or placebo 4 weeks repeated dosing.
Interventions: intervention 1: Ticagrelor Dose 1a + Dose 2a intervention 2: Ticagrelor Dose 1b + Dose 2b
Intervention descriptions: intervention 1: Ticagrelor Dose 1a and ticagrelor Dose 2a single doses + 1 week ticagrelor repeated dosing followed by 4 weeks repeated dosing ticagrelor or placebo. intervention 2: Ticagrelor Dose 1b and ticagrelor Dose 2b single doses + 1 week ticagrelor repeted dosing followed by 4 weeks repeated dosing ticagrelor or placebo.

Protocol documents:
Prot_001.pdf: 
Redacted


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
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PROTOCOL SYNOPSIS
Multicenter, open-label, randomised, pharmacokinetic (PK) and 
pharmacodynamic (PD) dose-ranging Phase II study of ticagrelor followed 
by a double-blind, randomised, parallel-group, placebo-controlled 4 weeks 
extension phase in paediatric patients with sickle cell disease
Study site(s) and number of subjects planned
This study is planned to be conducted in approximately 6-10 countries in North America, 
Europe, Middle East and Africa at approximately 30 - 37 sites, with a minimum of 36 patients 
and a maximum of 50 patients (including the patients already randomised to date) to be 
randomised in the study, depending on how many patients are required in order to have 36 
evaluable patients. Of these 36 evaluable patients, at least 12 patients must be 2 to 11 years of 
age and 12 patients must be 12 to 18 years. In addition, a minimum of 12 evaluable patients 
must complete Part B (through Visit 8).
Study period
Phase of development
Estimated date of first subject enrolled
Q3 2014
II
Estimated date of last subject completed
Q1 2017
Study design
This is a multicenter, open-label, dose-ranging study of ticagrelor followed by a double blind, 
placebo-controlled extension phase in paediatric patients with sickle cell disease (SCD). 
Part A: Patients will be randomised 1:1 to receive one of two dosing schedules. All patients 
will receive 0.75 mg/kg as their initial dose, followed 7 days later by 1.125 mg/kg or 
2.25 mg/kg with determination of pharmacokinetic (PK) parameters and pharmacodynamic 
(PD) platelet inhibition following each dose. The PK and platelet aggregation data are 
intended to support modelling-based selection of a weight-based dose for Phase III. Platelet 
aggregation will be measured using the VerifyNow™ P2Y12 assay and reported as P2Y12
reaction units (PRU).
Following the 2 single doses, all patients will receive open-label one-week treatment with 
ticagrelor 0.75 mg/kg twice daily to determine tolerability prior to randomisation into Part B. 
Part B: Part B will be optional for patients. The investigator should present Part B to each 
patient and the decision to participate in Part B should be made by the patient (or parents/legal 
guardian). In this part patients will be randomised (2:1 ratio) to ticagrelor 0.75 mg/kg twice 


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
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daily or placebo for a 4-week treatment phase. In some countries, Part B will not be 
performed.
During the study, patients will be followed for the occurrence of vaso-occlusive crisis (VOC) 
and for other disease manifestations such as daily pain, analgesic use and complications of 
SCD.
For safety reasons the dosing schedule will be modified for individual patients as follows: If 
PRU at 2 hr following dosing of 0.75 mg/kg is <95, the subsequent maximum dose for this 
patient will be 0.563 mg/kg throughout the study. If PRU <95 following dosing of 0.563
mg/kg, the patient will be discontinued from further study drug.
Since Part A of the study is open label, the PK and PD results will be monitored as the study 
proceeds and the doses may be further adjusted in both Part A and B based on emerging PK 
and PD results. Doses may be adjusted following assessment by AstraZeneca and the Steering 
Committee of open label Part A results in the first 6-12 patients randomised under this 
amendment. Dose adjustment decisions will be based upon a review of PK, PD and adverse 
events (see Section 8.6).


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
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Objectives
Primary Objective:
Outcome Measure:
To characterise the relationship between ticagrelor 
dose and inhibition of platelet aggregation in 
paediatric patients with SCD, using PK-PD 
modelling, to support dose selection for Phase III
PRU, Maximum Plasma Concentration (Cmax) 
and Area Under the Plasma Concentration Time 
Curve (AUC) 
Secondary Objective:
Outcome Measure:
To determine the PK properties of ticagrelor and its 
active metabolite in paediatric patients with SCD 
and to assess impact of weight, age and other 
demographic on the ticagrelor pharmacokinetics
Concentrations of ticagrelor and its active 
metabolite. Population PK parameters (Oral 
Clearance (CL/F) and AUC)
Investigation of efficacy of ticagrelor vs. placebo in 
paediatric patients with SCD in reducing:
Number of VOC*
Number of VOC requiring hospitalization or 
emergency department visits
Days hospitalized for VOC or other 
complications of SCD 
Days with pain (ages ≥4 years only)
Intensity of pain (ages ≥4 years only)
Days of analgesic use (ages ≥4 years only)
Days of opioid analgesic use
Days of absence from school or work (ages 
≥6 years only)


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
5(66)
Safety Objective:
Outcome Measure:
To assess safety and tolerability of single and 
multiple doses of ticagrelor in paediatric patients 
with SCD
Adverse Events (AE)/Serious Adverse Events 
(SAEs)
Vital signs, laboratory safety samples 
To determine the percent of patients with 
haemorrhagic events requiring medical intervention
Haemorrhagic events**
* VOC is defined as a painful sickle cell crisis requiring medical intervention including any of the following 
(1) hospitalization (2) emergency department or clinic visit (3) medically supervised outpatient treatment with 
escalated doses of drugs for management of painful crisis (may include oral or parenteral opioids or non-
steroidal anti-inflammatory drugs).
** A haemorrhagic event is defined as bleeding prompting an unscheduled visit or call to a medical provider and 
resulting in therapy or further investigation. 
Exploratory Objective:
Outcome Measure:
Investigation of efficacy of ticagrelor vs. placebo in 
paediatric patients with SCD in reducing:
Days with pain (ages <4 years only)
Intensity of pain (ages <4 years only)
Target subject population
Patients eligible for this study include all children aged ≥2 to <18 years of age (age from birth 
to Visit 1) who are diagnosed with sickle cell disease [homozygous sickle cell (HbSS) or 
sickle beta-zero-thalassemia (HbS/β0).
Duration of treatment
In Part A the treatment period consists of 2 single doses (separated by at least 7 days) 
followed by 7 days open label ticagrelor treatment twice daily. In Part B patients will be 
randomised to 4 weeks twice-daily treatment. There is no washout period between Part A and 
Part B. The total expected study duration for an individual patient participating in both Part A 
and Part B is approximately 3 months (including 30 days follow-up after last dose) and 
approximately 2 months for an individual patient participating in only Part A (including 30 
days follow-up after last dose).


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
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Investigational product, dosage and mode of administration
Part A: 
Ticagrelor 0.563 mg/kg, 0.75 mg/kg, 1.125 mg/kg or 2.25 mg/kg given as oral single doses.
Ticagrelor 0.563 mg/kg or 0.75 mg/kg twice daily given orally.
These doses may be adjusted based upon evaluation of PK/PD data as described in Appendix 
E.
Part B:
Ticagrelor 0.563 mg/kg or 0.75 mg/kg twice daily given orally and matching placebo.
These doses may be adjusted based upon evaluation of PK/PD data as described in Appendix 
E.
The investigational product (active or placebo) will be granules for oral suspension supplied in 
glass bottles. Before each dosing occasion the granules will be constituted with 10 mL of 
purified water in the glass bottle to form a suspension suitable for oral dosing.
Statistical methods
The relationship between ticagrelor dose, plasma concentration and PRU will be characterized 
using a population PK/PD approach (i.e non-linear mixed effect modeling). This analysis will 
be based on all available PK and PRU data from which complete dosing and sampling history 
is collected.
No statistical comparisons are planned for the primary objective. PK, PD and safety measures 
will be summarized descriptively. 
A statistical analysis will be done comparing ticagrelor and placebo for each of the following 
variables:
!
Percentage of days with pain (ages ≥4 years only)
!
Percentage of days of opioid analgesic use
!
Percentage of days of analgesic use (ages ≥4 years only)
!
Percentage of days hospitalized for VOC or other complications of SCD
!
Percentage days of absence from school or work (ages ≥6 years only)
A t-test will be performed for each of these variables at 5% significance level, provided that 
the efficacy analysis set contains at least 30 patients, otherwise only descriptive statistics will 
be used. The p-value and a 95% confidence interval for the difference between ticagrelor and 
placebo will be reported. There will be no adjustment for multiple comparisons. If it is 


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
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inappropriate to assume a normal distribution, a Wilcoxon rank sum test may be performed. 
Number of VOC requiring hospitalization and intensity of pain will be summarized 
descriptively.


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
8(66)
TABLE OF CONTENTS
PAGE
TITLE PAGE............................................................................................................................1
PROTOCOL SYNOPSIS .........................................................................................................2
TABLE OF CONTENTS .........................................................................................................8
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS...........................................13
1.
INTRODUCTION .................................................................................................15
1.1
Background and rationale for conducting this study .............................................15
1.1.1
Disease under treatment.........................................................................................15
1.1.2
Study drug..............................................................................................................16
1.1.3
Pharmacokinetic Properties and Product Metabolism in Humans.........................16
1.2
Rationale for study design, doses and control groups............................................17
1.2.1
Overall rationale and study population..................................................................17
1.2.2
Study design...........................................................................................................18
1.2.3
Primary and secondary outcome measures............................................................18
1.2.4
Dose and study duration.........................................................................................19
1.3
Benefit/risk and ethical assessment........................................................................19
1.4
Study Design..........................................................................................................21
2.
STUDY OBJECTIVES..........................................................................................22
2.1
Primary objective...................................................................................................22
2.2
Secondary objectives .............................................................................................22
2.3
Safety objectives ....................................................................................................22
2.4
Exploratory objectives ...........................................................................................23
3.
SUBJECT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL......................23
3.1
Inclusion criteria ....................................................................................................23
3.2
Exclusion criteria ...................................................................................................23
3.3
Patient enrolment and randomisation.....................................................................25
3.4
Procedures for handling incorrectly enrolled or randomised patients ...................26
3.5
Methods for assigning treatment groups................................................................26
3.6
Methods for ensuring blinding...............................................................................26
3.7
Methods for unblinding..........................................................................................27
3.8
Restrictions ............................................................................................................27


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
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3.9
Discontinuation of investigational product............................................................27
3.9.1
Criteria for interruption or discontinuation of investigational product 
(active and placebo) ...............................................................................................27
3.9.2
Permanent discontinuation from investigational product (active and 
placebo)..................................................................................................................28
3.9.3
Procedures for investigational product (active and placebo) in case of 
bleeding:.................................................................................................................28
3.9.4
Procedures for discontinuation of a patient from investigational product.............29
3.10
Criteria for withdrawal...........................................................................................29
3.10.1
Screen failures........................................................................................................29
3.10.2
Withdrawal of the informed consent......................................................................29
3.11
Discontinuation of the study..................................................................................30
4.
STUDY PLAN AND TIMING OF PROCEDURES.............................................31
4.1
Enrolment/screening period...................................................................................35
4.2
Treatment period....................................................................................................35
4.3
Follow-up period....................................................................................................37
5.
STUDY ASSESSMENTS .....................................................................................37
5.1
Efficacy assessments..............................................................................................37
5.1.1
Vaso-occlusive crisis (VOC) .................................................................................38
5.1.2
Pain ........................................................................................................................38
5.1.3
Other efficacy variables .........................................................................................38
5.2
Safety assessments.................................................................................................39
5.2.1
Laboratory safety assessments...............................................................................39
5.2.2
Physical examination .............................................................................................40
5.2.3
Vital signs ..............................................................................................................40
5.2.4
Electrocardiogram..................................................................................................40
5.3
Other assessments ..................................................................................................40
5.3.1
Patient reported outcomes......................................................................................40
5.3.1.1
Palatability assessment by age group.....................................................................40
5.3.1.2
Use of analgesic .....................................................................................................41
5.3.1.3
Absence from school/work ....................................................................................41
5.4
Pharmacokinetics ...................................................................................................41
5.4.1
Collection of samples.............................................................................................41
5.4.2
Determination of drug concentration.....................................................................42
5.4.3
Storage and destruction of pharmacokinetic samples............................................42
5.5
Pharmacodynamics ................................................................................................42
5.5.1
VerifyNow∀P2Y12 assay .....................................................................................42
5.5.2
Collection of samples.............................................................................................43
5.6
Pharmacogenetics (Not Applicable) ......................................................................43


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
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5.7
Biomarker analysis (Not Applicable) ....................................................................43
5.8
Volume of blood ....................................................................................................44
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT ..............................46
6.1
Definition of adverse events ..................................................................................46
6.2
Definitions of serious adverse event......................................................................46
6.3
Recording of adverse events ..................................................................................46
6.3.1
Time period for collection of adverse events.........................................................46
6.3.2
Follow-up of unresolved adverse events................................................................47
6.3.3
Variables ................................................................................................................47
6.3.4
Causality collection................................................................................................48
6.3.5
Adverse events based on signs and symptoms.......................................................48
6.3.6
Adverse events based on examinations and tests...................................................49
6.3.7
Hy’s Law................................................................................................................49
6.3.8
Assessment of bleeding events ..............................................................................49
6.3.9
Vaso-occlusive crisis (VOCs)................................................................................50
6.4
Reporting of serious adverse events.......................................................................50
6.5
Overdose ................................................................................................................50
6.6
Pregnancy...............................................................................................................51
6.6.1
Maternal exposure..................................................................................................51
6.6.2
Paternal exposure...................................................................................................51
6.7
Management of Investigational Product related toxicities.....................................51
6.8
Study governance and oversight ............................................................................51
6.8.1
Steering Committee (SC).......................................................................................51
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ....................53
7.1
Identity of investigational product(s).....................................................................53
7.2
Dose and treatment regimens.................................................................................53
7.3
Labelling ................................................................................................................54
7.4
Storage ...................................................................................................................54
7.5
Compliance ............................................................................................................54
7.6
Accountability........................................................................................................54
7.7
Concomitant and other treatments .........................................................................55
7.7.1
Blood transfusion...................................................................................................55
7.7.2
Other concomitant treatment..................................................................................55
7.8
Post Study Access to Study Treatment (Not applicable).......................................56
8.
STATISTICAL ANALYSES BY 
...............................................................56
8.1
Statistical considerations........................................................................................56
Redac
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Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
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8.2
Sample size estimate..............................................................................................56
8.3
Definitions of analysis sets ....................................................................................56
8.3.1
Efficacy analysis set...............................................................................................56
8.3.2
Safety analysis set..................................................................................................56
8.3.3
PK analysis set .......................................................................................................56
8.3.4
PD analysis set .......................................................................................................56
8.4
Outcome measures for analyses (Not applicable)..................................................56
8.5
Methods for statistical analyses .............................................................................56
8.6
Interim analysis and potential further dose adjustments........................................58
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA ..........................59
9.1
Training of study site personnel.............................................................................59
9.2
Monitoring of the study .........................................................................................59
9.2.1
Source data.............................................................................................................59
9.2.2
Study agreements...................................................................................................60
9.2.3
Archiving of study documents...............................................................................60
9.3
Study timetable and end of study...........................................................................60
9.4
Data management by AstraZeneca or delegate......................................................60
10.
ETHICAL AND REGULATORY REQUIREMENTS.........................................61
10.1
Ethical conduct of the study...................................................................................61
10.2
Subject data protection...........................................................................................61
10.3
Ethics and regulatory review..................................................................................61
10.4
Informed consent ...................................................................................................62
10.5
Changes to the protocol and informed consent form.............................................62
10.6
Audits and inspections ...........................................................................................63
11.
LIST OF REFERENCES.......................................................................................63
LIST OF TABLES
Table 1
Study Plan detailing the procedures................................................................31
Table 2
Blood sampling in patients with a weight of >21 kg ......................................34
Table 3
Blood sampling in patients with a weight of 16-21 kg...................................34
Table 4
Laboratory Safety Variables ...........................................................................39
Table 5
Palatability assessment....................................................................................41
Table 6
Volume of blood to be drawn from patients with a weight >21 kg................44


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Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
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Table 7
Volume of blood to be drawn from patient with a weight of 16-21 kg ..........45
LIST OF FIGURES
Figure 1
Study flow chart..............................................................................................21
Figure 2
Dosing schedule..............................................................................................37
LIST OF APPENDICES
Appendix A
Signatures (Not applicable)
Appendix B
Additional Safety Information 
Appendix C
IATA 6.2 Guidance document
Appendix D
Actions required in cases of combined increase of Aminotransferase and Total 
Bilirubin - Hy’s Law
Appendix E 
PK/PD monitoring dose adjustments
Appendix F
Dose tables with predefined weight brackets 
Appendix G
Patient Reported Outcomes
Appendix H
Child-Pugh Classification 


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Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation or 
special term
Explanation
ACS
Acute Coronary Syndrome
ADP
Adenosine Diphosphate
AE
Adverse event
ALT
Alanine transaminase
AST
Aspartate transaminase 
ATP
Adenosine Triphosphate 
AUC
Area Under the Plasma Concentration Time Curve
BP
Blood pressure
CL/F
Oral Clearance
CNS
Central Nervous System 
Cmax
Maximum Plasma Concentration
CPTP
Cyclopentyltriazolopyrimidines
CRF
Case Report Form (electronic/paper)
CRO
Contract Research Organization
CSA
Clinical Study Agreement
CSR
Clinical Study Report
CVA
Cerebrovascular accident
EC
Ethics Committee, synonymous with Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
ENT-1
Equilibrative nucleoside transporter-1
ePRO
Electronic devices for Patient Reported Outcomes
FHS
Faces Hedonic Scale
FLACC
Face, Legs, Activity, Cry, Consolability scale
FPS-R
Faces Pain Scale - Revised
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
GRand
Global Randomisation system 
HbSS
homozygous sickle cell anemia
HbS/β0
sickle beta-zero-thalassaemia
ICH
International Conference on Harmonisation


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
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Abbreviation or 
special term
Explanation
ICF
Informed consent form
INR
International Normalised Ratio
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. 
IPA
Inhibition of platelet aggregation 
IRB
Institutional Review Board
MedDRA
Medical Dictionary for Regulatory Activities
MTD
Maximum tolerated dose
NSAIDs
Non-steroidal anti-inflammatory drug
OSE
Office of Surveillance and Epidemiology 
PD
Pharmacodynamic
P-gp
P-glycoprotein 
PI
Principal Investigator 
PK
Pharmacokinetic 
PRO
Patient reported outcomes
PRU
P2Y12 reaction units 
PTT
Partial Thromboplastin Time
RBC
Red Blood Cells
SAE
Serious adverse event 
SC
Steering Committee
SCD
Sickle Cell Disease
SOC
Standard of care 
TAMMV
Time averaged mean of the maximum velocity 
TCD
Transcranial Doppler
TCDi
Imaging Transcranial Doppler
TIA 
Transient ischemic attack
tmax
Time to maximum plasma concentration
ULN
Upper Limit of Normal 
UK
United Kingdom
US
United States
VOC
Vaso-occlusive crisis
WBDC
Web Based Data Capture


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
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1.
INTRODUCTION
1.1
Background and rationale for conducting this study 
Ticagrelor is an orally active; reversibly binding cyclopentyl-triazolo-pyrimidine P2Y12
receptor antagonist that produces dose-related inhibition of adenosine diphosphate (ADP) 
induced platelet aggregation (Htun and Steinhubl 2013). Ticagrelor is indicated to reduce the 
rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS). The 
ticagrelor development program to date has focused on adult patients since there is no 
paediatric correlate for the adult condition of ACS. 
1.1.1
Disease under treatment
Sickle cell disease (SCD) is an autosomal recessive inherited disorder in which the abnormal 
gene product is an altered haemoglobin β-chain. Polymerization of deoxygenated sickle 
haemoglobin leads to decreased deformability of red blood cells (RBCs). Due to a complex 
interplay of adhesive events, these altered erythrocytes can obstruct the vasculature, producing 
episodes of pain, organ ischemia and infarction and early mortality.
Inhibition of platelet activation has been proposed as a potential therapeutic option in the 
treatment of children and adults with SCD. Sickling of RBCs is initiated by deoxygenation 
and subsequent polymerization of sickle haemoglobin resulting in mechanical vascular 
obstruction, and painful ischemia, commonly referred to as a vaso-occlusive crisis (VOC). 
Vaso-occlusion is initiated and sustained by interactions among sickle cells, endothelial cells, 
and constituents of plasma. Activated platelets promote the adherence of sickle cells to 
endothelial cells and thus participate in the vaso-occlusive process. 
In patients with SCD, platelets are activated during the non-crisis “steady state” and are 
further activated during painful episodes (Lee et al 2006). An exploratory study in adults with 
SCD suggested an association between a marker of platelet activation (soluble CD40 ligand) 
and frequency of pain episodes in the previous year (defined as a visit to a medical facility 
with administration of a parenteral analgesic) (Ataga et al 2012). 
The rationale for the use of antiplatelet therapies in management of SCD derives from the 
hypothesis that although platelets do not initiate VOC, they may play a role in amplifying and 
maintaining vaso-occlusion. The spectrum of clinical manifestations in SCD may result in part 
from recurrent episodes of disseminated microvascular ischemia-reperfusion injury
(Polanowska-Grabowska et al 2010) that triggers vascular inflammation, with platelet-
monocyte and platelet-neutrophil aggregates as important amplifiers of the process. In theory, 
antiplatelet therapy could decrease the incidence and severity of vaso-occlusion, and has the 
potential to affect other disease manifestations related to microvascular occlusion. This 
hypothesis positions platelets not only as players in acute VOC but also as important 
contributors to daily pain and to complications resulting from frequent microvascular 
occlusion such as pulmonary hypertension. 
Previous clinical trials of antiplatelet medications (aspirin (Osamo et al 1981), (Greenberg et 
al 1983), (Zago et al 1984), aspirin-dipyridamole (Chaplin et al 1980), ticlopidine (Cabannes 


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
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et al 1984), (Semple et al 1984) and eptifibatide (Lee et al 2007)) in preventing the thrombotic 
complications or effect on biomarkers of SCD in adults and children have been small and thus 
far inconclusive (recently reviewed and summarized by Charneski and Congdon 2010 and 
Wun et al 2013). A small double-blind, placebo controlled, Phase II trial with prasugrel 
administered for 30 days in adult patients with SCD demonstrated a trend toward fewer days 
with pain and decreased pain intensity in the prasugrel arm relative to placebo (Wun et 
al 2013). Platelet surface P-selectin and plasma soluble P-selectin, biomarkers of in vivo
platelet activation, were significantly reduced in the patients randomised to prasugrel. A low 
level of platelet inhibition with prasugrel for at least 9 months in children with SCD showed 
numerical reductions in rate of VOC’s and pain crises, but differences were not statistically 
significant compared to placebo (Heeney et al 2015).
1.1.2
Study drug
Ticagrelor, a member of the chemical class cyclopentyltriazolopyrimidines (CPTP), is a 
selective ADP receptor antagonist acting on the P2Y12 ADP-receptor that can prevent ADP-
mediated platelet activation and aggregation. Ticagrelor is orally active, and reversibly 
interacts with the platelet P2Y12 ADP-receptor. Ticagrelor does not interact with the ADP 
binding site itself, but interacts with platelet P2Y12 ADP-receptor to prevent signal 
transduction.
Ticagrelor has an additional mechanism of action, increasing local endogenous adenosine 
levels by inhibiting equilibrative nucleoside transporter-1 (ENT-1). Adenosine is formed 
locally at sites of hypoxia and tissue damage through degradation of released adenosine tri-
and di-phosphate (ATP and ADP). As adenosine degradation is mostly restricted to the 
intracellular space, inhibition of ENT-1 by ticagrelor prolongs the half-life of adenosine and 
thereby increases its local extracellular concentration. Ticagrelor has no significant direct 
effect on adenosine receptors. In addition to the antithrombotic effects of ticagrelor, the 
adenosine mechanism could be hypothesized to benefit ischemic tissues during impending or 
ongoing VOC, via anti-inflammatory or vasodilatory effects (Nylander et al 2013). 
Thus ticagrelor has two pharmacological properties with the potential to impact the 
manifestations of SCD. 
1.1.3
Pharmacokinetic Properties and Product Metabolism in Humans
Ticagrelor demonstrates linear pharmacokinetics and exposure to ticagrelor and the active 
metabolite (AR-C124910XX) are approximately dose proportional up to 1260 mg.
Absorption of ticagrelor is rapid with a median tmax of approximately 1.5 hours. The formation 
of the major circulating metabolite AR-C124910XX (also active) from ticagrelor is rapid with 
a median tmax of approximately 2.5 hours.
The mean absolute bioavailability of ticagrelor was estimated to be 36%. Ingestion of a high-
fat meal resulted in a 21% increase in the Area Under the Plasma Concentration Time Curve 
(AUC) of ticagrelor and 22% decrease in the active metabolite Cmax but had no effect on 


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Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
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ticagrelor Cmax or the AUC of the active metabolite. These small changes are considered of 
minimal clinical significance; therefore, ticagrelor can be given with or without food.
The steady state volume of distribution of ticagrelor is 87.5 L. Ticagrelor and the active 
metabolite are extensively bound to human plasma protein (>99.0%). CYP3A4 is the major 
enzyme responsible for ticagrelor metabolism and the formation of the active metabolite and 
their interactions with other CYP3A substrates range from activation to inhibition. Ticagrelor 
and the active metabolite are weak P-glycoprotein inhibitors. 
The major metabolite of ticagrelor is AR-C124910XX, which is also active as assessed by in 
vitro binding to the platelet P2Y12 ADP-receptor. The systemic exposure to the active 
metabolite is approximately 30-40% of that obtained for ticagrelor.
The primary route of ticagrelor elimination is via hepatic metabolism. When radiolabeled 
ticagrelor is administered, the mean recovery of radioactivity is approximately 84% (57.8% in 
faeces, 26.5% in urine). Recoveries of ticagrelor and the active metabolite in urine were both 
less than 1% of the dose. The primary route of elimination for the active metabolite is most 
likely via biliary secretion. The mean t1/2 was approximately 7 hours for ticagrelor and 
8.6 hours for the active metabolite.
1.2
Rationale for study design, doses and control groups 
1.2.1
Overall rationale and study population
This Phase II paediatric study is intended to determine appropriate dosing and tolerability in 
patients with SCD in preparation for a subsequent paediatric Phase III study. In addition, the 
current study will collect data on clinical manifestations such as pain and analgesic use to 
inform the choice of clinical outcome measures in the subsequent study and for exploratory 
efficacy. 
Although the manifestations of SCD begin in childhood and evolve with age, the unique 
circumstances of childhood SCD indicate that dosing strategies and assessment of efficacy 
and safety in adults with SCD are not directly applicable to children. As patients with SCD 
age, lesions are acquired that contribute to the risk of serious bleeding (central nervous system 
(CNS) and other organ infarction, retinopathy). For these risks, which are presumably 
cumulative over a lifetime, adults may be at greater risk of serious bleeding than children. 
With respect to efficacy, there are considerable data to indicate that the physiology of SCD 
pain in children may be different than in adults. Sickling pain in children is believed to be 
mostly ischemic in origin, and more likely to be impacted by inhibition of platelet 
aggregation. In contrast, painful crises in adults are more complicated, and may have ischemic 
and neuropathic components (Ballas 2007). Platelet inhibition may be less likely to influence 
painful crises in adults due to the multifactorial origin of the pain. Thus a well-designed study 
in paediatric SCD is likely to provide the most relevant, rigorous and scientific answer 
regarding the efficacy and safety of reversible P2Y12 platelet inhibition in the prevention of 
VOC in children with SCD.


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Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
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1.2.2
Study design
The current study will randomise a minimum of 36 patients with SCD aged ≥2 years to 
<18 years. An open-label, randomised pharmacokinetic (PK) and pharmacodynamic (PD) 
evaluation of 2 single doses will be followed by one week of treatment with ticagrelor twice 
daily to determine tolerability. This will be followed by an optional 4-week randomised, 
double blind placebo-controlled treatment with twice-daily ticagrelor or placebo. There is no 
washout period between Part A and Part B. All patients will receive 2 single open-label doses 
of ticagrelor separated by at least 7 days, with determination of PK parameters and PD 
(inhibition of platelet activation) after each dose, to support modelling-based selection of a 
weight-based dose for the subsequent Phase III study. The current study is designed to provide 
PK and PD data on ticagrelor in children, and to provide initial experience with chronic daily 
dosing. 
In addition to study drug and protocol procedures, all standard clinical management will be 
utilized for patients participating in this study. 
1.2.3
Primary and secondary outcome measures
The primary study endpoint is the evaluation of the PK and PD properties of ticagrelor and its 
active metabolite in children after administration as single doses and after attainment of 
steady-state following twice-daily administration of ticagrelor. PK will be determined using 
standard methodologies. The PD measure employed will be the VerifyNow P2Y12 assay 
(Jeong et al 2012) that is a well-validated and commercially available point-of-care assay to 
assess inhibition of the P2Y12 platelet receptor. 
The secondary PK objectives are to determine the PK properties of ticagrelor and its active 
metabolite and to access the impact of demographic characteristics on the PK of ticagrelor. 
Outcome measures including:
!
Concentrations of ticagrelor and its active metabolite.
!
Population PK parameters (Oral Clearance (CL/F) and AUC)
The secondary efficacy objectives will include a daily diary and data collection during clinic 
Visits to assess disease burden including the following: 
!
Occurrence of VOC
!
VOC requiring hospitalization or emergency department visits 
!
Days hospitalized for VOC or other complications of SCD 
!
Days with pain (ages ≥4 years only)
!
Intensity of pain (ages ≥4 years only)
!
Days of analgesic use (ages ≥4 years only)
!
Days of opioid analgesic use
!
Days of absence from school or work (ages ≥6 years only)


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Study Code D5136C00007
Edition Number 3
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The secondary safety endpoints will include caregiver or patient reports of adverse events 
(AEs) including bleeding. 
1.2.4
Dose and study duration
Assessment of the first 12 randomised patients indicates that higher doses are needed in order 
to accomplish the primary study objective of characterising the relationship between ticagrelor 
dose and inhibition of platelet aggregation to support dose selection for Phase III. This 
amendment provides for the following revised doses: The initial single dose will be a 0.75 
mg/kg (weight-based dose equivalent to 60 mg in adults). The second single dose of ticagrelor 
will be 1.125 mg/kg or 2.25 mg/kg (weight-based dose equivalent to 90 or 180 mg in adults). 
For safety reasons the dosing schedule will be modified for individual patients as follows: If 
PRU at 2 hr following dosing of 0.75 mg/kg is <95, subsequent maximum dose for this patient 
will be 0.563 mg/kg throughout the study. If PRU is <95 following dosing of 0.563 mg/kg, the 
patient will be discontinued from further study drug.
Dose selection in this study is informed by the interim data from 12 first patients in this study 
as well as the substantial clinical pharmacology programme for ticagrelor in adults, which 
included 41 studies in approximately 1000 subjects examining the exposure-response 
relationship, safety, and drug interactions. The dose range of ticagrelor administered during 
these studies was 0.1 to 1260 mg, and 900 mg was established as the maximum tolerated dose 
(MTD) in healthy volunteers. The approved dose regimen in adults with ACS consists of a 
loading dose of 180 mg followed by 90 mg twice daily for up to one year. In adult patients 
with prior myocardial infarction, a dose of 60 mg twice daily is approved by the US FDA and 
is under review in Europe and additional countries.
The 4-week duration of the second part of the study is intended to provide preliminary data on 
tolerability of daily dosing in children, without imposing a large burden on the patients but 
providing a period of potential benefit. 
For potential further dose adjustments after monitoring of PK and PD please see Appendix E
1.3
Benefit/risk and ethical assessment 
SCD is a chronic, lifelong condition with serious complications and manifestations in every 
organ system. The goals for management of this condition are prevention of infection, 
nutritional supplementation, management of pain, and prevention of complications; therefore, 
treatment is multifactorial. Bone marrow transplantation, although potentially curative, has the 
possibility of serious or fatal complications and therefore, is reserved for the most severe cases 
of SCD. Although VOC is a common cause of hospitalisation and treatment with opioids, only 
one drug, hydroxyurea (hydroxycarbamide) is currently approved for reduction in the 
frequency of VOC. Although hydroxyurea reduces the incidence of many manifestations, it 
does not eliminate them, is poorly tolerated by some patients, and can cause 
myelosuppression. Furthermore, the safety of lifelong exposure beginning in childhood is 
unknown. Until a genetic cure is available, there is a clear unmet need for additional therapies 
that are better tolerated, safer, and more effective than available treatments.


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Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
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Antiplatelet therapies have an established role in the treatment of many paediatric diseases, 
including thromboprophylaxis of stents, valves, shunts, and ventricular assist devices, and 
Kawasaki disease (Giglia et al 2013). Clinical experience with P2Y12 inhibitors such as 
clopidogrel and prasugrel is relevant to the proposed ticagrelor paediatric program. 
Clopidogrel has been marketed in the United States (US) since 1997, and there is substantial 
clinical experience in paediatric patients. Completed studies in adults and children with SCD 
treated with prasugrel provide evidence that targeting inhibition of platelet aggregation (IPA)
of 30% to 60% with a P2Y12 platelet aggregation inhibitor does not pose an unacceptable 
safety risk to either adults or children with SCD enrolled in a well-controlled clinical study 
(Styles 2012, Wun et al 2013). Collectively these data provide substantial reassurance that 
30%-60% IPA produced by treatment with a P2Y12 inhibitor, the same degree of platelet 
inhibition targeted in the current Phase II ticagrelor study, is well tolerated in children and in 
patients with SCD. 
Two randomised studies of clopidogrel in paediatric patients have been performed in infants 
with cyanotic congenital heart disease palliated with a systemic-to-pulmonary artery shunt, 
with the objective of prevention of shunt thrombosis. The largest study, CLARINET, was a 
randomised, double-blind, study in 906 infants aged 92 days or younger randomised to receive 
clopidogrel 0.2 mg/kg/day versus placebo for a median duration of 5.8 months, in addition to 
standard of care (Wessel et al 2013). This dose provides a level of platelet inhibition similar to 
that provided by a 75 mg dose in an adult (30% to 50% inhibition after stimulation with 5 μM 
ADP). Aspirin was administered concomitantly to 88.7% of patients in the clopidogrel group 
and 87.0% of patients randomised to placebo. Serious bleeding occurred in 6.5% in the 
clopidogrel group and 7.3% in the placebo group. These data provide substantial reassurance 
that 30%-50% IPA produced by treatment with a P2Y12 inhibitor is well tolerated even in a 
very young and vulnerable paediatric population. The DOVE study was a randomised, 
placebo controlled study of the P2Y12 inhibitor prasugrel in children with sickle cell disease 
evaluating doses of prasugrel providing a mean platelet inhibition of approximately 25%. This 
treatment was well tolerated with no significant differences in safety results compared to 
placebo, and numerical reduction in rate of pan crises although differences were not 
statistically significant compared to placebo (Heeney et al 2015).
The FDA Office of Surveillance and Epidemiology (OSE) recently evaluated post-market 
reports of AEs in paediatric patients (ages 0-17 years) treated with clopidogrel (FDA Office of 
Surveillance and Epidemiology report, 2013). The report concludes that there was no new 
safety concerns identified with the use of clopidogrel in paediatric patients. 
Prior to current study, there are no safety data regarding ticagrelor treatment in patients 
younger than 18 years. However, more than 25,000 adult healthy subjects or patients have 
been exposed to ticagrelor in the completed Phase I, II, and III studies and the overall 
conclusion based on these studies is that ticagrelor has generally been well tolerated. 
The proposed ticagrelor Phase II study design is focused on minimization of risk, including a 
low starting dose and conservative dose-ranging strategy, exclusion of patients with ocular or 
CNS clinical findings which might predispose to significant bleeding, and incorporating other 
exclusion criteria to minimize the bleeding risk. The potential benefit of ticagrelor is reduction 


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
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of the occurrence of VOC, based on its mechanism of action as a potent P2Y12 inhibitor and 
the potential to reduce the occurrence of VOC, although vascular occlusion in SCD is 
multifactorial and it is not known whether antiplatelet therapy will be beneficial. 
However, in the context of the unmet need for treatment of painful VOC in children with 
SCD, the benefit-risk balance for the program is believed to be favourable.
1.4
Study Design 
This study is planned to be conducted in approximately 6-10 countries in North America, 
Europe, Middle East and Africa at approximately 30-37 sites, with a minimum of 36 patients 
and a maximum of 50 patients (including the patients already randomised to date) to be 
randomised in the study, depending on how many patients are required in order to have 36 
evaluable patients. Of these 36 evaluable patients, at least 12 patients must be 2 to 11 years of 
age and 12 patients must be 12 to 18 years. In addition, a minimum of 12 evaluable patients 
must complete Part B (through Visit 8).
Figure 1
Study flow chart
R = randomisation; PRO = patient reported outcome
For safety reasons the dosing schedule will be modified for individual patients based on their 
PRU at Visit 2, 3 and 4 (see Figure 2). The dose modifications may occur at Visit 2, 3 and 4.


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
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2.
STUDY OBJECTIVES
2.1
Primary objective
Primary Objective:
Outcome Measure:
To characterise the relationship between ticagrelor 
dose and inhibition of platelet aggregation in 
paediatric patients with SCD, using PK-PD 
modelling, to support dose selection for Phase III
PRU, Maximum Plasma Concentration (Cmax) 
and Area Under the Plasma Concentration 
Time Curve (AUC)
2.2
Secondary objectives
Secondary Objective:
Outcome Measure:
To determine the PK properties of ticagrelor and its 
active metabolite in paediatric patients with SCD and 
to assess impact of weight, age and other 
demographic on the ticagrelor pharmacokinetics
Concentrations of ticagrelor and its active 
metabolite. Population PK parameters (Oral 
Clearance (CL/F) and AUC)
Investigation of efficacy of ticagrelor vs. placebo in 
paediatric patients with SCD in reducing:
Number of VOC*
Number of VOC requiring hospitalization or 
emergency department visits
Days hospitalized for VOC or other 
complications of SCD 
Days with pain (ages ≥4 years only)
Intensity of pain (ages ≥4 years only)
Days of analgesic use (ages ≥4 years only)Days 
of opioid analgesic use
Days of absence from school or work (ages 
≥6 years only)
2.3
Safety objectives
Safety Objective:
Outcome Measure:
To assess safety and tolerability of single and 
multiple doses of ticagrelor in paediatric patients 
with SCD
AEs/Serious Adverse Events (SAE)s
Vital signs, laboratory safety samples 
To determine the percent of patients with 
haemorrhagic events requiring medical intervention
Haemorrhagic events**
*
VOC is defined as a painful sickle cell crisis requiring medical intervention including any of the following 
(1) hospitalization (2) emergency department or clinic visit (3) medically supervised outpatient treatment with 
escalated doses of drugs for management of painful crisis (may include oral or parenteral opioids or non-
steroidal anti-inflammatory drugs).
** A haemorrhagic event is defined as bleeding prompting an unscheduled visit or call to a medical provider and 
resulting in therapy or further investigation for definitions, please see Section 6.3.8.


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Study Code D5136C00007
Edition Number 3
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2.4
Exploratory objectives 
Exploratory Objective:
Outcome Measure:
Investigation of efficacy of ticagrelor vs. placebo in 
paediatric patients with SCD in reducing:
Days with pain (ages <4 years only)
Intensity of pain (ages <4 years only)
3.
SUBJECT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL 
Each patient should 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 should fulfil the following criteria:
1.
Children aged ≥2 to <18 years* of age and body weight >16 kg diagnosed with 
homozygous sickle cell (HbSS) or sickle beta-zero-thalassaemia (HbS/β0)
2.
If ≤16 years, 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.
3.
If ≥6 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.
4.
If treated with an anti-sickling agent such as hydroxyurea, the weight-adjusted dose 
must be stable for 1 month before enrolment
5.
Suitable venous access for the study-related blood sampling
6.
Provision of signed and dated written 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)
*
Age from birth to Visit 1. 
3.2
Exclusion criteria
Subjects should not enter the study if any of the following exclusion criteria are fulfilled:
1.
Previous history of transient ischemic attack (TIA) or clinically overt 
cerebrovascular accident (CVA) (ischemic or haemorrhagic), severe head trauma, 
intracranial haemorrhage, intracranial neoplasm, arteriovenous malformation, 
aneurysm, or proliferative retinopathy


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2.
Findings on TCD: Current or previous values for time averaged mean of the 
maximum velocity (TAMMV) that are Conditional or Abnormal*.
Conditional TAMMV values are ≥153 cm/sec using imaging TCD (TCDi) 
technique (corresponding to ≥170 cm/sec by the non-imaging technique). Both the 
middle cerebral artery and the internal carotid artery should be considered.
Abnormal TAMMV values are ≥180 cm/sec using TCDi (corresponding to ≥200 
cm/sec by the non-imaging technique) and are an indication for chronic transfusions
because of a high stroke risk. Any other criteria that would locally be considered as 
TCD indications for chronic transfusion would also exclude the patient.
3.
Undergoing treatment with chronic RBC transfusion therapy 
4.
Use of non-steroidal anti-inflammatory drugs (NSAIDs) >3 days per week
5.
Receiving chronic treatment with anticoagulants or antiplatelet drugs that cannot be 
discontinued. 
6.
Moderate or severe hepatic impairment, defined as Child-Pugh Class B or C (see 
Appendix H) or renal failure requiring dialysis
7.
Active pathological bleeding or increased risk of bleeding complications according 
to Investigator
8.
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
9.
Concomitant oral or intravenous therapy (see Restrictions) with strong CYP3A4 
inhibitors**, CYP3A4 substrates with narrow therapeutic indices, or strong 
CYP3A4 inducers**, which cannot be stopped at least five half-lives, but not 
shorter than 10 days, before enrolment
10.
Surgical procedure planned to occur during the study
11.
Patients who are currently pregnant or breastfeeding, or planning to become 
pregnant during the study
12.
Females (if after menarche) who are not willing to use a highly effective method of 
contraception which results in a low failure rate (i.e. less than 1% per year)
13.
Known hypersensitivity or contraindication to ticagrelor
14.
Concern for the inability of the patient or parents to comply with study procedures 
and/or follow-up
15.
Any condition which, in the opinion of the Investigator, would make it unsafe or 
unsuitable for the patient to participate in this study
16.
Previous randomization in the present study***
17.
Participation in another clinical study with an investigational product or device 
during the last 30 days preceding enrolment.


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Study Code D5136C00007
Edition Number 3
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18.
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca staff and/or staff at the study site)
*
According to STOP study thresholds for non-imaging TCD technique (Adams et al 1998) and thresholds for 
imaging TCD (TCDi) technique as published by Bulas (Bulas et al 2005).
** Strong CYP3A inhibitors and inducers according to draft Guidance for Industry ‘Drug Interaction 
Studies - Study Design, Data Analysis, Implications for Dosing, and Labelling Recommendations’ (Food and 
Drug Administration, 2012) and EMA interaction guideline in act as of 01 Jan 2013.
*** As the eligibility criteria have been changed with this amendment, patients previously enrolled but not 
randomised may be reassessed for eligibility. Patients fulfilling all inclusion criteria and no exclusion criteria 
can be re-enrolled.
Procedures for withdrawal of incorrectly enrolled patients see Section 3.4.
3.3
Patient enrolment and randomisation
Investigator(s) should keep a record, the patient screening log, of patients who entered pre-
study screening.
The Investigator(s) will:
1.
Obtain signed informed consent from the parent/both parents/legal guardian 
(according to local regulations) and assent or consent from the child/adolescent 
(where required by local regulations) before any study specific procedures are 
performed. Patient is considered enrolled in the study after she/he has signed the 
informed consent form. If a patient was previously enrolled into the present study, 
but not randomised, a new informed consent document should be signed by the 
parent/both parents/legal guardian (according to local regulations) and assent or 
consent from the child/adolescent (where required by local regulations) before any 
study specific procedures are performed. The patient must receive a new unique 
enrolment number.
2.
Assign potential patient a unique enrolment number, beginning with E+4-digit site 
number +3-digit patient number starting with 001. For example, the first patient at 
site 9999 would be assigned the patient number: E9999001
3.
Determine patient eligibility. See Section 3.1 and 3.2. Patient who does not meet the 
eligibility criteria is considered as screening failure
4.
Assign eligible patient unique randomisation code. Patient will be randomised once 
or twice, both in Part A and Part B and will receive 2 unique randomisation codes
If a patient withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused.
Part A will be performed in open label fashion i.e. the patient as well as members of the study 
team, at investigational centres or third party vendors conducting the study or handling data, 
AstraZeneca R&D Supply Chain (including packaging and distribution vendors on their 
behalf) and bio analysis personnel analysing the PK samples will all have access to the 
randomisation schedule. Part B will be double blind i.e. no member of the study team at 


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AstraZeneca, the Steering Committee (SC), personnel at investigational centres or any 
contract Research Organization (CRO) handling data will have access to the randomisation 
scheme during the conduct of the study, with the exception of the Supply Chain Study 
Management department, CRO unblinded team and the Patient Safety department at 
AstraZeneca.
Randomisation codes will be assigned strictly sequentially as patients become eligible for 
randomisation for both Part A and/or Part B.
3.4
Procedures for handling incorrectly enrolled or randomised 
patients
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication. 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 
 Study Physician 
immediately, and a discussion should occur between the 
Study Physician and the 
Investigator regarding whether to continue or discontinue the patient from treatment. Patients 
who are withdrawn from the study due to error in randomisation in Part A will be replaced.
The 
Study Physician may consult with the AstraZeneca Physician for further discussion 
if necessary.
The ICON Study Physician must ensure all decisions are appropriately documented. In 
situations where an agreement cannot be reached, the patient should have his/her study 
therapy stopped.
3.5
Methods for assigning treatment groups
The randomisation codes will be computer generated by AstraZeneca R&D using the AZ 
Global Randomisation system (GRand). Randomisation codes will be generated in blocks to 
ensure approximate balance between dose schemes (1:1) in Part A and between the ticagrelor 
and placebo arms (2:1) in Part B. Randomisation codes will be assigned sequentially as 
patients become eligible for randomisation.
3.6
Methods for ensuring blinding
The treatment allocation in part B will be double blind. Ticagrelor and matching ticagrelor 
placebo granules will be provided (see Section 7), identical in appearance and packaging. 
Each kit will be labelled with a unique kit ID number that will be used to assign the treatment 
to the patient but will not indicate treatment allocation to the Investigator.
Redac
ted
Redact
ed
Redact
ed


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Edition Number 3
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3.7
Methods for unblinding 
Individual treatment codes, indicating the treatment randomisation for each randomised 
patient in part B, will be available to the Investigator(s) or pharmacists from the call center. 
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the subject requires knowledge of the treatment randomisation. The 
Investigator documents and reports the action to AstraZeneca, without revealing the treatment 
given to subject to the AstraZeneca staff.
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an investigational product 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 
subject have been made and documented.
3.8
Restrictions
Patients may not participate in another clinical study that involves an investigational product 
(active or placebo) during this study.
Females of child-bearing potential are not allowed to be included in this study unless they use 
a highly effective method of contraception, and must refrain from becoming pregnant from 1 
month following the last dose. A highly effective method is defined as the one which results in 
a low failure rate (i.e. less than 1% per year) when used consistently and correctly. Examples 
of highly effective methods include implants, injectables, combined oral contraceptives, some 
intrauterine devices, sexual abstinence or vasectomised partner. There are no restrictions 
against fathering a child when treated with ticagrelor. For further details, please see 
Section 6.6.
Grapefruit juice must not be consumed during the study.
Patients are not allowed to eat 2 hours before and 1 hour after dosing at Visit 2 and 3.
For concomitant medications which are restricted during the study, please see Section 7.7.
3.9
Discontinuation of investigational product
Patients should be discontinued from study medication in the following situations:
3.9.1
Criteria for interruption or discontinuation of investigational product (active 
and placebo)
!
Severe illness
!
Major or minor surgery or invasive procedures
!
Clinically significant thrombocytopenia which mandates an interruption of study 
drug due to patient safety in the assessment of the Investigator. Repeat laboratory 


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studies and standard of care (SOC) should be followed until resolution of laboratory 
abnormality
!
Need of treatment with prohibited concomitant medications, see Section 7.7
Elective procedures or surgery should be deferred until after completion of the study. For 
necessary minor surgery or other invasive procedures, study drug may be interrupted 
temporarily at the discretion of the Investigator; however, such cases should be discussed with 
the 
Study Physician as soon as the Investigator is aware. 
3.9.2
Permanent discontinuation from investigational product (active and placebo)
!
The patient (or parent/caregiver/legal guardian) is at any time free to discontinue 
treatment or advise the patient to discontinue treatment, without prejudice to further 
treatment
!
Any major bleeding
!
Risk to patients as judged by the Investigator
!
If PRU is <95 despite an individual dose reduction having already been made, the 
patient will be discontinued from further study drug for safety reasons
!
AE judged by the Investigator to be related to the investigational product, for which 
he/she feels continued participation would put the patient at undue risk. Examples 
of this could be:
#
Resting heart rate <40 bpm or any symptomatic bradycardia lasting for more 
than 60 seconds
#
Ventricular pauses longer than 3 seconds occurring more than twice during a 
60 second period
#
Atrioventricular block II/III suspected to be caused by ticagrelor
#
Development of a bundle branch block
!
Abnormal TCD indicating need for transfusion therapy
!
Development of proliferative retinopathy
!
Inability to manage pain without chronic NSAIDs
!
Severe non-compliance to study protocol
!
Pregnancy
3.9.3
Procedures for investigational product (active and placebo) in case of bleeding:
In case of a major bleeding event (see definitions in Section 6.3.8), investigational product 
(active and placebo) must be stopped immediately. The investigational product (active and 
placebo) administration need not be stopped in case of non-major bleeding. All bleeding 
events should be treated and followed up according to local clinical practice. Major bleeding 
events should be managed as medically indicated, with general support and transfusions as 
Redact
ed


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
29(66)
indicated. It should be noted that platelet transfusion has not been studied with ticagrelor; new 
platelets may be inhibited by ticagrelor as long as it is circulating in the blood (see 
Section 6.3.8 for bleeding definitions).
There is no antidote to ticagrelor and treatment of bleeding should therefore be symptomatic 
and handled according to the clinical routines at the investigational site.
Bleeding events should be recorded as AEs, see Section 6.3.
3.9.4
Procedures for discontinuation of a patient from investigational product 
At any time, patients are free to discontinue investigational product (active and placebo). If 
the patient is discontinued from investigational product after the second randomisation, the 
scheduled visits, data collection and procedures (except for blood sampling of PK and PD) 
should continue according to the study protocol, until patient completes Part B. 
At any time, patients are free to withdraw from the study (i.e., investigational product and 
assessments - see Section 3.10), without prejudice to further treatment. Such patients (or 
parent/legal guardian) will always be asked about the reason(s) and the presence of any AEs. 
Patient will be asked to complete a follow-up visit. Alternatively, if patient does not agree to 
the option, a modified follow up through e.g, regular telephone contacts or a contact at study 
closure should be arranged, if agreed to by the patient and in compliance with local data 
privacy laws/practices. AEs will be followed up (See Section 6.3); electronic devices for 
Patient Reported Outcomes (ePRO) and all study drugs should be returned by the patient.
If a subject is 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 ‘Eligibility criteria not fulfilled’ (i.e., patient does not meet the required 
inclusion/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 (investigational product (active and 
placebo) and assessments), without prejudice to further treatment.
A patient who withdraws consent will always be asked about the reason(s) and the presence of 
any AE. The Investigator will follow up AEs outside of the clinical study. The patient will 
return ePRO devices. 
If a patient withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused. Withdrawn patients who prematurely discontinue before completion of 
Visit 3 will be replaced. 36 evaluable patients with data from the two single doses are needed. 


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
30(66)
3.11
Discontinuation of the study
The study should be stopped if, in the judgment of AstraZeneca, trial patients are placed at 
undue risk because of clinically significant findings:
!
Major bleeding that is drug-related in >1 patient
!
If any of the heart rate/electrocardiogram (ECG) criteria below are fulfilled in >2 
patients and judged to be related to the investigational product (active)
#
Resting heart rate <40 bpm or any symptomatic bradycardia lasting for more 
than 60 seconds
#
Ventricular pauses longer than 3 seconds occurring more than twice during a 
60 second period
#
Atrioventricular block II/III suspected to be caused by ticagrelor
#
Development of bundle branch block
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 electronic Case Report Form (eCRF). All 
reasons for discontinuation of treatment must be documented.
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the patients’ interests.


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
31(66)
4.
STUDY PLAN AND TIMING OF PROCEDURES 
Table 1
Study Plan detailing the procedures 
Part A
Part B
Assessment
Enrolment
Dose 1
Dose 2
Repeated treatment phase
End of 
treatment
Follow-up
Visit
1m
2m
3
4l
5r
6
7r
8
9 l
Week
0
1
2
3
4
5
6
10
Day (Visit window)
-30 - -14
0
7 (+3)
14 (+7)
21 (+3)
28 (+3)
35 (+3)
42 (+3)
72-77
30-35 days 
following last 
dose for Visit 8
(or Visit 4)d
Signed Informed Assent/Consent
X
Randomisation
X
X
Inclusion/exclusion criteria
X
Xa
Relevant Medical and Surgical history, SCD 
characteristics and history
X
Demographics
X
Vital signs (BP, pulse)
X
X
X
X
Xr
X
Xr
X
X
Physical examination
X
X
Weight, heighte
X
X
X
X
Transcranial Doppler examo
X
Ophthalmological (Eye) examo
X
12-lead ECGp
Xp
X
Daily pain assessmentg
X
X
X
X
X
X
X
X
FLACC assessmentq
X
X
Daily recording of analgesic useg
X
X
X
X
X
X
X
X
Days absent from school/workg
X
X
X
X
X
X
X
X
Administration of IP at clinici
X
X
X
X
Treatment dispensed/returneds
X
Xj
X
X
X
Xj
Compliance/ Drug accountability
X
X
X
X
X
X
X


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
32(66)
Table 1
Study Plan detailing the procedures 
Part A
Part B
Assessment
Enrolment
Dose 1
Dose 2
Repeated treatment phase
End of 
treatment
Follow-up
Visit
1m
2m
3
4l
5r
6
7r
8
9 l
Week
0
1
2
3
4
5
6
10
Day (Visit window)
-30 - -14
0
7 (+3)
14 (+7)
21 (+3)
28 (+3)
35 (+3)
42 (+3)
72-77
30-35 days 
following last 
dose for Visit 8
(or Visit 4)d
Acceptability/Palatabilityh
X
Concomitant medication
X
X
X
X
X
X
X
X
X
Adverse event review (AEs and SAEs)
Xf
X
X
X
X
X
X
X
X
Blood samples for haematology and clinical 
chemistry (incl uric acid)
Xn
Xk
X
Blood samples for coagulation (INR and PTT)
Xn
VerifyNow™PRUc
X
X
X
Pregnancy test (dipstick)b
X
X
Xb
X
Collection of VOC in CRF
X
X
X
X
X
X
X
X
Collection of transfusion data in CRF
X
X
X
X
X
X
X
X
Collection of bleeding events in CRF
X
X
X
X
X
X
X
X
Urinalysis
Xn
X
X
Blood sampling for pharmacokineticsc
X
X
X
Abbreviations: AE = adverse event; BP = blood pressure; CRF = Case Report Form; ECG = electrocardiogram; eCRF = electronic Case Report Form;
FLACC = Face, Legs, Activity, Cry, Consolability form; INR = International Normalised Ratio; PK = pharmacokinetics; PRU = P2Y12 reaction units; 
PTT = Partial Thromboplastin Time; SAE = serious adverse event; SCD = Sickle Cell Disease; VOC = vaso-occlusive crisis
a
Results from local laboratory must have been received before first dose to check eligibility criteria.
b
In patient after menarche. Pregnancy testing at Visit 4 is only applicable for patients NOT performing Part B.
c
Actual time of PK and PRU sampling should be recorded in the eCRF. See Table 2 and Table 3 for PK sampling time points.
d
May occur following earlier visits than Visit 9.
e
Height only at enrolment.
f
Only SAE assessed at this time.


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
33(66)
g
Electronic diary recording by patient ≥4 years (when needed with parent/guardian help).
h
Questions assessed by nurse in children <6 years, Hedonic Faces Scale (HFS) for children ≥6 years
i
Actual time of dosing should be recorded in the eCRF.
j
The time of drug administration in the morning and evening before Visit 4 and 8 will be registered in a patient diary.
k
Blood sample for haematology and clinical chemistry (including uric acid) at Visit 4 will be collected 2h post-dose together with PK and PRU.
l
If patient only participates in Part A, the follow-up Visit 9 should be performed after Visit 4 according to schedule.
m Visit 2 should be at least 14 days apart from Visit 1.
n
Laboratory testing performed prior to Visit 1 as part of usual clinical care does not need to be repeated as long as the values were obtained within 30 days 
prior to Visit 2.
o
The most recent examination must be performed within 12 months before Visit 1. If this is not the case, the examination must be done before proceeding 
in the study.
p
12-lead ECG must be performed within 6 months before Visit 1. If this is not the case, the examination must be done before proceeding in the study.
q
FLACC for patients aged from 2 to <4 years only to be collected between Visit 1 and Visit 2, and between Visit 4 and Visit 5.
r
Visit 5 and Visit 7 may be performed as telephone contacts, based on the opinion of the Investigator.  Vital signs (BP and pulse) will only be measured if 
the patient visits the site.
s
If Visit 5 and/or Visit 7 are performed as telephone contacts, doubles kits of study treatment will be dispended on Visit 4 and/or Visit 6 to cover the whole 
period.
During visits when investigational product is administered at clinic perform the following protocol procedures prior to 
administration of study drug (if applicable to the visit): 
Review of AEs and concomitant medications, vital signs, weight, ECG, urine sampling (including pregnancy test if applicable), and 
pre-dose blood sampling (safety, PK, PD).


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
34(66)
Table 2
Blood sampling in patients with a weight of >21 kg
Assessment
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Coagulation (INR and PTT)
X
Haematology and clinical 
chemistry (incl uric acid)
X
2h post-dose
X
VerifyNow™PRU
Pre-dose, 2, 6h
post-dose
Pre-dose, 2, 6h
post-dose
Pre-dose, 2h
post-dose
Blood sampling for 
pharmacokinetics
1, 2, 4, 6h
post-dose
1, 2, 4, 6h
post-dose
Pre-dose, 1, 
2h post-dose
Abbreviations: INR = International Normalised Ratio; PK = pharmacokinetics; PRU = P2Y12 reaction units; PTT = Partial Thromboplastin Time
The 1, 2, 4, and 6 hour samples can be collected ±15 minutes from actual post-dose time point.
If applicable, PRU and PK sampling should be arranged at the same time to avoid repeated venipuncture.
A peripheral catheter can be used for blood sampling.
Table 3
Blood sampling in patients with a weight of 16-21 kg
Assessment
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Coagulation (INR and PTT)
X
Haematology and clinical 
chemistry (incl uric acid)
X
2h post-dose
X
VerifyNow™PRU
Pre-dose, 2h
post-dose
Pre-dose, 2h
post-dose
Pre-dose, 2h
post-dose
Blood sampling for 
pharmacokinetics
1, 2, 4, 6h
post-dose
1, 2, 4, 6h
post-dose
Pre-dose, 1,
2h post-dose
Abbreviations: INR = International Normalised Ratio; PK = pharmacokinetics; PRU = P2Y12 reaction units; PTT = Partial Thromboplastin Time
The 1, 2 and 4 and 6 hour samples can be collected ±15 minutes from actual post-dose time point.
If applicable, PRU and PK sampling should be arranged at the same time to avoid repeated venipuncture.
A peripheral catheter can be used for blood sampling.


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
35(66)
4.1
Enrolment/screening period
Procedures will be performed according to the Study Plan Table 1. 
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. It is planned for a 
minimum of 36 patients and a maximum of 50 patients (including the patients already 
randomised to date) to be randomised in the study, in order to ensure 36 evaluable patients 
completing two single doses in Part A. A patient is considered as evaluable if he/she has 
provided data up to and including Visit 3. Of these 36 evaluable patients, at least 12 patients 
must be 2 to 11 years of age and 12 patients must be 12 to 18 years. In addition, a minimum of 
12 evaluable patients must complete Part B (through Visit 8).
A complete medical, surgical and medication history will be recorded for each patient at 
enrolment. All relevant medical conditions that have occurred within the past or conditions 
that are ongoing are to be recorded in the eCRF. The medication history must identify any 
known drug allergies, and use of chronic medications. Safety laboratory samples should be 
sent to the local laboratory for analysis.
If the patient is 16 years old or younger, a TCD must have been done within the past 1 year. If 
this is not the case, a TCD exam needs to be done before proceeding in the study.
If the patient is six years or older, an eye exam must have been done within the past 1 year. If 
this is not the case, the patient will need to be examined by an ophthalmologist before 
proceeding in the study. 
At least a 14-day interval is needed between Visit 1 and Visit 2 to allow for the recording of 
the baseline data on patient diary (see Section 5.1.2) and to separate the blood sampling in 
time considering total blood sampling volume recommendations in children.
4.2
Treatment period
Descriptions of the procedures for this period are included in the Study Plan with exceptions 
of the following specific requirements for the treatment period: 
The study consists of two parts, Part A: an open label part and Part B: a double blind part.
Part A:
Visit 2, 3 & 4: Randomisation will take place 14 to 30 days after enrolment. Patients will be 
randomised 1:1 to receive one of two dosing schedules, with each dose separated by 7 days. 
Platelet aggregation will be measured using the VerifyNow™ P2Y12 assay and reported as 
PRU. PRU will determine continued dosing. Patients are not allowed to eat 2 hours before and 
1 hour after dosing at these visits. Palatability assessment will be performed (Visit 2). A study 
nurse will assess palatability directly after administration of dose (for more information see 
Section 5.3). The patients will be allowed to leave the clinic after all sampling has been 
completed. Following the 2 single doses, all patients will receive open-label one-week 
treatment with ticagrelor twice daily to determine tolerability prior to randomisation into 


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
36(66)
Part B. Dose to be administered twice daily within a 9-12 hours interval (starting in the 
evening the same day as Visit 3). For assessments performed during the visits see Table 1. For 
dosing see Figure 2, and Appendix E in case of potential change to dosing schedule. Patients 
only participating in Part A will complete Visit 4, see below, which will be their last visit on 
treatment and after Visit 4 perform Visit 9 (30-35 days following last dose for Visit 4).
Part B: 
Visit 4, 5, 6, 7 & 8: Visit 4 will be performed in all patients, including those not continuing to 
Part B. Participation in Part B is optional. The patient will register actual date and time of drug 
administration the morning and evening before Visit 4 in a Dosing Diary. He/she will be 
instructed to not take their dose at home in the morning of Visit 4. Study drug will be 
administered at the clinic and actual time of dosing should be recorded in the eCRF at Visit 4. 
For patients not participating in Part B, visit 4 will be the last visit on treatment. For patients 
continuing into Part B, patients will be randomised (2:1 ratio) to ticagrelor twice daily or 
placebo for a 4-week treatment phase and will return to the clinic on a weekly basis for study 
related procedures. Visit 5 and Visit 7 may optionally be performed as telephone contacts, 
based on the opinion of the Investigator (See Table 1, Visit 4-8). For dosing see Figure 2, and 
Appendix E in case of potential change to dosing schedule.
Patients will be followed for the occurrence of VOC events and for other disease 
manifestations such as daily pain, analgesic use, and complications of SCD throughout the 
study. Daily pain (ages ≥4 years only) and analgesic use will be reported by the patient (or if 
needed with the help of parent/guardian) using an electronic diary (for more information see 
Section 5.3). Specification of whether analgesics have been opiod or non-opiod will be done 
at follow-up site visit. Days of absence from school or work (ages ≥6 years only) will be 
collected weekly using the same electronic device.
For safety reasons the dosing schedule will be modified for individual patients based on their 
PRU at Visit 2, 3 and 4 (see Figure 2). The dose modifications may occur at Visit 2, 3 and 4.


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
37(66)
Figure 2
Dosing schedule
4.3
Follow-up period
Procedures will be performed according to the Study Plan Table 1. 
5.
STUDY ASSESSMENTS 
The Rave 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 study protocol and in accordance with the instructions provided.
The Investigator ensures 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 eCRF. A copy of the completed eCRF will be 
archived at the study site.
5.1
Efficacy assessments
Clinical efficacy events will be collected in the eCRF and by using a daily electronic diary. 
These events will be identified using standard questioning of the patient at each visit, by 
information collected in the electronic dairy or by information that the Investigator may 
receive as part of standard medical practice. 
For each event, the Investigator will complete necessary information in the eCRF. The 
Investigator should use the following definitions in assessing potential VOC. 


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
38(66)
5.1.1
Vaso-occlusive crisis (VOC)
VOC is defined as a painful sickle cell crisis requiring medical intervention including any of 
the following (1) hospitalization (2) emergency department, short-stay unit or clinic visit (3) 
medically supervised outpatient treatment with escalated doses of drugs for management of 
painful crisis (may include oral or parenteral opioids or non-steroidal anti-inflammatory 
drugs). At each visit, patients or guardians will be questioned regarding any painful sickle cell 
crises occurring since the last study visit. 
5.1.2
Pain
Pain is commonly reported in clinical trials by having patients provide a rating of their own 
pain. 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. The Faces Pain Scale - Revised 
(FSP-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 to 16 years of age (Cohen et al 2008) and will be 
administered to all patients in this study age ≥4 years. When needed, a parent/guardian can 
help the child with the assessment. 
The Faces Pain Scale will be collected daily at bedtime using an electronic device. The scale 
consists of six faces and scoring ranges between 0-10 (with an increase in numeric value by 
2 i.e. (0, 2, 4, 6, 8, 10)), where 0 is no pain. If the patient answers that he/she has pain a body 
outline diagram will be presented and the patient will be asked to indicate the location of the 
pain. Please see Appendix G.
For patients aged from 2 to <4 years, a Face, Legs, Activity, Cry, Consolability (FLACC)
form will be used for recording daily pain, between Visit 1 and 2 and between Visit 4 and 5. 
The FLACC form will be completed daily at bedtime by the primary caregiver, with the 
assessment of the time when the child is under the caregiver’s care. If possible, the reporter 
should be the same caregiver during the reporting period. Please see Appendix G.
5.1.3
Other efficacy variables
Daily variables will be collected using a daily electronic diary both in Part A and Part B:
!
Days of analgesic use (ages ≥4 years only)
!
Days of absence from school or work (ages ≥6 years only), excluding days of 
absence due to study visits
For more details see Section 5.3.


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
39(66)
5.2
Safety assessments
5.2.1
Laboratory safety assessments
Blood and urine samples for determination of clinical chemistry, haematology, coagulation, 
and urinalysis will be taken at the times indicated in the Study Plan (see Table 1).
At Visit 1, laboratory testing performed prior to enrolment as part of usual care does not need 
to be repeated as long as the values are obtained no more than 30 days prior to Visit 2.
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator. The date, time of collection and results (values, units and reference ranges) will 
be recorded on the appropriate eCRF.
The clinical chemistry, haematology and urinalysis will be performed at the same local 
laboratory at or near to the Investigator site during the whole study. Sample tubes and sample 
sizes may vary depending on laboratory method used and routine practice at the site but it is 
crucial that the blood volume is not exceeding the volume stated in Table 6 and Table 7. 
Urinalysis is to be performed at the investigational site by dipstick. A urine pregnancy test (U-
HCG) will be taken at Visit 1, Visit 2 and repeated at Visit 4 (for patients only completing 
Part A) or Visit 8 (for patients completing Part B) in 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 visit.
The following laboratory variables will be measured:
Table 4
Laboratory Safety Variables
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum) 
B-Haemoglobin (Hb) 
S-Creatinine
B-Haematocrit
S-Bilirubin, total
B-Leukocyte count
S-Alkaline phosphatise (ALP)
B-Leukocyte differential count (absolute count)
S-Aspartate transaminase (AST)
B-Platelet count
S-Alanine transaminase (ALT)
S-Uric acid
Urinalysis (dipstick)
S-Blood Urea Nitrogen (BUN)
U-Hb/Erythrocytes/Blood
S-Na
U-Protein/Albumin
S-Cl
U-Glucose
S-K
U-Specific gravity
S-Glucose
S-CO2
Coagulation
International Normalised Ratio (INR)


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
40(66)
Partial Thromboplastin Time (PTT)
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities. The laboratory results should be signed and dated and retained at 
centre 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 subject shows an Aspartate transaminase (AST) or Alanine transaminase (ALT)
≥3x Upper Limit of Normal (ULN) or total bilirubin ≥2x ULN please refer to Appendix D 
‘Actions required in cases of combined increase of Aminotransferase and Total Bilirubin -
Hy’s Law’, for further instructions.
5.2.2
Physical examination
A complete physical examination will be performed at enrolment and at the follow-up visit 
(Visit 9) and 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 (including spine and extremities) and neurological systems.
5.2.3
Vital signs
Vital signs consist of sitting pulse, sitting blood pressure (BP), weight and height.
BP and pulse will be measured at every on-site visit. Weight will be measured at 
Visit 1(enrolment), 2, 3 and 8 (follow-up). Height will only be measured at enrolment.
5.2.4
Electrocardiogram
12-lead ECG will be performed at Visit 1 (or within 6 months prior to enrolment) and at 
Visit 4. The following ECG parameters will be collected: heart rate and rhythm, PR interval, 
QRS duration, RR interval, QT interval, QTc interval (unspecified), and any abnormalities.
5.3
Other assessments 
5.3.1
Patient reported outcomes
Patient reported outcomes (PROs) are an umbrella term referring to all outcomes and 
symptoms that are directly reported by the patient. In addition to the PROs for efficacy 
described in Section 5.1.2, the following PROs will be administered: Palatability Assessment, 
Use of analgesic, and Days of absence from school/work.
Many Investigators cite palatability as an important factor in determining medication 
adherence and completion of drug therapy in children. It is reasonable to assume that a better 
tasting drug is easier to administer to infants and young children (Matsui 2007). The 
palatability of the study drug will be assessed at Visit 2.
5.3.1.1
Palatability assessment by age group
The Facial Hedonic Scale (FHS) is a well-established method for assessing paediatric 
patients’ responses to drug palatability (Davies and Tuleu 2008). The literature indicates that 


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
41(66)
the facial hedonic scale can be used for patients down to 3 years of age. The FHS consists of 
five faces with descriptions from ‘Dislike very much’ to ‘Like very much’. For infants and 
very young children, a study nurse observing the child’s behaviour when having received the 
study medication can perform an assessment of palatability.
Palatability will be assessed at Visit 2. Patients ≥6 years old will be asked to evaluate 
palatability immediately after dosing using the Hedonic Faces Scale. For patients under 
6 years of age a nurse’s assessment of the patient’s behaviour, including willingness to 
swallow, will be performed directly after the patient has received the investigational product. 
For more information please see Appendix G.
Table 5
Palatability assessment
Method
Age group 
Facial Hedonic Scale completed by patient
≥6 years to <18 years
Willingness to swallow, patient’s behaviour indicative of a negative 
response to the taste of the investigational product
2 years to <6 years
5.3.1.2
Use of analgesic
Patients will be asked about their use of analgesics. When needed a parent/guardian can help 
the child with the assessment. The question ‘Have you taken any medication because of your 
pain today’ will be administered daily in the electronic device. Response options will be 
dichotomous, i.e. ‘Yes’ or ‘No’. The question should be answered daily at bedtime. 
Specification of whether analgesics have been opiod or non-opiod will be done at follow-up 
site visit.
5.3.1.3
Absence from school/work
For patients aged ≥6 years, absence from school/work will be recorded. 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 
school due to study visits will not be recorded.
5.4
Pharmacokinetics
5.4.1
Collection of samples
Blood samples for determination of ticagrelor and its active metabolite in plasma will be taken 
at the times presented in the study plan 


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Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
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Table 2. The actual date and time will be collected in the eCRF.
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 drug concentration in plasma will be analysed by 
on 
behalf of AstraZeneca, using an LC/MS after protein precipitation. The lower limit of 
quantification of ticagrelor and its active metabolite in plasma is 1.00 ng/mL and 2.50 ng/mL, 
respectively. 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
PK samples will be disposed of after the Bioanalytical Report finalization or 6 months after 
issuance of the draft Bioanalytical Report (whichever is earlier), unless requested for future 
analyses. 
PK samples may be disposed of or destroyed and anonymised by pooling. Additional analyses 
may be conducted on the anonymised, pooled pharmacokinetic 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.
Any residual back-up PK samples may be used for future exploratory biomarker research (in 
this case, residual back-up PK samples will be shipped to AZ Biobank; see details in the 
Laboratory Manual).
5.5
Pharmacodynamics
5.5.1
VerifyNow∀P2Y12 assay
The VerifyNow∀P2Y12 test is a whole blood test used in the point-of-care setting to measure 
the level of platelet P2Y12 receptor blockade. Light transmittance increases as activated 
platelets bind and aggregate fibrinogen-coated beads. The instrument measures this change in 
optical signal and reports results in PRU. PRU <95 is associated with increased risk of 
bleeding based on data from patients with ACS.
Blood samples for determination of PRU in whole blood will be taken at the times presented 
in 
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Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
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Table 2. The actual date and time will be collected in the eCRF. VerifyNow™P2Y12 assay 
will be used.
5.5.2
Collection of samples
Samples will be collected and labeled as detailed in the VerifyNow User’s Manual. In 
addition, to reduce the blood volume required for the PD and PK samples, the following 
procedures will be utilized.
!
For VerifyNow samples obtained through a peripheral indwelling cannula: Discard 
saline remaining in the cannula and 1 mL of blood. Draw 1.2 mL for PK sample 
(discard this blood if there is no PK sample at this time point). Draw 2 mL into the 
VerifyNow partial fill tube.
!
For VerifyNow samples obtained through a central indwelling line: Discard saline or 
flush solution and 3.8 mL of blood. Draw 1.2 mL for PK sample (discard this blood if 
there is no PK sample at this time point). Draw 2 mL into the VerifyNow partial fill 
tube.
!
For samples obtained through direct phlebotomy: Use a 21 gauge or larger needle or 
butterfly device and ensure an atraumatic venipuncture. Draw and discard 1 mL of 
blood. Draw 1.2 mL for PK sample (discard this blood if there is no PK sample at this 
time point). Draw 2 mL into the VerifyNow partial fill tube.
5.6
Pharmacogenetics (Not Applicable)
5.7
Biomarker analysis (Not Applicable)


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Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
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5.8
Volume of blood 
The total volume of blood that will be drawn from each patient is shown in Table 6 and Table 7.
Table 6
Volume of blood to be drawn from patients with a weight >21 kg
Assessment
Sample 
volume 
(mL)
No. of 
samples 
Visit 1
Total 
volume 
Visit 1 
(mL)
No. of 
samples 
Visit 2
Total 
volume 
Visit 2 
(mL)
No. of 
samples 
Visit 3
Total 
volume 
Visit 3 
(mL)
No. of 
samples 
Visit 4
Total 
volume 
Visit 4 
(mL)
No. of 
samples 
Visit 8
Total 
volume 
Visit 8 
(mL)
Total 
(mL)
Haematology
1.2
1
1.2
0
0
0
0
1
1.2
1
1.2
Clinical 
Chemistry
1.1
1
1.1
0
0
0
0
1
1.1
1
1.1
Coagulation
1.2
1
1.2
0
0
0
0
0
0
0
0
Pharmacokinetic
1.2
0
0
2
2.4
2
2.4
1
1.2
0
0
PRU*
4.0
0
0
1
4.0
1
4.0
0
0
0
0
Pharmacokinetic 
+ PRU**
4.2
0
0
2
8.4
2
8.4
2
8.4
0
0
Total
3.5
14.8
14.8
11.9
2.3
47.3
* PRU sampling via a central catheter may require up to an additional 3 mL at each PRU sampling timepoint.
** Timepoint with both PRU + PK required volume is 4.2 mL total for both.


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Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
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Table 7
Volume of blood to be drawn from patient with a weight of 16-21 kg
Assessment
Sample 
volume 
(mL)
No. of 
samples 
Visit 1
Total 
volume 
Visit 1 
(mL)
No. of 
samples 
Visit 2
Total 
volume 
Visit 2 
(mL)
No. of 
samples 
Visit 3
Total 
volume 
Visit 3 
(mL)
No. of 
samples 
Visit 4
Total 
volume 
Visit 4 
(mL)
No. of 
samples 
Visit 8
Total 
volume 
Visit 8 
(mL)
Total 
(mL)
Haematology
1.2
1
1.2
0
0
0
0
1
1.2
1
1.2
Clinical 
Chemistry
1.1
1
1.1
0
0
0
0
1
1.1
1
1.1
Coagulation
1.2
1
1.2
0
0
0
0
0
0
0
0
Pharmacokinetic
1.2
0
0
3
3.6
3
3.6
1
1.2
0
0
PRU*
4.0
0
0
1
4.0
1
4.0
0
0
0
0
Pharmacokinetic 
+ PRU**
4.2
0
0
1
4.2
1
4.2
2
8.4
0
0
Total
3.5
11.8
11.8
11.9
2.3
41.3
* PRU sampling via a central catheter may require up to an additional 3 mL at each PRU sampling timepoint.
** Timepoint with both PRU + PK required volume is 4.2 mL total for both.
Reference Ethical considerations paediatric 2008
The maximum blood withdrawal during any 4 week period is 41.5 mL for patients weighing >21 kg and 35.5 mL for patients 
weighing 16-21 kg.


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Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
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6.
SAFETY REPORTING AND MEDICAL MANAGEMENT
The Principal Investigator (PI) is responsible for ensuring that all staff involved in the study is 
familiar with the content of this section.
6.1
Definition of adverse events
An AE is the development of an undesirable medical condition or the deterioration of a pre-
existing medical condition following or during exposure to a pharmaceutical product, whether 
or not considered causally related to the product. An undesirable medical condition can be 
symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal 
results of an investigation (e.g., laboratory findings, ECG). In clinical studies, an AE can 
include an undesirable medical condition occurring at any time, including run-in or washout 
periods, even if no study treatment has been administered.
The term AE is used to include both serious and non-serious AEs.
6.2
Definitions of serious adverse event
A SAE is an AE occurring during any study phase (i.e., run-in, treatment, washout, follow-
up), that fulfils one 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/incapacity or substantial disruption of 
the ability to conduct normal life functions
!
Is a congenital abnormality or birth defect
!
Is an important medical event that may jeopardise the subject or may require 
medical intervention to prevent one of the outcomes listed above
For further guidance on the definition of a SAE, see Appendix B to the Clinical Study 
Protocol (CSP).
6.3
Recording of adverse events
6.3.1
Time period for collection of adverse events
AEs will be collected from first randomisation (Visit 2) throughout the treatment period and 
including the follow-up period up to Visit 9.
SAEs will be recorded from the time of informed consent and throughout the study.


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Drug Substance Ticagrelor
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Edition Number 3
Date 22 December 2015
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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 
eCRF. AstraZeneca retains the right to request additional information for any subject with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
6.3.3
Variables 
The following variables will be collect for each AE;
!
AE (verbatim)
!
The date and time when the AE started and stopped (time to be collected only at 
Visit 2 to end of Visit 3)
!
Maximum intensity
!
Whether the AE is serious or not
!
Investigator causality rating against the Investigational Product (yes or no)
!
Action taken with regard to investigational product
!
AE caused subject’s withdrawal from study (yes or no)
!
Outcome
In addition, the following variables will be collected for SAEs:
!
Date AE met criteria for serious AE
!
Date Investigator became aware of serious AE
!
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 in relation 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 


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Edition Number 3
Date 22 December 2015
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shown in Section 6.2. On the other hand, a stroke that results in only a limited degree of 
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:
1. Mild (awareness of sign or symptom, but easily tolerated)
2. Moderate (discomfort sufficient to cause interference with normal activities)
3. Severe (incapacitating, with inability to perform normal activities)
6.3.4
Causality collection
The Investigator will assess causal relationship between Investigational Product 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 investigational product?’
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 B to the CSP.
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 personnel: ‘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 CRF. 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.


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6.3.6
Adverse events based on examinations and tests
The results from protocol mandated laboratory tests and vital signs will be summarised in the 
CSR. Deterioration as compared to 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 investigational product.
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 (e.g., 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.
6.3.7
Hy’s Law
Cases where a subject shows an AST or ALT ≥3xULN or total bilirubin ≥2xULN may need to 
be reported as SAEs. Please refer to Appendix D for further instruction in cases of combined 
increase of aminotransferase and total bilirubin.
6.3.8
Assessment of bleeding events
One of the safety objectives in this study is to determine the percent of patients with 
haemorrhagic events requiring medical intervention. Bleeding events will be recorded as AEs. 
The Investigator will do the classification of bleeding events; there will be no committee for 
assessment of these events.
Bleeding events will be recorded in the bleeding event eCRF.
For patients experiencing a bleeding event that fulfils criteria in more than one category, the 
bleed will be assigned to the most severe category. The bleeding definitions are (Mitchell et 
al 2011):
Major bleeding: defined as any fatal bleeding, clinically overt bleeding associated with a 
decrease in Hb of at least 20 g L-1 (2 g dL-1), bleeding that is retroperitoneal, pulmonary, 
intracranial, or otherwise involves the CNS 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 hemostasis, 
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. 


Revised Clinical Study Protocol
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Study Code D5136C00007
Edition Number 3
Date 22 December 2015
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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)
VOC will be recorded as AEs. For definition of VOC please see Section 5.1.1.
6.4
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the CRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate
 representatives within one day i.e., immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated 
 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 adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately. Investigators or other site personnel inform 
 representatives of any follow-up information on a previously reported SAE within one 
calendar day i.e., 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 
 and/or AstraZeneca representative.
If the WBDC system is not available, then the Investigator or other study site personnel 
reports a SAE to the appropriate 
 representative by telephone.
The 
 representative will advise the Investigator/study site personnel how to proceed. 
The reference document for definition of expectedness/listedness is the Investigator’s 
Brochure for the AstraZeneca drug. 
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.
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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 with VerifyNow 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 eCRF and on the Overdose eCRF module.
!
An overdose without associated symptoms is only reported on the Overdose eCRF 
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 
 representatives immediately, or 
no later than 24 hours of when he or she becomes aware of it.
The designated 
 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 other overdoses, reporting must occur within 30 days.
6.6
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to 
6.6.1
Maternal exposure
Women of childbearing potential are not allowed to be included in this study unless they use a 
highly effective method of contraception which results in a low failure rate (i.e. less than 1% 
per year), and must refrain from becoming pregnant from 1 month following the last dose. 
Should a pregnancy still occur, the investigational product should be discontinued 
immediately and the pregnancy reported to designated ICON representative within 1 day.
6.6.2
Paternal exposure 
There are no restrictions against fathering a child when treated with ticagrelor. 
6.7
Management of Investigational Product related toxicities 
Please see Section 3.9 and 3.11.
6.8
Study governance and oversight
6.8.1
Steering Committee (SC)
The SC 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 
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of the clinical study. A member of the SC will be designated as the Coordinating Investigator 
and will be responsible for review and signature of the CSR.
The SC will also be responsible for the overall design, including the development of any 
protocol amendments, supervision, interpretation and reporting (presentations at international 
congresses and publications in peer reviewed journals) of the study. The SC will make 
recommendations to AstraZeneca with regard to early stopping or modifications of the study 
based on accumulated study data (data from the double blind phase will be reviewed without 
unblinding). The SC will be comprised of 2 to 3 Investigators in the study and non-voting 
members of the Sponsor, and will operate under a separate charter. 
The SC charter will be prepared to detail precise roles and responsibilities and procedures to 
ensure integrity of the study in the review of accumulating data.
In addition AstraZeneca representatives in consultation with the AZ Patient Safety 
Department closely monitor the safety of all AstraZeneca clinical studies on an on-going 
basis. Issues identified will be addressed; for instance this could involve amendments to the 
study protocol and letters to Investigators.


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
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7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS 
7.1
Identity of investigational product(s)
Investigational product
Dosage form and strength
Manufacturer
Ticagrelor 
Granules for oral suspension 45 mg
Almac Pharma Services
Matching placebo for Ticagrelor 
Granules for oral suspension
Almac Pharma Services
Ticagrelor granules for suspension and its matching placebo will be provided in brown glass 
bottles containing 1 g of granules.
7.2
Dose and treatment regimens
Part A:
Open-label single doses (Visit 2 and 3):
All patients will receive 0.75 mg/kg as their initial dose, followed 7 days later by 1.125 mg/kg 
or 2.25 mg/kg. Single doses will be administered at the clinic by site staff. Patients are not 
allowed to eat 2 hours before and 1 hour after dosing at Visit 2 and 3.
Repeated dosing (Visit 3-4):
Patients will self-administer 0.75 mg/kg of open label ticagrelor for 1 week. Dose to be 
administered twice daily within a 9-12 hours interval. The first dose will be administered in 
the evening the same day as Visit 3. 
Doses may be adjusted following assessment by AstraZeneca and the Steering Committee of 
open label Part A results in the first 6-12 patients. Dose adjustment decisions will be based 
upon a review of PK, PD and adverse events (see Section 8.6).
Part B:
Repeated dosing (Visit 4-8):
Randomisation to twice daily treatment with ticagrelor or placebo will occur at Visit 4. 
Patients will self-administer 0.75 mg/kg of ticagrelor dose or placebo for 4 weeks. Dose will
be administered twice daily within a 9-12 hours interval. The first dose will be administered in 
the evening the same day as Visit 4. 
Doses may be adjusted following assessment by AstraZeneca and the Steering Committee of 
open label Part A results in the first 6-12 patients. Dose adjustment decisions will be based 
upon a review of PK, PD and adverse events (see Section 8.6).


Revised Clinical Study Protocol
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Study Code D5136C00007
Edition Number 3
Date 22 December 2015
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Before each dosing occasion the granules will be constituted with 10 mLof purified water to 
form a homogenous suspension suitable for oral dosing. Dosing will be weight based and a 
suitable volume of suspension should be withdrawn from the bottle using a syringe suitable 
for oral dosing. For more information regarding volume to be administered please see dose 
tables, appendix F. The dose tables are based on predefined weight brackets in order to ensure 
dose accuracy and that the correct treatment strength is given to patient. All patients will 
receive a handling instruction together with study drug at each visit starting at Visit 3. The 
Investigator will enter the individual volume to be given in the handling instruction before the 
patient leaves the clinic.
For safety reasons the dosing schedule will be modified for individual patients based on their 
PRU at Visit 2, 3 and Visit 4, see Figure 2. The dose modifications may occur at Visit 2, 3
and 4.
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. 
7.4
Storage
All study drugs should be kept in a secure place under appropriate storage conditions. The 
investigational product label on the bottles specifies the appropriate storage.
7.5
Compliance
The single doses (Visit 2 and 3) will be administered by the study personnel to the patients in 
Part A. 
In the repeated dosing part, the patient will bring the investigational product (active or 
placebo) to their home, with instructions for mixing the appropriate weight-based dose. The 
patients will receive a Dosing Diary to record intake of investigational products (active or 
placebo). 
The administration of all investigational products (active or placebo) should be recorded in the 
appropriate sections of the eCRF. Time of dose intake (both in the morning and evening) 
should be recorded on the day before Visit 4 and 8.
Compliance will also be checked by measurement of PRU at Visit 4 and Visit 8 (if 
applicable).
7.6
Accountability
The study drug provided for this study will be used only as directed in the study protocol.
The study personnel will account for all study drugs dispensed to and returned from the 
patient.


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Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
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Study site personnel or the
 monitor will account for all study drugs received at the site, 
unused study drugs and for appropriate destruction. Certificates of delivery, destruction and 
return should be signed. 
7.7
Concomitant and other treatments 
Use of ADP receptor blockers (eg. clopidogrel, prasugrel, ticlopidine), dipyridamole and 
cilostazol is not allowed in the study.
Treatment with oral or parenteral anticoagulants, and daily aspirin is not allowed in the study 
except for prophylactic doses of heparins, eg, flushing of catheters (see exclusion criteria in 
Section 3.2). NSAIDs may not be administered more frequently than 3 days per week.
CYP3A4 inhibitors
Concomitant use of inhibitors of CYP3A4 (eg, atanazavir, boceprevir, clarithromycin, [but not 
erythromycin or azithromycin], conivaptan, indinavir, itraconazole, ketoconazole, 
lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, 
telaprevir, telithromycin, voriconazole) is not allowed. 
CYP3A4 substrates or inducers
Co-administration of CYP3A4 substrates with a narrow therapeutic index is not allowed. Co-
administration of strong inducers of CYP3A4 (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 
investigational product and with any change in investigational product.
7.7.1
Blood transfusion
If a patient requires any blood transfusion during the study, this information will be captured 
in the eCRF.
7.7.2
Other concomitant treatment
Other medication other than that described above, which is considered necessary for the 
patient’s safety and well-being, may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the eCRF.
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7.8
Post Study Access to Study Treatment (Not applicable)
8.
STATISTICAL ANALYSES BY 
8.1
Statistical considerations 
A Statistical Analysis Plan containing further details will be prepared before first enrolled 
subject.
8.2
Sample size estimate
No formal sample size calculation has been performed. The sample size was selected to 
provide adequate PK/PD data to support the modelling-based dose selection and at the same 
exposing a minimum number of patients.
8.3
Definitions of analysis sets
8.3.1
Efficacy analysis set
All patients randomised in Part B will be included in the efficacy analysis set. Patients will be 
analysed according to their randomised study medication. 
8.3.2
Safety analysis set
All patients who received at least one single dose of ticagrelor or at least one dose of 
randomised investigational product, ticagrelor or placebo, will be included in the safety 
population.
8.3.3
PK analysis set
The pharmacokinetic analysis set is a subset of the safety analysis set, including all patients 
having at least one PK variable calculated.
8.3.4
PD analysis set
The PD analysis set is a subset of the safety analysis set, including all patients having at least 
one PRU measured.
8.4
Outcome measures for analyses (Not applicable)
8.5
Methods for statistical analyses
The relationship between ticagrelor dose, plasma concentration and PRU will be characterized 
using a population PK/PD approach (i.e non-linear mixed effect modelling). This analysis will 
be based on all available PK and PRU data from which complete dosing and sampling history 
is collected. The PK/PD analyses will be performed sequentially, where first the PK of 
ticagrelor and its active metabolite will be characterized and followed by characterizing of the 
PK/PD relationship. Prior PK/PD knowledge from ticagrelor in adult ACS patients will serve 
as basis during analyses. A detailed analysis plan will be written prior to data base lock.
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Drug Substance Ticagrelor
Study Code D5136C00007
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Date 22 December 2015
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No statistical comparisons are planned for the primary objective. PK, PD and safety measures 
will be summarized descriptively using respective analysis set. Palatability measures will also 
be summarized descriptively for all patients for whom the assessment is performed.
A statistical analysis comparing ticagrelor and placebo will be performed for each of the 
following variables using the efficacy analysis set for Part B of the study:
!
Percentage of days with pain (ages ≥4 years only)
!
Percentage of days of opioid analgesic use
!
Percentage of days of analgesic use (ages ≥4 years only)
!
Percentage of days hospitalized for VOC or other complications of SCD
!
Percentage days of absence from school or work (ages ≥6 years only)
A t-test will be performed for each of these variables at 5% significance level, provided that 
the efficacy analysis set contains at least 30 patients, otherwise only descriptive statistics will 
be used. The p-value and a 95% confidence interval for the difference between ticagrelor and 
placebo will be reported. There will be no adjustment for multiple comparisons. If it is 
inappropriate to assume a normal distribution, a Wilcoxon rank sum test may be performed. In 
case more than one adult equivalent dose is studied in Part B, the analysis will be repeated 
both for all ticagrelor doses versus placebo and for the dose the majority of patients received 
versus placebo.
Number of VOC, number of VOC requiring hospitalization and intensity of pain will be 
summarized descriptively by treatment group in Part B.
Efficacy variables collected in Part A, i.e. percentage of days with pain, percentage of days of 
opioid analgesic use, percentage of days of analgesic use, percentage of days of absence from 
school or work and intensity of pain will be summarized descriptively using the safety 
analysis set. 
Exploratory variables, days with pain and intensity of pain (ages <4 years only), will be 
presented descriptively using the safety analysis set.


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
58(66)
8.6
Interim analysis and potential further dose adjustments
An interim analysis was conducted per protocol after 12 patients had completed dosing in part 
A. The mean PRU reduction 2 hours post-dose at Visit 4 was <20%, and plasma ticagrelor 
concentrations were lower than expected. This triggered a protocol amendment to increase the 
weight-adjusted dosing in order to achieve a higher level of platelet inhibition.
Doses may be further adjusted following assessment by AstraZeneca and the Steering 
Committee of Part A results in the first 6-12 patients randomised under this amendment. Dose 
adjustment decisions will be based upon a review of PK, PD and adverse events and will 
apply only to patients randomised subsequent to the dose change decision.
For more details on potential dose adjustment see Appendix E.


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
59(66)
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA
9.1
Training of study site personnel
Before the first patient is entered into the study, AstraZeneca or its representatives will review 
and discuss the requirements of the CSP and related documents with the investigational staff 
and also train them in any study specific procedures and the WBDC and ePROs system(s) 
utilised.
The PI will ensure that appropriate training relevant to the study is given to all of these staff, 
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).
Site training will be recorded on the site-training log.
9.2
Monitoring of the study
During the study, AstraZeneca or its representatives 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 protocol, that data are being 
accurately and timely recorded in the eCRFs, 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 eCRFs with the 
subject’s medical records at the hospital or practice, and other records relevant to 
the study) including verification of informed consent/assent of participating 
patients. This will require direct access to all original records for each patient (e.g., 
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 /destroyed 
accordingly, and the action is documented, and reported to the patient
AstraZeneca or its representatives 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
Please see the CSA for location of source data.


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
60(66)
9.2.2
Study agreements
The PI at each/the 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 CSP and the 
CSA, the terms of CSP shall prevail with respect to the 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 or
 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 subject undergoing the study’.
The study is expected to start in Q3 2014 and to end by Q1 2017.
The Sponsor will notify the PI(s) when recruitment is complete.
The study may be terminated at individual centres if the study procedures are not being 
performed according to GCP, or if recruitment is slow. AstraZeneca may also terminate the 
entire study prematurely if concerns for safety arise within this study or in any other study 
with ticagrelor.
9.4
Data management by AstraZeneca or delegate
Data management will be performed by 
.
The data collected through third party sources will be obtained and reconciled against study 
data.
AE and medical/surgical history will be classified according to the terminology of the latest 
version the Medical Dictionary for Regulatory Activities (MedDRA). Medications will be 
classified according to the AstraZeneca Drug Dictionary. All coding will be performed by 
Data queries will be raised for inconsistent, impossible or missing data. All entries to the study 
database will be available in an audit trail.
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.
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Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
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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.
Serious Adverse Event (SAE) Reconciliation
SAE reconciliation reports are produced and reconciled with the Patient Safety database 
and/or the investigational site. 
Data associated with biological samples will be transferred from laboratory(ies) internal or 
external to AstraZeneca.
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 Conference on Harmonisation 
(ICH)/Good Clinical Practice (GCP), applicable regulatory requirements and the AstraZeneca 
policy on Bioethics and Human Biological Samples.
10.2
Subject data protection
The Informed Consent Form (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 study 
protocol, including the final version(s) of the assent/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 or its representatives 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 assent/ICF that are needed to meet local 
requirements.
If required by local regulations, the protocol should be re-approved by the EC/IRB annually.
Before enrolment of any patient into the study, the national regulatory authority approves the 
final study protocol, including the final version of the assent/ICF, or a notification to the 
national regulatory authority is done, according to local regulations.


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
62(66)
AstraZeneca or its representatives will handle the distribution of any of these documents to the 
national regulatory authorities.
AstraZeneca or its representatives will provide Regulatory Authorities, EC/IRB and PIs 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 investigational product. 
AstraZeneca or its representatives will provide this information to the PI so that he/she can 
meet these reporting requirements.
10.4
Informed consent
The PI (s) at each centre will:
!
Ensure each patient, parent or legal guardian is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the study 
(before any study procedures are performed) as per local requirements. The 
assent/ICF form needs to be adjusted as per local requirements
!
Ensure each patient, parent or legal guardian is notified that they are free to 
discontinue from the study at any time
!
Ensure that each patient, parent or legal guardian is given the opportunity to ask 
questions and allowed time to consider the information provided
!
Ensure each patient, parent or legal guardian provides signed and dated 
assent/informed consent before conducting any procedure specifically for the study. 
Local regulations are to be followed in determining the assent/consent requirements 
for children of different age groups
!
Ensure the original, signed assent/ICF(s) is/are stored in the Investigator’s Study 
File
!
Ensure a copy of the signed assent/ICF is given to the patient, parent or legal 
guardian
!
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 informed consent form that is approved by an EC/IRB
10.5
Changes to the protocol and informed consent form
Study procedures will not be changed without the mutual agreement of the PI and 
AstraZeneca.
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol (Revised Clinical Study Protocol).


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
63(66)
The amendment is to be approved by the relevant Ethics Committee and if applicable, also the 
national regulatory authority approval, before implementation. Local requirements are to be 
followed for revised protocols.
AstraZeneca will distribute any subsequent amendments and new versions of the protocol to 
each PIs. For distribution to EC see Section 10.3.
If a protocol amendment requires a change to a centre’s ICF, AstraZeneca and the centre’s EC
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 Ethics Committee.
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 protocol, GCP, guidelines of the ICH, and 
any applicable regulatory requirements. The Investigator will contact AstraZeneca 
immediately if contacted by a regulatory agency about an inspection at the centre.
11.
LIST OF REFERENCES
Adams et al 1998
Adams RJ, Mckie V, Hsu L et al. Prevention of a first stroke by transfusions in children with 
sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J 
Med 1998;339(1):5-11
Ataga et al 2012
Ataga KI, Brittain JE, Desai P, May R, Jones S, Delaney J et al. Association of coagulation 
activation with clinical complications in sickle cell disease. 
PLoS ONE 2012;7(1) doi:10.1371/journal.pone.0029786
Ballas 2007
Ballas SK. Current issues in sickle cell pain and its management. 
Hematology Am Soc Hematol Educ Program 2007:97-105
Bulas et al 2005
Bulas D. Screening children for sickle cell vasculopathy: guidelines for transcranial Doppler 
evaluation. Paediatric Radiology 2005;35:235-241


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
64(66)
Cabannes et al 1984
Cabannes R, Lonsdorfer J, Castaigne JP, Ondo A, Plassard A, Zohoun I et al. Clinical and 
biological double-blind-study of ticlopidine in preventive treatment of sickle-cell crises. 
Agents Actions 1984;Suppl 15:199-212
Chaplin et al 1980
Chaplin H, Alkjaersig N, Fletcher AP, Michael JM, Joist JH. Aspirin-dipyridamole 
prophylaxis of sickle cell disease pain crises. Thromb Haemost 1980;43:218-21
Charneski and Congdon 2010
Charneski L and Congdon HB. Effects of antiplatelet and anticoagulant medications on the 
vasoocclusive and thrombotic complications of sickle cell disease: A review of the literature. 
Am J Health-Syst Pharm 2010;67:895-900
Cohen et al 2008
Cohen L, Lemanek K, Blount R, Dahlquist L, Lim C, Palermo T et al. Evidence-based 
assessment of paediatric pain. J Pedatric Psychology 2008;33(9):939-55
Davies and Tuleu 2008
Davies EH and Tuleu C. Medicines for children: a matter of taste. 
J Pediatrics 2008;153(5):599-604
Ethical considerations paediatric 2008
Recommendations of the ad hoc group for the development of implementing guidelines for 
Directive 2001/20/EC relating to good clinical practice in the conduct of clinical trials on 
medicinal products for human use (Final, 2008)
FDA Office of Surveillance and Epidemiology report, 2013
FDA Office of Surveillance and Epidemiology. Pediatric Postmarket Pharmacovigilance and 
Drug Utilization Review. Plavix (clopidogrel bisulfate), June 5, 2013
Giglia et al 2013
Giglia TM, Massicotte MP, Tweddell JS, Barst RJ, Bauman M, Erickson CC et al, on behalf 
of the American Heart Association Congenital Heart Defects Committee of the Council on 
Cardiovascular Disease in the Young, Council on Cardiovascular and Stroke Nursing, Council 
on Epidemiology and Prevention, and Stroke Council. Prevention and treatment of thrombosis 
in pediatric and congenital heart disease: A scientific statement from the American Heart 
Association. Circulation 2013;128:2622-2703
Greenberg et al 1983
Greenberg J, Ohene-Frempong K, Halus J, Way C, Schwartz E. Trial of low doses of aspirin 
as prophylaxis in sickle cell disease. J Pediatrics 1983;102:781-4
Heeney et al 2015
Heeney MM, Hoppe CC, Abboud MR, Inusa B, Kanter J, Ogutu B et al. A multinational trial 
of prasugrel for sickle cell vaso-occlusive events.


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
65(66)
NEJM, online before print Dec 8, 2015
Hicks et al 2001
Hicks C, Baeyer C, Spafford P, Korlaar I, Goodenough B. The faces pain scale - revised: 
toward a common metric in pediatric pain measurement. Pain 2001;93(2):173-83 
Htun and Steinhubl 2013
Htun WW and Steinhubl SR. Ticagrelor: the first novel reversible P2Y12 inhibitor. 
Expert Opin Pharmacother 2013;14(2):237-45
Jeong et al 2012
Jeong YH, Bliden KP, Antonino MJ, Park KS, Tantry US, Gurbel PA. Usefulness of the 
VerifyNow P2Y12 assay to evaluate the antiplatelet effects of ticagrelor and clopidogrel 
therapies. Am Heart J 2012;164:35-42
Lee et al 2006
Lee SP, Ataga KI, Orringer EP, Phillips DR, Parise LV. Biologically active CD40 ligand is 
elevated in sickle cell disease: potential role for platelet mediated inflammation. 
Arterioscler Thromb Vasc 2006;26:1626-31
Lee et al 2007
Lee SP, Ataga KI, Zayed M, Manganello JM, Orringer EP, Phillips DR et al. Phase 1 study of 
eptifibatide in patients with sickle cell anaemia. Brit J Haematol 2007;139:612-20
Matsui 2007
Matsui D. Assessing the palatability of medications in children. 
Paediatric and Perinatal Drug Therapy 2007;8(2):55-60
Mitchell et al 2011
Mitchell LG, Goldenberg NA, Male C, Kenet G, Monagle P, Nowak-Göttl U. Definition of 
clinical efficacy and safety outcomes for clinical trials in deep venous thrombosis and 
pulmonary embolism in children. J Thromb Haemost 2011;9:1856-8
Nylander et al 2013
Nylander S, Femia EA, Scavone M, Berntsson P, Asztély AK, Nelander K et al. Ticagrelor 
inhibits human platelet aggregation via adenosine in addition to P2Y12 antagonism. 
J Thromb Haemost 2013;11(10):1867-76
Osamo et al 1981
Osamo NO, Photiades DP, Famodu AA. Therapeutic effect of aspirin in sickle cell anemia. 
Acta Haematol 1981;66:102-7
Polanowska-Grabowska et al 2010
Polanowska-Grabowska R, Wallace K, Field JJ, Chen L, Marshall MA, Figler R et al. 
Original Research: Focus on Platelets. P-selectin-mediated platelet-neutrophil aggregate 
formation activates neutrophils in mouse and human sickle cell disease. 
Arterioscler Thromb Vasc Biol 2010:30(12):2392-9


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December 2015
66(66)
Semple et al 1984
Semple MJ, Al-Hasani SF, Kioy P, Savidge GF. A double-blind trial of ticlopidine in sickle 
cell disease. Thromb Haemost 1984;51:303-6
Styles 2012
Styles L. Prasugrel in children with sickle cell disease: Pharmacokinetic and 
pharmacodynamic characteristics from an open-label, adaptive-design, dose-ranging study. 
Abstract presented at American Society of Hematology Annual Meeting, Dec 2012. 
Blood vol 120
Wessel et al 2013
Wessel DL, Berger F, Li JS, Dähnert I, Rakhit A, Fontecave S et al. Clopidogrel in infants 
with systemic-to-pulmonary-artery shunts. N Engl J Med 2013;368(25):2377-84
Wun et al 2013
Wun T, Soulieres D, Frelinger AL, Krishnamurti L, Novelli EM, Kutlar A et al. A double-
blind, randomized, multicenter phase 2 study of prasugrel versus placebo in adult patients with 
sickle cell disease. J Hematol Oncol 2013;6:17
Zago et al 1984
Zago MA, Costa FF, Ismael S, Tone LG, Bottura C. Treatment of sickle cell diseases with 
aspirin. Acta Haematol 1984;72:61-4


 
 
Clinical Study Protocol Appendix B 
 
Drug Substance 
Ticagrelor 
 
Study Code 
D5136C00007 
 
Edition Number 
1 
 
Date 
5 March, 2014 
 
 
 
 
 
 
 
 
 
 
Appendix B 
Additional Safety Information 
 
 


Clinical Study Protocol Appendix B 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Edition Number 1 
Date 5 March, 2014 
2(3) 
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 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 
Outpatient 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 subject 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 jeopardize the subject or may require 
medical intervention to prevent one 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. 
Examples of such events are: 
x
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment 
x
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring 
treatment with N-acetylcysteine 
x
Intensive treatment in an emergency room or at home for allergic bronchospasm 
x
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalisation 
x
Development of drug dependency or drug abuse. 


Clinical Study Protocol Appendix B 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Edition Number 1 
Date 5 March, 2014 
3(3) 
A GUIDE TO INTERPRETING THE CAUSALITY QUESTION 
The following factors should be considered when deciding if there is a “reasonable 
possibility” that an AE may have been caused by the drug. 
x
Time Course. Exposure to suspect drug. Has the subject actually received the 
suspect drug? Did the AE occur in a reasonable temporal relationship to the 
administration of the suspect drug? 
x
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? 
x
Dechallenge experience. Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug? 
x
No alternative cause. The AE cannot be reasonably explained by another aetiology 
such as the underlying disease, other drugs, other host or environmental factors. 
x
Rechallenge experience. Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support 
a rechallenge. 
x
Laboratory tests. A specific laboratory investigation (if performed) has confirmed 
the relationship? 
A “reasonable possibility” could be considered to exist for an AE where one or more of these 
factors exist. 
In contrast, there would not be a “reasonable possibility” of causality if none of the above 
criteria apply or where there is evidence of exposure and a reasonable time course but any 
dechallenge (if performed) is negative or ambiguous or there is another more likely cause of 
the AE. 
In difficult cases, other factors could be considered such as: 
x
Is this a recognised feature of overdose of the drug? 
x
Is there a known mechanism? 
Ambiguous cases should be considered as being a “reasonable possibility” of a causal 
relationship unless further evidence becomes available to refute this. 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 C 
 
Drug Substance 
Ticagrelor 
 
Study Code 
D5136C00007 
 
Edition Number 
1 
 
Date 
5 March, 2014 
 
 
 
 
 
 
 
 
 
 
Appendix C 
International Airline Transportation Association (IATA) 6.2 Guidance 
Document 
 


Clinical Study Protocol Appendix C 
Drug Substance Ticagrelor 
Study Code D5136C00007  
Edition Number 1 
Date 5 March, 2014 
2(2) 
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES 
International Airline Transportation Association (IATA) classifies biohazardous agents into 
3 categories (http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.htm). 
For transport purposes the classification of infectious substances according to risk groups was 
removed from the Dangerous Goods Regulations (DGR) 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: 
x
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 virus (HIV) types 1 and 2. They are assigned the following UN 
number and proper shipping name: 
x
UN 3373 - Biological Substance, Category B 
x
are to be packed in accordance with UN3373 and IATA 650 
Exempt - all other materials with minimal risk of containing pathogens 
x
Clinical trial samples will fall into Category B or exempt under IATA regulations 
x
Clinical trial samples will routinely be packed and transported at ambient 
temperature in IATA 650 compliant packaging 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.htm) 
x
Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content 
x
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 
x
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 D 
 
Drug Substance 
Ticagrelor 
 
Study Code 
D5136C00007 
 
Edition Number 
1 
 
Date 
5 March, 2014 
 
 
 
 
 
 
 
 
 
Appendix D 
Actions Required in Cases of Combined Increase of Aminotransferase and 
Total Bilirubin - Hy’s Law 
 


Clinical Study Protocol Appendix D 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Edition Number 1 
Date 5 March, 2014 
2(6) 
TABLE OF CONTENTS 
PAGE
TABLE OF CONTENTS.........................................................................................2 
1. 
INTRODUCTION ...................................................................................................3 
2. 
DEFINITIONS.........................................................................................................3 
3. 
IDENTIFICATION OF POTENTIAL HY’S LAW CASES...................................3 
4. 
FOLLOW-UP ..........................................................................................................4 
4.1 
Potential Hy’s Law Criteria not met ........................................................................4 
4.2 
Potential Hy’s Law Criteria met ..............................................................................4 
5. 
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW CASES...............5 
6. 
REFERENCES ........................................................................................................6 
 


Clinical Study Protocol Appendix D 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Edition Number 1 
Date 5 March, 2014 
3(6) 
1. 
INTRODUCTION 
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a patient 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 Hy’s Law (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 (AE) and Serious Adverse Events (SAE) according to the outcome 
of the review and assessment in line with standard safety reporting processes. 
2. 
DEFINITIONS 
Potential Hy’s Law (PHL) 
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT)  3x Upper Limit of 
Normal (ULN) and Total Bilirubin (TBL)  2xULN at any point during the study irrespective 
of an increase in Alkaline Phosphatase (ALP). The elevations do not have to occur at the same 
time or within a specified time frame. 
Hy’s Law (HL) 
AST or ALT  3x ULN and TBL  2xULN, 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. The elevations do not have to occur at the same time or within a 
specified time frame. 
3. 
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 patient who meets any of the following identification criteria in 
isolation or in combination: 
x
ALT  3xULN 
x
AST  3xULN 
x
TBL  2xULN 


Clinical Study Protocol Appendix D 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Edition Number 1 
Date 5 March, 2014 
4(6) 
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will: 
x
Notify the AstraZeneca representative 
x
Determine whether the patient meets PHL criteria (see Section 2 of this Appendix 
for definition) by reviewing laboratory reports from all previous visits 
x
Promptly enter the laboratory data into the laboratory CRF 
4. 
FOLLOW-UP 
4.1 
Potential Hy’s Law Criteria not met 
If the patient does not meet PHL criteria the Investigator will: 
x
Inform the AstraZeneca representative that the patient has not met PHL criteria. 
x
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol. 
4.2 
Potential Hy’s Law Criteria met 
If the patient does meet PHL criteria the Investigator will: 
x
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 patients’ follow-up and the continuous review of data. Subsequent to 
this contact the Investigator will: 
x
Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated  
x
Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician 
x
Complete the three Liver CRF Modules as information becomes available  
x
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 


Clinical Study Protocol Appendix D 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Edition Number 1 
Date 5 March, 2014 
5(6) 
5. 
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 Medical Science Director 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 TBL 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: 
x
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF 
x
If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF 
accordingly and follow the AZ standard processes 
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP: 
x
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: 
x
Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and 
causality assessment as per above 
x
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 


Clinical Study Protocol Appendix D 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Edition Number 1 
Date 5 March, 2014 
6(6) 
6. 
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 Protocol Appendix E
Drug Substance
Ticagrelor
Study Code
D5136C00007
Edition Number
3
Date
22 December, 2015
Appendix E
PK/PD monitoring dose adjustments


Clinical Study Protocol Appendix E
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December, 2015
2(5)
An interim analysis was conducted per protocol after 12 patients had completed dosing in part 
A. The mean PRU reduction 2 hours post-dose at Visit 4 was <20%, and plasma ticagrelor 
concentrations were lower than expected. This triggered a protocol amendment to increase 
the weight-adjusted dosing in order to achieve a higher level of platelet inhibition.
Doses may be further adjusted following assessment by AstraZeneca and the Steering 
Committee of results in the first 6-12 patients randomised under this amendment. Dose 
adjustment decisions will be based upon a review of PK, PD and adverse events and will 
apply only to patients randomised subsequent to the dose change decision.
Alternative Dosing Schedule 1:
The dose for Visit 2, Part A and Part B may be reduced from 0.75 mg/kg to 0.563 
mg/kg and the highest dose administered on Visit 3 may be reduced from 2.25 mg/kg 
to 1.69 mg/kg. 
Refer to Figure 1: Alternative dosing schedule 1, reduced doses in Appendix E 
Alternative Dosing Schedule 2:
If two or more patients exceed the paediatric exposure limit (Cmax 2000 ng/mL) after 
receiving 2.25 mg/kg as single dose on visit 3, this dose will be reduced from 2.25 
mg/kg to 1.69 mg/kg. 
Refer to Figure 2: Alternative dosing schedule 2, reduced top dose in Appendix E 
Alternative Dosing Schedule 3:
The dose at visit 2 and during repeated dosing in Part A and Part B may be increased 
from 0.75 mg/kg to 1.125 mg/kg, and the single doses at visit 3 may be increased to 
1.69 mg/kg and 2.25 mg/kg 
Refer to Figure 3:  Alternative dosing schedule 3, increased doses in Appendix E
Table 1
Adult equivalents of doses in the alternative dosing schedules
Weight-based Dose (mg/kg)
Adult equivalent dose (mg)
0.375
30
0.563
45
0.75
60
1.125
90
1.69
135
2.25
180


Clinical Study Protocol Appendix E
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December, 2015
3(5)
Figure 1 in this Appendix will replace Figure 2 in the main body of the Clinical Study Protocol if the doses are reduced, see 
Section 4.2
Figure 1
Alternative dosing schedule 1, reduced doses


Clinical Study Protocol Appendix E
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December, 2015
4(5)
Figure 2 in this Appendix will replace Figure 2 in the main body of the Clinical Study Protocol if the top dose is reduced, see 
Section 4.2.
Figure 2
Alternative dosing schedule 2, reduced top dose:


Clinical Study Protocol Appendix E
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December, 2015
5(5)
Figure 3 in this Appendix will replace Figure 2 in the main body of the Clinical Study Protocol if the doses are increased, see 
Section 4.2.
Figure 3
Alternative dosing schedule 3, increased doses:


Clinical Study Protocol Appendix F
Drug Substance
Ticagrelor
Study Code
D5136C00007
Edition Number
3
Date
22 December, 2015
Appendix F 
Dose tables with predefined weight brackets


Clinical Study Protocol Appendix F
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December, 2015
2(3)
Before each dosing occasion the granules will be constituted with a 10 mL volume of purified 
water to form a homogenous suspension suitable for oral dosing. Dosing will be weight based 
and a suitable volume of suspension should be withdrawn from the bottle using a syringe 
suitable for oral dosing. The dose volume to be given to the patient is defined in Table 1-6. 
The dose tables are based on predefined weight brackets in order to ensure dose accuracy 
(only whole mL to be given, except for the 0.375 mg/kg dose) and that the correct treatment
dose strength is given to patient. All patients will receive a handling instruction together with 
study drug at each visit starting at Visit 3. The investigator will enter the individual volume to 
be given in the handling instruction before the patient leaves the clinic. For more information, 
please see Section 7.2 in the Clinical Study Protocol. 
Table 1
0.375 mg/kg
Weight (kg)
Bottle strength (mg)
Dose volume (mL)
Actual dose (mg) *
16-27
45
1.3
6
28-41
45
3
13.5
42-55
45
4
18
56-69
45
5
22.5
≥70
45
7
31.5
Table 2
0.563 mg/kg
Weight (kg)
Bottle strength (mg)
Dose volume (mL)
Actual dose (mg) *
16-27
45
2
9
28-41
45
4
18
42-55
45
6
27
56-69
45
8
36
≥70
45
10
45
Table 3
0.75 mg/kg
Weight (kg)
Bottle strength (mg)
Dose volume (mL)
Actual dose (mg) *
16-27
45
3
13.5
28-41
45
6
27
42-55
45
8
36
56-69
45
10
45
≥70
45
13
58.5


Clinical Study Protocol Appendix F
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 3
Date 22 December, 2015
3(3)
Table 4
1.125 mg/kg 
Weight (kg)
Bottle strength (mg)
Dose volume (mL)
Actual dose (mg) *
16-27
45
4
18
28-41
45
9
40.5
42-55
45
12
54
56-69
45
16
72
≥70
45
20
90**
Table 5
1.69 mg/kg 
Weight (kg)
Bottle strength (mg)
Dose volume (mL)
Actual dose (mg) *
16-27
45
6
27
28-41
45
13
58.5
42-55
45
18
81
56-69
45
23
103.5
≥70
45
30
135
Table 6
2.25 mg/kg 
Weight (kg)
Bottle strength (mg)
Dose volume (mL)
Actual dose (mg) *
16-27
45
8
36
28-41
45
17
76.5
42-55
45
24
108
56-69
45
31
139.5
≥70
45
40
180**
* Actual doses were calculated using the mean weight in the weight bands ((Upper weight-Lower 
weight)/2+Lower weight) except for the highest and lowest weight bands, where 80kg and the 16kg was used 
respectively.  
** The highest dose in this study is 180 mg for single doses, and 90 mg for repeated doses.


Clinical Study Protocol Appendix G
Drug Substance
Ticagrelor
Study Code
D5136C00007
Edition Number
2
Date
5 March, 2014
Appendix G
Patient Reported Outcomes


Clinical Study Protocol Appendix G
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 2
Date 5 March, 2014
Study Medication Palatability Assessment
Observer Assessment for Patients Under 6 Years of Age
Instructions to Study Staff
Immediately after administration of Brilinta at Visit 2, capture the patients’ reaction of the taste 
of the medication. Use this CRF for all patients taking the study drug who are under 6 years of 
age.
1.
Choose the response that best matches a description of what you observe of the patients’ 
willingness to swallow the study medication.
Willingness to Swallow
Swallowed without problem
Some resistance but did swallow
Spit out some / all of medication
Vomited up medication
2.
Was any behavior 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?
YES
NO
If answered YES, please answer the following questions:
2a. Did the patient turn their head to reject intake of the medication? 
YES
NO
2b. Did the patient twist their face or mouth in an expression of displeasure? 
YES
NO
2c. Did the patient display any other negative behavior? 
YES
NO
If YES, please describe: _______________________________________________________
__________________________________________________________________________
Patient ID: _____________________________________
Assessment Date: ________________________________
Assessment Time: _______________________________
Initials of person administering the assessment: ________


Clinical Study Protocol Appendix G
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 2
Date 5 March, 2014
Study Medication Palatability Assessment
Instructions to Study Staff
Immediately after administration of Brilinta on visit 2, capture the patients’ assessment of the 
taste of the medication. Use this question for all patients taking the study drug who are 6 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 one 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 Protocol Appendix G 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Edition Number 2 
Date 5 March, 2014 
Faces Pain Scale - Revised 
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 how much pain you have had today. 
Patient ID: _____________________________________  
Assessment Date: _______________________________  
Assessment Time: _______________________________  
Initials of person administering the assessment: ________  


Clinical Study Protocol Appendix G
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 2
Date 5 March, 2014
SICKLE CELL PAIN DIARY (children aged 2-3)
Instruction for Caregiver (e.g. parent) on completion 
__________________ (child’s name) is taking part in a study of children with sickle cell 
disease. The study is collecting information about pain, so that we can learn how to help 
children with sickle cell disease feel better. Please complete the sickle pain diary every evening
from _______________ (date) until your next clinic visit _______________ (date).  
1.Enter assessment date for each day of assessment.
2.Answer the question: Has your child had any sickle cell pain during the last 24 
hours?
If your child has had any sickle cell pain during the last 24 hours, please describe how 
your child behaved while under your care due to the pain. For each category (face, legs, 
activity, crying, and consolability), please mark an X in the one box that best describes 
your answer.
Please remember the same caregiver (e.g. parent) is to complete the diary every evening.
Please contact Your Study Doctor or Study Nurse if you have doubts how to complete diary.
Please remember to return the completed sickle cell pain diary on the next visit to the clinical 
site. 


Clinical Study Protocol Appendix G
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 2
Date 5 March, 2014
6(7)
SICKLE CELL PAIN Diary – patients ages 2 through <4 
Patient ID/E-code : ________________ Assessment Date : _____________
Instructions
Please answer this question every night when participating in the study. 
Has your child had any sickle cell pain during the last 24 hours?
No
Yes
If Yes, please continue to the next page
English for USA
Merkel, S., Voepel-Lewis, T., Shayevitz, J., & Malviya, S. (1997). The FLACC: A behavioral 
scale for scoring postoperative pain in young children. Pediatric Nursing 23(3),293-297.  © 
2002, The Regents of the University of Michigan. All Rights Reserved.


Clinical Study Protocol Appendix G
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 2
Date 5 March, 2014
7(7)
Please describe how your child behaved because of the pain. For each category (face, legs, 
activity, cry and consolability), please mark an X in the box that best describes your answer.
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
English for USA
Merkel, S., Voepel-Lewis, T., Shayevitz, J., & Malviya, S. (1997). The FLACC: A behavioral 
scale for scoring postoperative pain in young children. Pediatric Nursing 23(3),293-297.  © 
2002, The Regents of the University of Michigan. All Rights Reserved.


Clinical Study Protocol Appendix H
Drug Substance
Ticagrelor
Study Code
D5136C00007
Edition Number
2
Date
05 March 2015
Appendix H
Child-Pugh Classification


Clinical Study Protocol Appendix H
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 2
Date 05 March 2015
2(3)
Child-Pugh classification
The Child-Pugh score is a FDA-recommended classification for assessing hepatic impairment. 
Drugs that are predominantly metabolized by the liver must be studied in a controlled trial 
with patients who have varying degrees of liver impairment. Dosage modifications due to 
hepatic impairment may be based on the Child-Pugh score1.
Table 1
Child-Pugh Classification2 (modified from Pugh 1973)
Clinical and Biochemical Markers
Points scored for observed findings
1
2
3
Hepatic encephalopathy (grade)*
Absent
Moderate
(1 or 2)
Severe
(3 or 4)
Ascites
Absent
Slight
Moderate
Bilirubin (mg/dL)
< 2.0
2.0 - 3.0
> 3.0
Serum albumin (g/dL)
> 3.5
2.8 - 3.5
< 2.8
Prothrombin time (seconds prolonged)
or
Prothrombin time (INR)
< 4
< 1.7
4 - 6
1.7 - 2.3
> 6
> 2.3
Total Child-Pugh Scoring 
Total Points
Grade
Description
5-6
A
Mild: well-compensated disease
7-9
B
Moderate: significant functional compromise
10-15
C
Severe: decompensated disease
                                                
*Grade 0: normal consciousness, personality, neurological examination, electroencephalogram.
Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cycles per second (cps) 
waves.
Grade 2:lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves.
Grade 3:somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves.
Grade 4:unrousable coma, no personality/behavior, decerebrate, slow 2-3 cps delta activity.


Clinical Study Protocol Appendix H
Drug Substance Ticagrelor
Study Code D5136C00007
Edition Number 2
Date 05 March 2015
3(3)
References
1 US Department of Health and Human Services Food and Drug Administration. Guidance for 
industry: pharmacokinetics in patients with impaired hepatic function: study design, data 
analysis, and impact on dosing and labeling.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
/ucm072123.pdf. Updated May 30, 2003. Accessed March 21, 2011.
2 Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC and Williams R. Transection of the 
oesophagus for bleeding oesophageal varices. Br J Surg 1973;60(8):646-9.


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Clinical Study Protocol Amendment 
Amendment Number 
2 
Drug Substance 
Ticagrelor 
Study Code 
D5136C00007 
Date 
05 March 2015 
Protocol Dated 
05 March 2014 
 
 
 
 
 
 
 
 
Multicenter, open-label, randomised, pharmacokinetic (PK) and 
pharmacodynamic (PD) dose-ranging Phase II study of ticagrelor followed 
by a double-blind, randomised, parallel-group, placebo-controlled 4 weeks 
extension phase in paediatric patients with sickle cell disease 
 
 
 
This submission /document contains trade secrets and confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object. 
 
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden. 
 
Centres affected by the Amendment: 
 
This amendment affects all centres in the study. 
 
The protocol for the study is to be amended as follows: 
Section of protocol affected: 
3.1 Inclusion criteria, 3.2 Exclusion criteria, 3.8 Restrictions, 3.9.1 Criteria for interruption or 
discontinuation of investigational product (active and placebo), 6.6.1 Women of childbearing 
potential 
 
Previous text: 
 
Inclusion criterion 3. If ≤16 years, must have had transcranial Doppler within the past year prior 
to enrolment 
 
Inclusion criterion 4. If ≥6 years old, must have had an ophthalmological examination within the 
past year prior to enrolment 
 
Inclusion criterion 5. If treated with an anti-sickling agent such as hydroxyurea, dose must be 
stable for 3 months before enrolment. 
 
Exclusion criterion 2. Abnormal or conditional transcranial Doppler (velocity in middle or 
anterior cerebral, or internal carotid artery ≥170 centimeter per second) within the past 
year prior to enrolment  
 


Clinical Study Protocol Amendment 2
Drug Substance Ticagrelor
Study Code D5136C00007
Date 05 March 2015
2
 
 
 
 
 
 
Exclusion criterion 3. History of, or are undergoing treatment with, chronic RBC transfusion 
therapy 
Exclusion criterion 4. Receiving chronic treatment (>3 days per week) with non-steroidal 
anti-inflammatory drugs (NSAIDs)
Exclusion criterion 6. Moderate or severe hepatic impairment, or renal failure requiring dialysis
Exclusion criterion 7. Increased risk of bleeding complications according to investigator
Exclusion criterion 12. Females (if after menarche) who are not willing to use a medically 
accepted method of contraception that is considered reliable in the judgment of the 
investigator during the study
3.8 Restrictions
Females of child-bearing potential are not allowed to be included in this study unless they use an 
approved pregnancy prevention method and must refrain from becoming pregnant from 1 
month following the last dose. There are no restrictions against fathering a child when treated 
with ticagrelor. For further details, please see Section 6.6.
3.9.1 Criteria for interruption or discontinuation of investigational product (active and 
placebo)
x
Thrombocytopenia (platelet count <80,000/uL). Repeat laboratory studies and 
standard of care (SOC) should be followed until resolution of laboratory abnormality
6.6.1 Maternal exposure
Women of childbearing potential are not allowed to be included in this study unless they use an 
approved pregnancy prevention method and must refrain from becoming pregnant from 
1 month following the last dose. Should a pregnancy still occur, the investigational product 
should be discontinued immediately and the pregnancy reported to designated 
 
representative within 1 day.
 
Revised text:
 
Inclusion criterion 3. If ≤16 years, 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.
Inclusion criterion 4. If ≥6 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.
Inclusion criterion 5. If treated with an anti-sickling agent such as hydroxyurea, the 
weight-adjusted dose must be stable for 3 months before enrolment
Redac


Clinical Study Protocol Amendment 2 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 05 March 2015 
3 
 
 
 
 
 
 
 
Exclusion criterion 2. Findings on TCD: Current or previous values for time averaged 
mean of the maximum velocity (TAMMV) that are Conditional or Abnormal*. 
Conditional TAMMV values are ≥153 cm/sec using imaging TCD (TCDi) technique 
(corresponding to ≥170 cm/sec by the non-imaging technique). Both the middle cerebral 
artery and the internal carotid artery should be considered. Abnormal TAMMV values 
are ≥180 cm/sec using TCDi (corresponding to ≥200 cm/sec by the non-imaging technique) 
and are an indication for chronic transfusions because of a high stroke risk. Any other 
criteria that would locally be considered as TCD indications for chronic transfusion would 
also exclude the patient. 
* According to STOP study thresholds for non-imaging TCD technique (Adams et al.1998) and thresholds 
for imaging TCD (TCDi) technique as published by Bulas et al. (2005). 
 
Exclusion criterion 3. Undergoing treatment with chronic RBC transfusion therapy  
 
Exclusion criterion 4. Use of non-steroidal anti-inflammatory drugs (NSAIDs) >3 days per 
week 
 
Exclusion criterion 6. Moderate or severe hepatic impairment, defined as Child-Pugh Class B 
or C (see Appendix H) or renal failure requiring dialysis 
 
Exclusion criterion 7. Active pathological bleeding or increased risk of bleeding complications 
according to Investigator 
 
Exclusion criterion 12. Females (if after menarche) who are not willing to use a highly effective 
method of contraception which results in a low failure rate (i.e. less than 1% per year) 
 
3.8 Restrictions 
 
Females of child-bearing potential are not allowed to be included in this study unless they use a 
highly effective method of contraception, and must refrain from becoming pregnant from 1 
month following the last dose. A highly effective method is defined as the one which results 
in a low failure rate (i.e. less than 1% per year) when used consistently and correctly. 
Examples of highly effective methods include implants, injectables, combined oral 
contraceptives, some intrauterine devices, sexual abstinence or vasectomised partner. 
There are no restrictions against fathering a child when treated with ticagrelor. For further 
details, please see Section 6.6. 
 


Clinical Study Protocol Amendment 2
Drug Substance Ticagrelor
Study Code D5136C00007
Date 05 March 2015
4
 
 
 
 
 
 
3.9.1 Criteria for interruption or discontinuation of investigational product (active and 
placebo)
x
Clinically significant thrombocytopenia which mandates an interruption of 
study drug due to patient safety in the assessment of the investigator. Repeat 
laboratory studies and standard of care (SOC) should be followed until resolution of 
laboratory abnormality
6.6.1 Maternal exposure
Women of childbearing potential are not allowed to be included in this study unless they use a
highly effective method of contraception which results in a low failure rate (i.e. less than 
1% per year), and must refrain from becoming pregnant from 1 month following the last dose. 
Should a pregnancy still occur, the investigational product should be discontinued immediately 
and the pregnancy reported to designated 
representative within 1 day.
Section of protocol affected:
 
Synopsis, 1.2.3 Primary and secondary outcome measures, 1.4 Study design, 2.2 Secondary
Objectives, 2.4 Exploratory Objectives (newly added section), 8.5 Methods for statistical 
analyses
Previous text:
 
Synopsis
Study site(s) and number of subjects planned
This study is planned to be conducted in approximately 4 countries (United States (US), 
United Kingdom (UK), South Africa and Canada) and approximately 8 to 20 sites, with a 
minimum of 36 patients and a maximum of 50 patients to be randomised in the study, 
depending on how many patients are required in order to have 36 evaluable patients.
Secondary Objective:
Outcome Measure:
To determine the PK properties of ticagrelor in 
paediatric patients with SCD and to assess impact of 
weight, age and other demographic on the ticagrelor 
pharmacokinetics
Ticagrelor concentrations. Population PK 
parameters (Oral Clearance (CL/F) and AUC)
 
1.2.3 Primary and secondary outcome measures
The primary study endpoint is the evaluation of the PK and PD properties of ticagrelor in 
children after each of 3 dose strengths given as single doses (0.125 mg/kg, 0.375 mg/kg or 0.563 
mg/kg) and after attainment of steady-state following twice-daily administration of 0.125 mg/kg.
PK will be determined using standard methodologies. The PD measure employed will be the 
VerifyNow P2Y12 assay (Jeong et al 2012) that is a well-validated and commercially 
Redac


Clinical Study Protocol Amendment 2 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 05 March 2015 
5 
 
 
 
 
 
 
available point-of-care assay to assess inhibition of the P2Y12 platelet receptor. 
 
1.4 Study design 
 
This study is planned to be conducted in approximately 4 countries (United States [US], United 
Kingdom [UK], South Africa and Canada) and approximately 8 to 20 sites, with a minimum of 
36 patients and a maximum of 50 patients to be randomised in the study, depending on how 
many patients are required in order to have 36 evaluable patients. 
 
2.2 Secondary objectives 
 
Secondary Objective: 
Outcome Measure: 
To determine the PK properties of ticagrelor in 
paediatric patients with SCD and to assess impact of 
weight, age and other demographic on the ticagrelor 
pharmacokinetics 
Ticagrelor concentrations. Population PK 
parameters (Oral Clearance [CL/F] and AUC) 
 
8.5 
Methods for statistical analyses 
 
The relationship between ticagrelor dose, plasma concentration and PRU will be characterized 
using a population PK/PD approach (i.e. non-linear mixed effect modeling). This analysis will 
be based on all available PK and PRU data from which complete dosing and sampling history is 
collected. The PK/PD analyses will be performed sequentially, where first the PK of ticagrelor 
will be characterized and followed by characterizing of the PK/PD relationship. Prior PK/PD 
knowledge from ticagrelor in adults ACS patients will serve as basis during analyses. A detailed 
analysis plan will be written prior to data base lock. 
 
No statistical comparisons are planned for the primary objective. PK, PD and safety measures 
will be summarized descriptively using respective analysis set. Palatability measures will also be 
summarized descriptively for all patients for whom the assessment is performed. 
 
A statistical analysis comparing ticagrelor and placebo will be performed for each of the 
following variables using the efficacy analysis set for Part B of the study: 
x 
Percentage of days with pain  
x 
Percentage of days of opioid analgesic use 
x 
Percentage of days of analgesic use 
x 
Percentage of days hospitalized for VOC or other complications of SCD 
x 
Percentage days of absence from school or work  
 
A t-test will be performed for each of these variables at 5% significance level. The p-value and 
a 95% confidence interval for the difference between ticagrelor and placebo will be reported. 
There will be no adjustment for multiple comparisons. If it is inappropriate to assume a normal 
distribution, a Wilcoxon rank sum test may be performed. In case more than one adult 
equivalent dose is studied in Part B, the analysis will be repeated both for all ticagrelor doses 


Clinical Study Protocol Amendment 2 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 05 March 2015 
6 
 
 
 
 
 
 
versus placebo and for the dose the majority of patients received versus placebo. 
Number of VOC, number of VOC requiring hospitalization and intensity of pain will be 
summarized descriptively by treatment group in Part B. 
 
Efficacy variables collected in Part A, ie percentage of days with pain, percentage of days of 
opioid analgesic use, percentage of days of analgesic use, percentage of days of absence from 
school or work and intensity of pain will be summarized descriptively using the safety analysis 
set.  


Clinical Study Protocol Amendment 2 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 05 March 2015 
7 
 
 
 
 
 
 
Revised text 
 
Synopsis 
 
Study site(s) and number of subjects planned 
 
This study is planned to be conducted in approximately 4 countries (United States (US), 
United Kingdom (UK), South Africa and Canada) and approximately 8 to 20 sites, with a 
minimum of 36 patients and a maximum of 50 patients to be randomised in the study, 
depending on how many patients are required in order to have 36 evaluable patients. Of these 
36 evaluable patients, at least 12 patients must be 2 to 11 years of age and 12 patients 
must be 12 to 18 years. In addition, a minimum of 12 evaluable patients must complete 
Part B (through Visit 8). 
 
Secondary Objective: 
Outcome Measure: 
To determine the PK properties of ticagrelor and its 
active metabolite in paediatric patients with SCD 
and to assess impact of weight, age and other 
demographic on the ticagrelor pharmacokinetics 
Concentrations of ticagrelor and its active 
metabolite. Population PK parameters (Oral 
Clearance (CL/F) and AUC) 
 
Exploratory Objective: 
Outcome Measure: 
Investigation of efficacy of ticagrelor vs. placebo in 
paediatric patients with SCD in reducing: 
 
Days with pain (ages <4 years only) 
Intensity of pain (ages <4 years only) 
 
1.2.3 Primary and secondary outcome measures 
 
The primary study endpoint is the evaluation of the PK and PD properties of ticagrelor and 
its active metabolite in children after each of 3 dose strengths given as single doses 
(0.125 mg/kg, 0.375 mg/kg or 0.563 mg/kg) and after attainment of steady-state following 
twice-daily administration of 0.125 mg/kg. PK will be determined using standard 
methodologies. The PD measure employed will be the VerifyNow P2Y12 assay (Jeong et al 
2012) that is a well-validated and commercially available point-of-care assay to assess 
inhibition of the P2Y12 platelet receptor.  
 
The secondary PK objectives are to determine the PK properties of ticagrelor and its 
active metabolite and to access the impact of demographic characteristics on the PK of 
ticagrelor. Outcome measures including: 
 
x 
Concentrations of ticagrelor and its active metabolite. 
x 
Population PK parameters (Oral Clearance (CL/F) and AUC) 
 
1.4 Study design 
 
This study is planned to be conducted in approximately 4 countries (US, United Kingdom (UK), 
South Africa and Canada) and approximately 8 to 20 sites, with a minimum of 36 patients and a 
maximum of 50 patients to be randomised in the study, depending on how many patients are 


Clinical Study Protocol Amendment 2 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 05 March 2015 
8 
 
 
 
 
 
 
required in order to have 36 evaluable patients. Of these 36 evaluable patients, at least 12 
patients must be 2 to 11 years of age and 12 patients must be 12 to 18 years. In addition, a 
minimum of 12 evaluable patients must complete Part B (through Visit 8). 
 
2.2 Secondary objectives 
 
Secondary Objective: 
Outcome Measure: 
To determine the PK properties of ticagrelor and its 
active metabolite in paediatric patients with SCD and 
to assess impact of weight, age and other demographic 
on the ticagrelor pharmacokinetics 
Concentrations of ticagrelor and its active 
metabolite. Population PK parameters (Oral 
Clearance (CL/F) and AUC) 
 
2.4 Exploratory objectives 
 
Exploratory Objective: 
Outcome Measure: 
Investigation of efficacy of ticagrelor vs. placebo in 
paediatric patients with SCD in reducing: 
 
Days with pain (ages <4 years only) 
Intensity of pain (ages <4 years only) 
 
8.5 
Methods for statistical analyses 
 
The relationship between ticagrelor dose, plasma concentration and PRU will be characterized 
using a population PK/PD approach (i.e. non-linear mixed effect modeling). This analysis will 
be based on all available PK and PRU data from which complete dosing and sampling history is 
collected. The PK/PD analyses will be performed sequentially, where first the PK of ticagrelor 
and its active metabolite will be characterized and followed by characterizing of the PK/PD 
relationship. Prior PK/PD knowledge from ticagrelor in adult ACS patients will serve as basis 
during analyses. A detailed analysis plan will be written prior to data base lock. 
 
No statistical comparisons are planned for the primary objective. PK, PD and safety measures 
will be summarized descriptively using respective analysis set. Palatability measures will also 
be summarized descriptively for all patients for whom the assessment is performed. 
A statistical analysis comparing ticagrelor and placebo will be performed for each of the 
following variables using the efficacy analysis set for Part B of the study: 
 
x 
Percentage of days with pain (ages ≥4 years only) 
x 
Percentage of days of opioid analgesic use 
x 
Percentage of days of analgesic use (ages ≥4 years only) 
x 
Percentage of days hospitalized for VOC or other complications of SCD 
x 
Percentage days of absence from school or work (ages ≥6 years only) 
 
A t-test will be performed for each of these variables at 5% significance level. The p-value and a 
95% confidence interval for the difference between ticagrelor and placebo will be reported. 
There will be no adjustment for multiple comparisons. If it is inappropriate to assume a normal 
distribution, a Wilcoxon rank sum test may be performed. In case more than one adult 
equivalent dose is studied in Part B, the analysis will be repeated both for all ticagrelor doses 


Clinical Study Protocol Amendment 2 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 05 March 2015 
9 
 
 
 
 
 
 
versus placebo and for the dose the majority of patients received versus placebo. 
 
Number of VOC, number of VOC requiring hospitalization and intensity of pain will be 
summarized descriptively by treatment group in Part B. 
 
Efficacy variables collected in Part A, i.e. percentage of days with pain, percentage of days of 
opioid analgesic use, percentage of days of analgesic use, percentage of days of absence from 
school or work and intensity of pain will be summarized descriptively using the safety analysis 
set.  
 
Exploratory variables, days with pain and intensity of pain (ages <4 years only), will be 
presented descriptively using the safety analysis set. 
 
 
Section of protocol affected: 
 
4 Study plan and timing of procedures: Table 1, Table 2, Table 3, Table 6, Table 7, 
4.1 Enrolment/screening period, 4.2 Treatment period 
 
Previous text:  
 


Clinical Study Protocol Amendment 2 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 05 March 2015 
 
 
 
 
 
10 
 
 
Table 1 
Study Plan detailing the procedures 
 
Part A 
Part B 
Assessment 
Enrolment 
Dose 1 
Dose 2 
Repeated treatment phase 
End of 
treatment 
Follow-up 
Visit 
Visit window: 
 
1  
Days -30 to 0 
for Visit 1 
2 
 ±0 day for 
Visit 2 
3 
+ 7 days 
4 
+7 days 
5 
+ 7 days 
6 
+ 7 days 
7 
+ 7 days 
8 
+ 7 days 
9 
30-35 days 
following last dose 
for Visit 8d 
Week 
 
0 
1 
2 
3 
4 
5 
6  
10 
Day 
 
0 
7 
14 
21 
28 
35 
42 
72-77 
Signed Informed Assent/Consent 
X 
 
 
 
Randomisation 
 
X 
 
X 
Inclusion/exclusion criteria 
X 
Xa 
 
 
Relevant Medical and Surgical history, SCD 
characteristics and history 
X 
 
 
 
Demographics 
X 
 
 
 
Vital signs (BP, pulse) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination  
X 
 
 
 
X 
Weight, heighte 
X 
X 
X 
 
X 
Transcranial Doppler exam (within past 1 year) 
X 
 
 
 
Ophthalmological (Eye) exam (within past 1 year) 
X 
 
 
 
12-lead ECG (within past 6 months) 
X 
 
 
 
12-lead ECG 
 
 
 
X 
Daily pain assessmentg 
X 
X 
X 
X 
X 
X 
X 
X 
Daily recording of analgesic useg 
X 
X 
X 
X 
X 
X 
X 
X 
Days absent from school/workg 
X 
X 
X 
X 
X 
X 
X 
X 
Administration of IP at clinici 
 
X 
X 
X 
X 
Treatment dispensed/returned 
 
 
X 
Xj 
X 
X 
X 
Xj 
Compliance/ Drug accountability 
 
X 
X 
X 
X 
X 
X 
X 
Acceptability/Palatabilityh 
 
X 
 
 
Concomitant medication  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event review (AEs and SAEs) 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 


Clinical Study Protocol Amendment 2 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 05 March 2015 
 
 
 
 
 
11 
 
Part A 
Part B 
Assessment 
Enrolment 
Dose 1 
Dose 2 
Repeated treatment phase 
End of 
treatment 
Follow-up 
Visit 
Visit window: 
 
1  
Days -30 to 0 
for Visit 1 
2 
 ±0 day for 
Visit 2 
3 
+ 7 days 
4 
+7 days 
5 
+ 7 days 
6 
+ 7 days 
7 
+ 7 days 
8 
+ 7 days 
9 
30-35 days 
following last dose 
for Visit 8d 
Week 
 
0 
1 
2 
3 
4 
5 
6  
10 
Day 
 
0 
7 
14 
21 
28 
35 
42 
72-77 
Blood samples for haematology and clinical chemistry 
(incl uric acid) 
X 
 
 
X 
X 
Blood samples for coagulation (INR and PTT) 
X 
 
 
 
VerifyNow™ PRUc 
 
X 
X 
X 
X 
Pregnancy test (dipstick)b 
X 
 
X 
 
X 
Collection of VOC in CRF 
 
X 
X 
X 
X 
X 
X 
X 
X 
Collection of transfusion data in CRF 
 
X 
X 
X 
X 
X 
X 
X 
X 
Collection of bleeding events in CRF 
 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
 
X 
X 
Blood sampling for pharmacokineticsc 
 
X 
X 
X 
X 
a Results from local laboratory must have been received before first dose to check eligibility criteria. 
b In patient after menarche. 
c Actual time of PK and PRU sampling should be recorded in the eCRF. 
d May occur following earlier visits than Visit 9. 
e Height only at enrolment. 
f 
Only SAE assessed at this time. 
g Electronic diary recording by patient (when needed with parent/guardian help, daily pain assessment only for ages ≥4 years) 
h Questions assessed by nurse in children <6 years, Hedonic Faces Scale (HFS) for children ≥6 years 
i 
Actual time of dosing should be recorded in the eCRF. 
j 
The time of drug administration the morning and evening before Visit 4 and 8 will be registered in a patient diary. 


Clinical Study Protocol Amendment 2 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 05 March 2015 
 
 
 
 
 
12 
 
 
Table 2 
Blood sampling in patients with a weight of >21 kg 
Assessment 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Coagulation (INR and PTT) 
X 
 
 
 
Haematology and clinical 
chemistry (incl uric acid) 
X 
 
 
Pre-dose 
X 
VerifyNow™ PRU 
 
Pre-dose, 2, 8h 
Pre-dose, 2, 8h 
2h 
Pre-dose, 2h 
Blood sampling for 
pharmacokinetics 
 
1, 2, 4, 8 h 
1, 2, 4, 8 h 
2h 
Pre-dose, 1, 2, 4h 
The 1, 2, 4, and 8 hour samples can be collected ±15 minutes from actual post-dose time point. 
A peripheral catheter can be used for blood sampling. 
Table 3 
Blood sampling in patients with a weight of 16-21 kg 
Assessment 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Coagulation (INR and PTT) 
X 
 
 
 
Haematology and clinical 
chemistry (incl uric acid) 
X 
 
 
Pre-dose 
X 
VerifyNow™ PRU 
 
Pre-dose, 2h 
Pre-dose, 2h 
2h 
Pre-dose, 2h 
Blood sampling for 
pharmacokinetics 
 
1, 2, 4, 8 h 
1, 2, 4, 8 h 
2h 
Pre-dose, 2h 
The 1, 2 and 4 and 8 hour samples can be collected ±15 minutes from actual post-dose time point. 
A peripheral catheter can be used for blood sampling. 
 


Clinical Study Protocol Amendment 2 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 05 March 2015 
 
 
 
 
 
13 
 
Table 1 
Volume of blood to be drawn from patients with a weight >21 kg 
Assessment 
Sample 
volume 
(mL) 
No. of 
samples 
Visit 1 
Total 
volume 
Visit 1 (mL) 
No. of 
samples 
Visit 2 
Total 
volume 
Visit 2 
(mL) 
No. of 
samples 
Visit 3 
Total 
volume 
Visit 3 
(mL) 
No. of 
samples 
Visit 4 
Total 
volume 
Visit 4 
(mL) 
No. of 
samples 
Visit 8 
Total 
volume 
Visit 8 
(mL) 
Total 
(mL) 
Haematology 
1.2 
1 
1.2 
0 
0 
0 
0 
1 
1.2 
1 
1.2 
Clinical Chemistry 1.1 
1 
1.1 
0 
0 
0 
0 
1 
1.1 
1 
1.1 
Coagulation 
1.2 
1 
1.2 
0 
0 
0 
0 
0 
0 
0 
0 
Pharmacokinetic 
1.2 
0 
0 
4 
4.8 
4 
4.8 
1 
1.2 
4 
4.8 
PRU 
4.0 
0 
0 
3 
12.0 
3 
12 
1 
4 
2 
8 
Total 
 
3.5 
 
16.8 
16.8 
7.5 
15.1 
59.7 
 
Table 2 
Volume of blood to be drawn from patient with a weight of 16-21 kg 
Assessment 
Sample 
volume 
(mL) 
No. of 
samples 
Visit 1 
Total 
volume 
Visit 1 (mL) 
No. of 
samples 
Visit 2 
Total 
volume 
Visit 2 
(mL) 
No. of 
samples 
Visit 3 
Total 
volume 
Visit 3 
(mL) 
No. of 
samples 
Visit 4 
Total 
volume 
Visit 4 
(mL) 
No. of 
samples 
Visit 8 
Total 
volume 
Visit 8 
(mL) 
Total 
(mL) 
Haematology 
1.2 
1 
1.2 
0 
0 
0 
0 
1 
1.2 
1 
1.2 
Clinical Chemistry 1.1 
1 
1.1 
0 
0 
0 
0 
1 
1.1 
1 
1.1 
Coagulation 
1.2 
1 
1.2 
0 
0 
0 
0 
0 
0 
0 
0 
Pharmacokinetic 
1.2 
0 
0 
4 
4.8 
4 
4.8 
1 
1.2 
2 
1.4 
PRU 
4.0 
0 
0 
2 
8 
2 
8 
1 
4 
2 
8 
Total 
 
3.5 
 
12.8 
12.8 
7.5 
11.7 
48.3 
Reference Ethical considerations paediatric 2008 
 


Clinical Study Protocol Amendment 2 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 05 March 2015 
 
 
 
 
 
14 
 
4.1 
Enrolment/screening period 
 
Procedures will be performed according to the Study Plan Table 1.  
 
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. It is planned for a minimum of 36 
patients and a maximum of 50 patients to be randomised in the study, in order to ensure 36 
evaluable patients completing two single doses in Part A. A patient is considered as evaluable if 
he/she has completed the study up to and including Visit 3.  
 
A complete medical, surgical and medication history will be recorded for each patient at 
enrolment. All relevant medical conditions that have occurred within the past or conditions that 
are ongoing are to be recorded in the eCRF. The medication history must identify any known drug 
allergies, and use of chronic medications. Safety laboratory samples should be sent to the local 
laboratory for analysis. 
 
If the patient is 16 years old or younger, a transcranial Doppler examination (TCD) must have 
been done within the past 1 year. If this is not the case, a TCD exam needs to be done before 
proceeding in the study.  
 
If the patient is six years or older, an eye exam must have been done within the past 1 year. If this 
is not the case, the patient will need to be examined by an ophthalmologist before proceeding in 
the study.  
 
4.2 
Treatment period 
 
Part A: 
 
Visit 2 & 3: Patients will be randomised 1:1 to receive one of two dosing schedules, with each dose 
separated by 7 days. Platelet aggregation will be measured using the VerifyNow™ P2Y12 assay 
and reported as PRU. PRU will determine continued dosing. Patients are not allowed to eat 2 hours 
before and 1 hour after dosing at these visits. Palatability assessment will be performed (Visit 2). A 
study nurse will assess palatability directly after administration of dose (for more information see 
Section 5.3). The patients will be allowed to leave the clinic after all sampling has been completed. 
Following the 2 single doses, all patients will receive open-label one-week treatment with 
ticagrelor twice daily to determine tolerability prior to randomisation into Part B. Dose to be 
administered twice daily within a 9-12 hours interval (starting in the morning the day after Visit 3). 
For assessments performed during the visits see Table 1. For dosing before interim analysis see 
Figure 2 and for dosing after interim analysis see Appendix E. 
 
Part B:  
Visit 4, 5, 6, 7 & 8: The patient will register actual date and time of drug administration the 
morning and evening before Visit 4 in a Dosing Diary. He/she will be instructed to not take their 
dose at home in the morning of Visit 4. Study drug will be administered at the clinic and actual 
time of dosing should be recorded in the eCRF at Visit 4. Patients will be randomised (2:1 ratio) to 


Clinical Study Protocol Amendment 2 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 05 March 2015 
 
 
 
 
 
15 
 
ticagrelor twice daily or placebo for a 4-week treatment phase and will return to the clinic on a 
weekly basis for study related procedures. (See Table 1, Visit 4-8). The patient will register actual 
date and time of drug administration the morning and evening before Visit 8 in a Dosing Diary. 
He/she will be instructed to not take their dose at home in the morning of Visit 8. Study drug will 
be administered at the clinic and actual time of dosing should be recorded in the eCRF at Visit 8. 
For dosing before interim analysis see Figure 2 and for dosing after interim analysis see Appendix 
E. 
 
Revised Text:  


Clinical Study Protocol Amendment 2 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 05 March 2015 
 
 
 
 
 
16 
 
Table 1 
Study Plan detailing the procedures 
 
Part A 
Part B 
Assessment 
Enrolment 
Dose 1 
Dose 2 
Repeated treatment phase 
End of 
treatment 
Follow-up 
Visit 
Visit window: 
 
1m  
Days -30 to -7 
for Visit 1 
2m 
 ±0 day for 
Visit 2 
3 
+ 7 days 
4 
+7 days 
5r 
+ 7 days 
6 
+ 7 days 
7r 
+ 7 days 
8 
+ 7 days 
9 
30-35 days 
following last dose 
for Visit 8d 
Week 
 
0 
1 
2 
3 
4 
5 
6  
10 
Day 
 
0 
7 
14 
21 
28 
35 
42 
72-77 
Signed Informed Assent/Consent 
X 
 
 
 
Randomisation 
 
X 
 
X 
Inclusion/exclusion criteria 
X 
Xa 
 
 
Relevant Medical and Surgical history, SCD 
characteristics and history 
X 
 
 
 
Demographics 
X 
 
 
 
Vital signs (BP, pulse) 
X 
X 
X 
X 
Xr 
X 
Xr 
X 
X 
Physical examination  
X 
 
 
 
X 
Weight, heighte 
X 
X 
X 
 
X 
Transcranial Doppler examo  
X 
 
 
 
Ophthalmological (Eye) examo  
X 
 
 
 
12-lead ECGp  
X 
 
 
 
12-lead ECG 
 
 
 
X 
Daily pain assessmentg 
X 
X 
X 
X 
X 
X 
X 
X 
FLACC assessmentq 
X 
 
 
X 
Daily recording of analgesic useg 
X 
X 
X 
X 
X 
X 
X 
X 
Days absent from school/workg 
X 
X 
X 
X 
X 
X 
X 
X 
Administration of IP at clinici 
 
X 
X 
X 
X 
Treatment dispensed/returneds 
 
 
X 
Xj 
X 
X 
X 
Xj 
Compliance/ Drug accountability 
 
X 
X 
X 
X 
X 
X 
X 
Acceptability/Palatabilityh 
 
X 
 
 
Concomitant medication  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event review (AEs and SAEs) 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 


Clinical Study Protocol Amendment 2 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 05 March 2015 
 
 
 
 
 
17 
 
Part A 
Part B 
Assessment 
Enrolment 
Dose 1 
Dose 2 
Repeated treatment phase 
End of 
treatment 
Follow-up 
Visit 
Visit window: 
 
1m  
Days -30 to -7 
for Visit 1 
2m 
 ±0 day for 
Visit 2 
3 
+ 7 days 
4 
+7 days 
5r 
+ 7 days 
6 
+ 7 days 
7r 
+ 7 days 
8 
+ 7 days 
9 
30-35 days 
following last dose 
for Visit 8d 
Week 
 
0 
1 
2 
3 
4 
5 
6  
10 
Day 
 
0 
7 
14 
21 
28 
35 
42 
72-77 
Blood samples for haematology and clinical chemistry 
(incl uric acid) 
Xn 
 
 
Xk 
X 
Blood samples for coagulation (INR and PTT) 
Xn 
 
 
 
VerifyNow™ PRUc 
 
X 
X 
Xl 
X 
Pregnancy test (dipstick)b 
X 
 
X 
 
X 
Collection of VOC in CRF 
 
X 
X 
X 
X 
X 
X 
X 
X 
Collection of transfusion data in CRF 
 
X 
X 
X 
X 
X 
X 
X 
X 
Collection of bleeding events in CRF 
 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
Xn 
 
 
X 
X 
Blood sampling for pharmacokineticsc 
 
X 
X 
Xl 
X 
Abbreviations: AE = adverse event; BP = blood pressure; CRF = Case Report Form; ECG = electrocardiogram; eCRF = electronic Case Report Form; 
FLACC = the Face, Legs, Activity, Cry, Consolability form; INR = International Normalized Ratio; PK = pharmacokinetics; PRU = P2Y12 reaction 
units; PTT = Partial Thromboplastin Time; SAE = serious adverse event; SCD = Sickle Cell Disease; VOC = vaso-occlusive crisis 
a Results from local laboratory must have been received before first dose to check eligibility criteria. 
b In patient after menarche. 
c Actual time of PK and PRU sampling should be recorded in the eCRF. 
d May occur following earlier visits than Visit 9. 
e Height only at enrolment. 
f 
Only SAE assessed at this time. 
g Electronic diary recording by patient ≥4 years (when needed with parent/guardian help). 
h Questions assessed by nurse in children <6 years, Hedonic Faces Scale (HFS) for children ≥6 years 
i 
Actual time of dosing should be recorded in the eCRF. 
j 
The time of drug administration in the morning and evening before Visit 4 and 8 will be registered in a patient diary. 
k Blood sample for haematology and clinical chemistry (including uric acid) at Visit 4 will be collected 2h post-dose together with PK and PRU. 
l 
PK and PRU sampling at Visit 4 will be performed at 2 hours post-dose ONLY. 
m Visit 2 should be at least 7 days apart from Visit 1. 
n Laboratory testing performed prior to Visit 1 as part of usual clinical care does not need to be repeated as long as the values were obtained within 
30 days prior to Visit 2. 


Clinical Study Protocol Amendment 2 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 05 March 2015 
 
 
 
 
 
18 
 
o The most recent examination must be performed within 12 months before Visit 1. If this is not the case, the examination must be done before 
proceeding in the study. 
p 12-lead ECG must be performed within 6 months before Visit 1. If this is not the case, the examination must be done before proceeding in the study. 
q FLACC for patients aged from 2 to <4 years only to be collected between Visit 1 and Visit 2, and between Visit 4 to Visit 5. 
r Visit 5 and Visit 7 may be performed as telephone contacts, based on the opinion of the Investigator.  Vital signs (BP and pulse) will only be 
measured if the patient visits the site. 
s 
If Visit 5 and/or Visit 7 are performed as telephone contacts, doubles kits of study treatment will be dispended on Visit 4 and/or Visit 6 to cover the 
whole period. 


Clinical Study Protocol Amendment 2 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 05 March 2015 
 
 
 
 
 
19 
 
Table 2 
Blood sampling in patients with a weight of >21 kg 
Assessment 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Coagulation (INR and PTT) 
X 
 
 
 
Haematology and clinical 
chemistry (incl uric acid) 
X 
 
 
2h 
post-dose 
X 
VerifyNow™ PRU 
 
Pre-dose, 2, 6h 
post-dose 
Pre-dose, 2, 6h 
post-dose 
2h 
post-dose 
Pre-dose, 2h 
post-dose 
Blood sampling for 
pharmacokinetics 
 
1, 2, 4, 6h 
post-dose 
1, 2, 4, 6h 
post-dose 
2h 
post-dose 
Pre-dose, 1, 2, 4h 
post-dose 
Abbreviations: INR = International Normalized Ratio; PK = pharmacokinetics; PRU = P2Y12 reaction units; PTT = Partial Thromboplastin Time 
The 1, 2, 4, and 6 hour samples can be collected ±15 minutes from actual post-dose time point. 
If applicable, PRU and PK sampling should be arranged at the same time to avoid repeated venipuncture. 
A peripheral catheter can be used for blood sampling. 
Table 3 
Blood sampling in patients with a weight of 16-21 kg 
Assessment 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Coagulation (INR and PTT) 
X 
 
 
 
Haematology and clinical 
chemistry (incl uric acid) 
X 
 
 
2h 
post-dose 
X 
VerifyNow™ PRU 
 
Pre-dose, 2h 
post-dose 
Pre-dose, 2h 
post-dose 
2h 
post-dose 
Pre-dose, 2h 
post-dose 
Blood sampling for 
pharmacokinetics 
 
1, 2, 4, 6h 
post-dose 
1, 2, 4, 6h 
post-dose  
2h 
post-dose 
Pre-dose, 2h 
post-dose 
Abbreviations: INR = International Normalized Ratio; PK = pharmacokinetics; PRU = P2Y12 reaction units; PTT = Partial Thromboplastin Time 
The 1, 2, 4 and 6 hour samples can be collected ±15 minutes from actual post-dose time point. 
If applicable, PRU and PK sampling should be arranged at the same time to avoid repeated venipuncture. 
A peripheral catheter can be used for blood sampling. 


Clinical Study Protocol Amendment 2 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 05 March 2015 
 
 
 
 
 
20 
 
Table 3 
Volume of blood to be drawn from patients with a weight >21 kg 
Assessment 
Sample 
volume 
(mL) 
No. of 
samples 
Visit 1 
Total 
volume 
Visit 1 (mL) 
No. of 
samples 
Visit 2 
Total 
volume 
Visit 2 
(mL) 
No. of 
samples 
Visit 3 
Total 
volume 
Visit 3 
(mL) 
No. of 
samples 
Visit 4 
Total 
volume 
Visit 4 
(mL) 
No. of 
samples 
Visit 8 
Total 
volume 
Visit 8 
(mL) 
Total 
(mL) 
Haematology 
1.2 
1 
1.2 
0 
0 
0 
0 
1 
1.2 
1 
1.2 
Clinical Chemistry 1.1 
1 
1.1 
0 
0 
0 
0 
1 
1.1 
1 
1.1 
Coagulation 
1.2 
1 
1.2 
0 
0 
0 
0 
0 
0 
0 
0 
Pharmacokinetic 
1.2 
0 
0 
4 
4.8 
4 
4.8 
1 
1.2 
4 
4.8 
PRU* 
4.0 
0 
0 
3 
12.0 
3 
12 
1 
4 
2 
8 
Total 
 
3.5 
 
16.8 
16.8 
7.5 
15.1 
59.7 
* PRU sampling via a central catheter may require up to an additional 3 mL at each PRU sampling timepoint. 
Table 4 
Volume of blood to be drawn from patient with a weight of 16-21 kg 
Assessment 
Sample 
volume 
(mL) 
No. of 
samples 
Visit 1 
Total 
volume 
Visit 1 (mL) 
No. of 
samples 
Visit 2 
Total 
volume 
Visit 2 
(mL) 
No. of 
samples 
Visit 3 
Total 
volume 
Visit 3 
(mL) 
No. of 
samples 
Visit 4 
Total 
volume 
Visit 4 
(mL) 
No. of 
samples 
Visit 8 
Total 
volume 
Visit 8 
(mL) 
Total 
(mL) 
Haematology 
1.2 
1 
1.2 
0 
0 
0 
0 
1 
1.2 
1 
1.2 
Clinical Chemistry 1.1 
1 
1.1 
0 
0 
0 
0 
1 
1.1 
1 
1.1 
Coagulation 
1.2 
1 
1.2 
0 
0 
0 
0 
0 
0 
0 
0 
Pharmacokinetic 
1.2 
0 
0 
4 
4.8 
4 
4.8 
1 
1.2 
2 
2.4 
PRU* 
4.0 
0 
0 
2 
8 
2 
8 
1 
4 
2 
8 
Total 
 
3.5 
 
12.8 
12.8 
7.5 
12.7 
49.3 
* PRU sampling via a central catheter may require up to an additional 3 mL at each PRU sampling timepoint. 
Reference Ethical considerations paediatric 2008 
 


Clinical Study Protocol Amendment 2 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 05 March 2015 
 
 
 
 
 
21 
 
4.1 
Enrolment/screening period 
 
Procedures will be performed according to the Study Plan Table 1.  
 
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. It is planned for a minimum of 36 
patients and a maximum of 50 patients to be randomised in the study, in order to ensure 36 
evaluable patients completing two single doses in Part A. A patient is considered as evaluable if 
he/she has provided data up to and including Visit 3. Of these 36 evaluable patients, at least 12 
patients must be 2 to 11 years of age and 12 patients must be 12 to 18 years. In addition, a 
minimum of 12 evaluable patients must complete Part B (through Visit 8). 
 
A complete medical, surgical and medication history will be recorded for each patient at enrolment. 
All relevant medical conditions that have occurred within the past or conditions that are ongoing 
are to be recorded in the eCRF. The medication history must identify any known drug allergies, 
and use of chronic medications. Safety laboratory samples should be sent to the local laboratory for 
analysis. 
 
If the patient is 16 years old or younger, a TCD must have been done within the past 1 year. If this 
is not the case, a TCD exam needs to be done before proceeding in the study.  
 
If the patient is six years or older, an eye exam must have been done within the past 1 year. If this 
is not the case, the patient will need to be examined by an ophthalmologist before proceeding in the 
study.  
 
At least a 7-day interval is needed between Visit 1 and Visit 2 to allow for the recording of the 
baseline data on patient diary (see Section 5.1.2). 
 
4.2 
Treatment period 
 
Part A: 
 
Visit 2 & 3: Randomisation will take place 7 to 30 days after enrolment. Patients will be 
randomised 1:1 to receive one of two dosing schedules, with each dose separated by 7 days. 
Platelet aggregation will be measured using the VerifyNow™ P2Y12 assay and reported as PRU. 
PRU will determine continued dosing. Patients are not allowed to eat 2 hours before and 1 hour 
after dosing at these visits. Palatability assessment will be performed (Visit 2). A study nurse will 
assess palatability directly after administration of dose (for more information see Section 5.3). The 
patients will be allowed to leave the clinic after all sampling has been completed. Following the 
2 single doses, all patients will receive open-label one-week treatment with ticagrelor twice daily to 
determine tolerability prior to randomisation into Part B. Dose to be administered twice daily 
within a 9-12 hours interval (starting in the evening the same day as Visit 3). For assessments 
performed during the visits see Table 1. For dosing before interim analysis see Figure 2 and for 
dosing after interim analysis see Appendix E. 
 


Clinical Study Protocol Amendment 2 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 05 March 2015 
 
 
 
 
 
22 
 
Part B:  
Visit 4, 5, 6, 7 & 8: The patient will register actual date and time of drug administration the 
morning and evening before Visit 4 in a Dosing Diary. He/she will be instructed to not take their 
dose at home in the morning of Visit 4. Study drug will be administered at the clinic and actual 
time of dosing should be recorded in the eCRF at Visit 4. Patients will be randomised (2:1 ratio) to 
ticagrelor twice daily or placebo for a 4-week treatment phase and will return to the clinic on a 
weekly basis for study related procedures. Visit 5 and Visit 7 may optionally be performed as 
phone contacts, based on the opinion of the Investigator (See Table 1, Visit 4-8). The patient 
will register actual date and time of drug administration the morning and evening before Visit 8 in 
a Dosing Diary. He/she will be instructed to not take their dose at home in the morning of Visit 8. 
Study drug will be administered at the clinic and actual time of dosing should be recorded in the 
eCRF at Visit 8. For dosing before interim analysis see Figure 2 and for dosing after interim 
analysis see Appendix E. 
 
Section of protocol affected: 
 
5.1.1 Vaso-occlusive crisis (VOC), 5.1.2 Pain, 5.1.3 Other efficacy variables, 
5.2.1 Laboratory safety assessment, 5.2.3 Vital signs, 5.2.4 Electrocardiogram (newly added 
section), 5.5.2 Collection of samples, 7.7 Concomitant and other treatments, 7.7.1 Blood 
transfusion (newly added section), 7.7.2 Other concomitant treatment 
 
Previous text:  
5.1.1 Vaso-occlusive crisis (VOC) 
 
VOC is defined as a painful sickle cell crisis requiring medical intervention including any of the 
following (1) hospitalization (2) emergency department or clinic visit (3) medically supervised 
outpatient treatment with escalated doses of drugs for management of painful crisis (may include oral 
or parenteral opioids or non-steroidal anti-inflammatory drugs). At each visit, patients or guardians 
will be questioned regarding any painful sickle cell crises occurring since the last study visit. 
 
5.1.2 Pain 
 
Pain is commonly reported in clinical trials by having patients provide a rating of their own 
pain. 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. The Faces Pain Scale - Revised 
(FSP-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 to 16 years of age (Cohen et al 2008) and will 
be administered to all patients in this study age ≥4 years. When needed a parent/guardian 
can help the child with the assessment.  
 
The Faces Pain Scale will be collected daily at bedtime using an electronic device. The 
scale consists of six faces and scoring ranges between 0-10 (with an increase in numeric 
value by 2 i.e. (0,2,4,6,8,10)), where 0 is no pain. If the patient answers that he/she has pain 
a body outline diagram will be presented and the patient will be asked to indicate 
the location of the pain. Please see Appendix G. 


Clinical Study Protocol Amendment 2 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 05 March 2015 
 
 
 
 
 
23 
 
 
5.1.3 Other efficacy variables 
 
Daily variables will be collected using a daily electronic diary both in Part A and Part B: 
 
x Days of analgesic use 
 
x Days of absence from school or work (ages ≥6 years only) 
 
For more details see Section 5.3. 
 
5.2.1 Laboratory safety assessments 
 
Blood and urine samples for determination of clinical chemistry, haematology, coagulation, and 
urinalysis will be taken at the times indicated in the Study Plan (see Table 1). 
 
Additional safety samples may be collected if clinically indicated at the discretion of the Investigator. 
The date, time of collection and results (values, units and reference ranges) will be recorded on the 
appropriate eCRF. 
 
5.2.3 Vital signs 
 
BP and pulse will be measured at every visit. Weight will be measured at Visit 1(enrolment), 2, 3 and 
8 (follow-up). Height will only be measured at enrolment. 
 
5.5.2 Collection of samples 
 
Samples will be collected and labeled as detailed in the Laboratory Manual. 
 
7.7 
Concomitant and other treatments 
 
Treatment with oral or parenteral anticoagulants, and daily aspirin or non-steroidal anti-inflammatory 
agents is not allowed in the study except for prophylactic doses of heparins, eg, flushing of catheters 
(see exclusion criteria in Section 3.2). 
 
7.7.1 Other concomitant treatment 
 
Other medication other than that described above, which is considered necessary for the patient’s 
safety and well-being, may be given at the discretion of the Investigator and recorded in the 
appropriate sections of the eCRF. 
 
Revised text:  
 
5.1.1 Vaso-occlusive crisis (VOC) 
 
VOC is defined as a painful sickle cell crisis requiring medical intervention including any of the 
following (1) hospitalization (2) emergency department, short-stay unit or clinic visit (3) medically 
supervised outpatient treatment with escalated doses of drugs for management of painful crisis (may 
include oral or parenteral opioids or non-steroidal anti-inflammatory drugs). At each visit, patients or 
guardians will be questioned regarding any painful sickle cell crises occurring since the last study 
visit. 


Clinical Study Protocol Amendment 2 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 05 March 2015 
 
 
 
 
 
24 
 
 
5.1.2 Pain 
 
Pain is commonly reported in clinical trials by having patients provide a rating of their own 
pain. 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. The Faces Pain Scale - Revised 
(FSP-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 to 16 years of age (Cohen et al 2008) and will 
be administered to all patients in this study age ≥4 years. When needed, a parent/guardian 
can help the child with the assessment.  
 
The Faces Pain Scale will be collected daily at bedtime using an electronic device. The 
scale consists of six faces and scoring ranges between 0-10 (with an increase in numeric 
value by 2 i.e. (0, 2, 4, 6, 8, 10)), where 0 is no pain. If the patient answers that he/she has 
pain a body outline diagram will be presented and the patient will be asked to indicate 
the location of the pain. Please see Appendix G. 
 
For patients aged from 2 to <4 years, a Face, Legs, Activity, Cry, Consolability 
(FLACC) form will be used for recording daily pain, between visit 1 and 2 and 
between visit 4 and 5. The FLACC form will be completed daily at bedtime by the 
primary caregiver, with the assessment of the time when the child is under the 
caregiver’s care. If possible, the reporter should be the same caregiver during the 
reporting period. Please see Appendix G. 
 
5.1.3 Other efficacy variables 
 
Daily variables will be collected using a daily electronic diary both in Part A and Part B: 
 
x 
Days of analgesic use (ages ≥4 years only) 
x 
Days of absence from school or work (ages ≥6 years only), excluding days of absence due 
to  study visits 
 
For more details see Section 5.3. 
 
 
5.2.1 Laboratory safety assessments 
 
Blood and urine samples for determination of clinical chemistry, haematology, coagulation, and 
urinalysis will be taken at the times indicated in the Study Plan (see Table 1). 
 
At Visit 1, laboratory testing performed prior to enrolment as part of usual care does not need 
to be repeated as long as the values are obtained no more than 30 days prior to Visit 2. 
 
Additional safety samples may be collected if clinically indicated at the discretion of the Investigator. 
The date, time of collection and results (values, units and reference ranges) will be recorded on the 
appropriate eCRF. 


Clinical Study Protocol Amendment 2 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 05 March 2015 
 
 
 
 
 
25 
 
 
5.2.3 Vital signs 
 
BP and pulse will be measured at every on-site visit. Weight will be measured at Visit 1(enrolment), 
2, 3 and 8 (follow-up). Height will only be measured at enrolment. 
 
5.2.4 Electrocardiogram 
 
12-lead ECG will be performed at Visit 1 (or within 6 months prior to enrolment) and at Visit 4. 
The following ECG parameters will be collected: heart rate and rhythm, PR interval, QRS 
duration, RR interval, QT interval, QTc interval (unspecified), and any abnormalities. 
 
5.5.2 Collection of samples 
 
Samples will be collected and labeled as detailed in the VerifyNow User’s Manual. In addition, 
to reduce the blood volume required for the PD and PK samples, the following procedures will 
be utilized.  
 
x For VerifyNow samples obtained through a peripheral indwelling cannula: Discard saline 
remaining in the cannula and 1 mL of blood. Draw 1.2 mL for PK sample (discard this 
blood if there is no PK sample at this time point). Draw 2 mL into the VerifyNow partial fill 
tube. 
 
x For VerifyNow samples obtained through a central indwelling line: Discard saline or flush 
solution and 3.8 mL of blood. Draw 1.2 mL for PK sample (discard this blood if there is no 
PK sample at this time point). Draw 2 mL into the VerifyNow partial fill tube. 
 
x For samples obtained through direct phlebotomy: Use a 21 gauge or larger needle or 
butterfly device and ensure an atraumatic venipuncture. Draw and discard 1 mL of blood. 
Draw 1.2 mL for PK sample (discard this blood if there is no PK sample at this time point). 
Draw 2 mL into the VerifyNow partial fill tube. 
 
7.7 
Concomitant and other treatments 
 
Treatment with oral or parenteral anticoagulants, and daily aspirin is not allowed in the study except 
for prophylactic doses of heparins, eg, flushing of catheters (see exclusion criteria in Section 3.2). 
NSAIDs may not be administered more frequently than 3 days per week. 
 
7.7.1 Blood transfusion 
 
If a patient requires any blood transfusion during the study, this information will be captured 
in the eCRF. 
 
7.7.2 Other concomitant treatment 
 
Other medication other than that described above, which is considered necessary for the patient’s 
safety and well-being, may be given at the discretion of the Investigator and recorded in the 
appropriate sections of the eCRF. 
 


Clinical Study Protocol Amendment 2 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 05 March 2015 
 
 
 
 
 
26 
 
Section of protocol affected: 
 
11 List of References, Appendix F: Table 5, Appendix G FLACC form (newly added); 
Appendix H Child-Pugh Classification (newly added) 
 
Previous text: 
 
11 
List of References 
 
Ataga et al 2012 
Ataga KI, Brittain JE, Desai P, May R, Jones S, Delaney J et al. Association of coagulation activation 
with clinical complications in sickle cell disease.  
PLoS ONE 2012;7(1) doi:10.1371/journal.pone.0029786 
 
Ballas 2007 
Ballas SK. Current issues in sickle cell pain and its management.  
Hematology Am Soc Hematol Educ Program 2007:97-105 
 
Cabannes et al 1984 
Cabannes R, Lonsdorfer J, Castaigne JP, Ondo A, Plassard A, Zohoun I et al. Clinical and biological 
double-blind-study of ticlopidine in preventive treatment of sickle-cell crises. Agents Actions 
1984;Suppl 15:199-212 
 
Appendix F 
 
Table 5 
0.563 mg/kg 
 
Weight (kg) 
Bottle strength (mg) 
Dose volume (mL) 
Actual dose (mg) 
16-27 
45 
2 
9 
28-41 
45 
4 
18 
42-55 
45 
6 
27 
56-69 
45 
8 
36 
70-120 
45 
10 
45 
 
Revised text:  
 
11 
List of References 
 
Adams et al 1998 
Adams RJ, Mckie V, Hsu L et al. Prevention of a first stroke by transfusions in children with 
sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J 
Med 1998;339(1):5-11 
 
Ataga et al 2012 
Ataga KI, Brittain JE, Desai P, May R, Jones S, Delaney J et al. Association of coagulation activation 
with clinical complications in sickle cell disease.  
PLoS ONE 2012;7(1) doi:10.1371/journal.pone.0029786 


Clinical Study Protocol Amendment 2 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 05 March 2015 
 
 
 
 
 
27 
 
Ballas 2007 
Ballas SK. Current issues in sickle cell pain and its management.  
Hematology Am Soc Hematol Educ Program 2007:97-105 
 
Bulas et al 2005 
Bulas D. Screening children for sickle cell vasculopathy: guidelines for transcranial Doppler 
evaluation. Paediatric Radiology 2005;35:235-241 
 
Cabannes et al 1984 
Cabannes R, Lonsdorfer J, Castaigne JP, Ondo A, Plassard A, Zohoun I et al. Clinical and biological 
double-blind-study of ticlopidine in preventive treatment of sickle-cell crises. Agents Actions 
1984;Suppl 15:199-212 
 
Appendix F 
 
Table 5 
0.563 mg/kg 
 
Weight (kg) 
Bottle strength (mg) 
Dose volume (mL) 
Actual dose (mg) 
16-27 
45 
2 
9 
28-41 
45 
4 
18 
42-55 
45 
6 
27 
56-69 
45 
8 
36 
70-120 
45 
10 
45* 
* The highest dose in this study is 45 mg, even if the patient weight is >120 kg. 
 


Clinical Study Protocol Amendment 2 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 05 March 2015 
 
 
 
 
 
28 
 
Appendix G 
 
FLACC form 
 
SICKLE CELL PAIN DIARY (children aged 2-3) 
Instruction for Caregiver (e.g. parent) on completion  
 
__________________ (child’s name) is taking part in a study of children with sickle cell disease.  The study is 
collecting information about pain, so that we can learn how to help children with sickle cell disease feel better. 
Please complete the sickle pain diary every evening from _______________ (date) until your next clinic visit 
_______________ (date).    
 
1. Enter assessment date for each day of assessment. 
 
2. Answer the question: Has your child had any sickle cell pain during the last 24 hours? 
If your child has had any sickle cell pain during the last 24 hours, please describe how your 
child behaved while under your care due to the pain. For each category (face, legs, activity, 
crying, and consolability), please mark an X in the one box that best describes your answer. 
 
Please remember the same caregiver (e.g. parent) is to complete the diary every evening. 
Please contact Your Study Doctor or Study Nurse if you have doubts how to complete diary. 
Please remember to return the completed sickle cell pain diary on the next visit to the clinical site.  


Clinical Study Protocol Amendment 2 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 05 March 2015 
 
 
 
 
 
29 
 
 
 
 
SICKLE CELL PAIN Diary – patients ages 2 through <4  
 
Patient ID/E-code : ________________ Assessment Date : _____________ 
 
 
Instructions 
 
Please answer this question every night when participating in the study.  
 
 
Has your child had any sickle cell pain during the last 24 hours? 
 
 
 
No 
 
 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
If Yes, please continue to the next page 
 
 
 
 
 
English for USA 
 
Merkel, S., Voepel-Lewis, T., Shayevitz, J., & Malviya, S. (1997). The FLACC: A behavioral scale for 
scoring postoperative pain in young children. Pediatric Nursing 23(3),293-297.  © 2002, The 
Regents of the University of Michigan. All Rights Reserved. 


Clinical Study Protocol Amendment 2 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 05 March 2015 
 
 
 
 
 
30 
 
 
Please describe how your child behaved because of the pain. For each category (face, legs, activity, cry and 
consolability), please mark an X in the box that best describes your answer. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
English for USA 
 
Merkel, S., Voepel-Lewis, T., Shayevitz, J., & Malviya, S. (1997). The FLACC: A behavioral scale for 
scoring postoperative pain in young children. Pediatric Nursing 23(3),293-297.  © 2002, The 
Regents of the University of Michigan. All Rights Reserved. 


Clinical Study Protocol Amendment 2 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 05 March 2015 
 
 
 
 
 
31 
 
Appendix H 
Child-Pugh classification 
The Child-Pugh score is a FDA-recommended classification for assessing hepatic impairment. Drugs that are 
predominantly metabolized by the liver must be studied in a controlled trial with patients who have varying 
degrees of liver impairment. Dosage modifications due to hepatic impairment may be based on the Child-Pugh 
score1. 
Table 5 
 Child-Pugh Classification2 (modified from Pugh 1973) 
Clinical and Biochemical Markers 
Points scored for observed findings 
1 
2 
3 
Hepatic encephalopathy (grade)* 
Absent 
Moderate 
(1 or 2) 
Severe 
(3 or 4) 
Ascites 
Absent 
Slight 
Moderate 
Bilirubin (mg/dL) 
< 2.0 
2.0 - 3.0 
> 3.0 
Serum albumin (g/dL) 
> 3.5 
2.8 - 3.5 
< 2.8 
Prothrombin time (seconds prolonged) 
or 
Prothrombin time (INR) 
< 4 
 
< 1.7 
4 - 6 
 
1.7 - 2.3 
> 6 
 
> 2.3 
 
Total Child-Pugh Scoring  
Total Points 
Grade 
Description 
5-6 
A 
Mild: well-compensated disease 
7-9 
B 
Moderate: significant functional compromise 
10-15 
C 
Severe: decompensated disease 
                                                          
*Grade 0: normal consciousness, personality, neurological examination, electroencephalogram. 
Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cycles per second (cps) waves.  
Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves. 
Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves. 
Grade 4: unrousable coma, no personality/behavior, decerebrate, slow 2-3 cps delta activity. 


Clinical Study Protocol Amendment 2 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 05 March 2015 
 
 
 
 
 
32 
 
References 
1 US Department of Health and Human Services Food and Drug Administration. Guidance for industry: 
pharmacokinetics in patients with impaired hepatic function: study design, data analysis, and impact on dosing 
and labeling. 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072123.pdf. 
Updated May 30, 2003. Accessed March 21, 2011. 
2 Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC and Williams R. Transection of the oesophagus for 
bleeding oesophageal varices. Br J Surg 1973;60(8):646-9.  
 


Clinical Study Protocol Amendment 2 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 05 March 2015 
33 
 
 
 
 
 
 
 
Reason for Amendment: 
 
The purposes of this amendment are to: 
 
Update the secondary objective to include the PK properties of the active metabolite of ticagrelor. 
Re-word some inclusion/exclusion criteria for clarification and consistency with other parts of the 
CSP. 
 
x Patients aged ≤16 years must have a TCD exam before proceeding in the study if he/she 
hasn’t had a TCD exam within the past year prior to Visit 1. 
x Patients aged ≤6 years must be examined by an ophthalmologist before proceeding in the 
study if he/she hasn’t had an ophthalmological examination within the past year prior to Visit 
1. 
x Weight-adjusted dose of hydroxyurea must be stable for 3 months to be eligible for enrolment. 
x The TCD exclusion criterion was re-worded consistent with STOP study criteria and to 
include values for imaging TCD equipment.  
x The exclusion concerning chronic transfusion was reworded to exclude only patients currently 
on a chronic transfusion program.  
x Active pathological bleeding was added to exclusion criteria. 
x Moderate or severe hepatic impairment which excludes a patient from the study is now 
defined specifically as Child-Pugh Class B or C.  
 
Define a highly effective method of contraception as the one which results in a low failure rate (i.e. 
less than 1% per year) for consistency with UK regulatory definition. The methods meeting this 
definition are now specifically listed in section 3.8. 
 
Highlight that at least a 7-day interval is needed between Visit 1 and Visit 2 to allow for baseline 
patient diary recording. 
 
State that randomisation will take place 7 to 30 days after enrolment. 
 
Change collection of haematology and clinical chemistry sample at visit 4 to 2 hours post-dose, to 
minimize number of separate venipunctures for the patient. 
 
Shorten the PK and PRU sampling time for Visit 2 and Visit 3 as last measurement will occur at 6 
hours post-dose; correct the volume of blood collection for patients with a weight of 16 to 21 kg; and 
clarify that an additional 3 mL of blood sample may be needed when using a central catheter for PRU 
sampling at each PRU sampling timepoint. 
 
Clarify that days absent from school or work due to clinical study visits do not count as “days absent 
from school/work” on the eDiary. 
 
Update the protocol to reflect the request of the Paediatric Committee (PDCO) that the 36 evaluable 
patients will include at least 12 patients aged 2 to 11 years and at least 12 patients aged 12 to 18 
years; moreover, a minimum of 12 evaluable patients must complete Part B (through Visit 8). 


Clinical Study Protocol Amendment 2 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 05 March 2015 
34 
 
 
 
 
 
 
 
Clarify that open-label one week treatment will start in the evening the same day as Visit 3. 
 
Confirm that Visit 5 and Visit 7 may optionally be performed as telephone contacts rather than clinic 
visits if the investigator deems this acceptable. 
 
Update the criteria for interruption or discontinuation of investigational product. 
 
State that laboratory testing performed prior to enrolment as part of usual clinical care does not need 
to be repeated as long as the values were obtained no more than 30 days prior to Visit 2. 
 
Add a new section (Section 5.2.4) to specify ECG parameters collected for the study. 
 
State that NSAIDs drugs may not be administered more frequently than 3 days per week during the 
study. 
 
Add a new section (Section 7.7.1) to clarify that any blood transfusion during the study will be 
recorded in the eCRF. 
 
State the maximum dose of ticagrelor in this study is 45 mg, regardless of the weight of a patient. 
 
Update the CSP to reflect the request from PDCO to add pain assessment for SCD pain for children 
aged 2 to < 4 years. FLACC form and instructions for completion of the form are added. This will be 
studied as exploratory objective with days of pain and intensity of pain as outcome measures. 
 
Added description of how PD (VerifyNow P2Y12) samples are collected and handled. 
 
Clarify that definition of VOC includes medical intervention at short-stay unit. 
 
Add new reference articles. 
 
Correct typographical errors and make general and administrative updates. 
 
Persons who initiated the Amendment: 
 
AstraZeneca Study Team initiated the amendment to clarify wording, decrease patient burden, and to 
incorporate requests from the Paediatric Committee of the European Medicines Agency and the 
MHRA.  
 


 
 
Clinical Study Protocol Amendment 
 
Amendment Number 
3 
 
Drug Substance 
Ticagrelor 
 
Study Code 
D5136C00007 
 
Date 
22 December 2015 
 
Protocol Dated 
05 March 2014 
 
 
 
Multicenter, open-label, randomised, pharmacokinetic (PK) and 
pharmacodynamic (PD) dose-ranging Phase II study of ticagrelor followed 
by a double-blind, randomised, parallel-group, placebo-controlled 4 weeks 
extension phase in paediatric patients with sickle cell disease 
 
This submission /document contains trade secrets and confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object. 
Sponsor: 
AstraZeneca AB, 151 85 Södertälje, Sweden.   
Centres affected by the Amendment: 
This amendment affects all centres in the study. 
The protocol for the study is to be amended as follows:  
Section of protocol affected: 
Synopsis; 1.4 Study design; 4.1 Enrolment/screening period 
Previous text: 
This study is planned to be conducted in approximately 4 countries (United States (US), 
United Kingdom (UK), South Africa and Canada) and approximately 8 to 20 sites, with a 
minimum of 36 patients and a maximum of 50 patients to be randomised in the study, 
depending on how many patients are required in order to have 36 evaluable patients. Of these 
36 evaluable patients, at least 12 patients must be 2 to 11 years of age and 12 patients must be 
12 to 18 years. In addition, a minimum of 12 evaluable patients must complete Part B 
(through Visit 8). 


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
2 
 
 
Study period 
Phase of development 
Estimated date of first subject enrolled 
Q3 2014 
II 
Estimated date of last subject completed 
Q2-Q3 2015 
Revised text: 
This study is planned to be conducted in approximately 6-10 countries in North 
America, Europe, Middle East and Africa at approximately 30 - 37 sites, with a minimum 
of 36 patients and a maximum of 50 patients (including the patients already randomised to 
date) to be randomised in the study, depending on how many patients are required in order to 
have 36 evaluable patients. Of these 36 evaluable patients, at least 12 patients must be 2 to 11 
years of age and 12 patients must be 12 to 18 years. In addition, a minimum of 12 evaluable 
patients must complete Part B (through Visit 8). 
 
Study period 
Phase of development 
Estimated date of first subject enrolled 
Q3 2014 
II 
Estimated date of last subject completed 
Q1 2017 
 
Section of protocol affected: 
Synopsis 
Previous text: 
Part A: Patients will be randomised 1:1 to receive one of two dosing schedules. All patients 
will receive 0.125 mg/kg as their initial dose, followed 7 days later by 0.375 mg/kg or 
0.563 mg/kg with determination of pharmacokinetic (PK) parameters and pharmacodynamic 
(PD) platelet inhibition following each dose. The PK and platelet aggregation data are 
intended to support modelling-based selection of a weight-based dose for Phase III. Platelet 
aggregation will be measured using the VerifyNow™ P2Y12 assay and reported as P2Y12 
reaction units (PRU). 
Following the 2 single doses, all patients will receive open-label one-week treatment with 
ticagrelor 0.125 mg/kg twice daily to determine tolerability prior to randomisation into Part B.  
Part B: In this part patients will be randomised (2:1 ratio) to ticagrelor 0.125 mg/kg twice 
daily or placebo for a 4-week treatment phase.  
During the study, patients will be followed for the occurrence of vaso-occlusive crisis (VOC) 
and for other disease manifestations such as daily pain, analgesic use and complications of 
SCD. 


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
3 
 
For safety reasons the dosing schedule will be modified for individual patients as follows: If 
PRU at 2 hr following dosing of 0.125 mg/kg is <95, the subsequent maximum dose for this 
patient will be 0.0625 mg/kg throughout the study. If PRU <95 on any two dosing occasions 
following dosing of 0.0625 mg/kg, the patient will be discontinued from further study drug. 
After 12 patients have completed dosing in Part A, a PK/PD evaluation (interim 
analysis) of the data will be conducted and the dose for the repeated dosing in both Part 
A and B for the remaining patients may be revised (aiming for a mean reduction in PRU 
2 hour post-dose of 45%). 
Revised text: 
Part A: Patients will be randomised 1:1 to receive one of two dosing schedules. All patients 
will receive 0.75 mg/kg as their initial single dose, followed 7 days later by 1.125 mg/kg or 
2.25 mg/kg with determination of pharmacokinetic (PK) parameters and pharmacodynamic 
(PD) platelet inhibition following each single dose. The PK and platelet aggregation data are 
intended to support modelling-based selection of a weight-based dose for Phase III. Platelet 
aggregation will be measured using the VerifyNow™ P2Y12 assay and reported as P2Y12 
reaction units (PRU). 
Following the 2 single doses, all patients will receive open-label one-week treatment with 
ticagrelor 0.75 mg/kg twice daily to determine tolerability prior to randomisation into Part B.  
Part B: Part B will be optional for patients. The investigator should present Part B to 
each patient and the decision to participate in Part B should be made by the patient (or 
parents/legal guardian). In this part patients will be randomised (2:1 ratio) to ticagrelor 0.75 
mg/kg twice daily or placebo for a 4-week treatment phase. In some countries, Part B will 
not be performed. 
During the study, patients will be followed for the occurrence of vaso-occlusive crisis (VOC) 
and for other disease manifestations such as daily pain, analgesic use and complications of 
SCD. 
For safety reasons the dosing schedule will be modified for individual patients as follows: If 
PRU at 2 hr following dosing of 0.75 mg/kg is <95, the subsequent maximum dose for this 
patient will be 0.563 mg/kg throughout the study. If PRU <95 following dosing of 0.563 
mg/kg, the patient will be discontinued from further study drug. 
Since Part A of the study is open label, the PK and PD results will be monitored as the 
study proceeds and the doses may be further adjusted in both Part A and B based on 
emerging PK and PD results. Doses may be adjusted following assessment by 
AstraZeneca and the Steering Committee of open label Part A results in the first 6-12 
patients randomised under this amendment. Dose adjustment decisions will be based 
upon a review of PK, PD and adverse events (see Section 8.6). 


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
4 
 
Section of protocol affected: 
Synopsis 
Previous text: 
Target subject population 
Patients eligible for this study include all children aged ≥2 to <18 years of age (age from birth 
to Visit 1) who are diagnosed with sickle cell disease [homozygous sickle cell (HbSS) or 
sickle beta-zero-thalassemia (HbS/β0)] and have experienced at least two VOC requiring 
medical intervention during the past 12 months.  
Duration of treatment 
In Part A the treatment period consists of 2 single doses (separated by at least 7 days) 
followed by 7 days open label ticagrelor treatment twice daily. In Part B patients will be 
randomised to 4 weeks twice-daily treatment. There is no washout period between Part A and 
Part B. The total expected study duration for an individual patient is approximately 3 months 
(including 30 days follow-up after last dose). 
Investigational product, dosage and mode of administration 
Part A:  
Ticagrelor 0.0625 mg/kg, 0.125 mg/kg, 0.375 mg/kg or 0.563 mg/kg given as oral single 
doses. 
Ticagrelor 0.0625, 0.125 mg/kg or potentially 0.25 mg/kg twice daily given orally. 
Part B: 
Ticagrelor 0.0625, 0.125 mg/kg or potentially 0.25 mg/kg twice daily given orally and 
corresponding placebo. 
Revised text: 
Target subject population 
Patients eligible for this study include all children aged ≥2 to <18 years of age (age from birth 
to Visit 1) who are diagnosed with sickle cell disease [homozygous sickle cell (HbSS) or 
sickle beta-zero-thalassemia (HbS/β0)]. and have experienced at least two VOC requiring 
medical intervention during the past 12 months. 
Duration of treatment 
In Part A the treatment period consists of 2 single doses (separated by at least 7 days) 
followed by 7 days open label ticagrelor treatment twice daily. In Part B patients will be 
randomised to 4 weeks twice daily treatment. There is no washout period between Part A and 
Part B. The total expected study duration for an individual patient participating in both Part 
A and Part B is approximately 3 months (including 30 days follow-up after last dose) and 


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
5 
 
approximately 2 months for an individual patient participating in only Part A (including 
30 days follow-up after last dose). 
Investigational product, dosage and mode of administration 
Part A:  
Ticagrelor 0.563 mg/kg, 0.75 mg/kg, 1.125 mg/kg, or 2.25 mg/kg given as oral single doses. 
Ticagrelor 0.563 mg/kg or 0.75 mg/kg twice daily given orally. 
These doses may be adjusted based upon evaluation of PK/PD data as described in 
Appendix E. 
Part B: 
Ticagrelor 0.563 mg/kg or 0.75 mg/kg twice daily given orally and matching placebo. 
These doses may be adjusted based upon evaluation of PK/PD data as described in 
Appendix E. 
Section of protocol affected: 
Synopsis, statistical methods 
Previous text: 
A t-test will be performed for each of these variables at 5% significance level. The p-value 
and a 95% confidence interval for the difference between ticagrelor and placebo will be 
reported. There will be no adjustment for multiple comparisons. If it is inappropriate to 
assume a normal distribution, a Wilcoxon rank sum test may be performed. Number of VOC 
requiring hospitalization and intensity of pain will be summarized descriptively. 
Revised text: 
A t-test will be performed for each of these variables at 5% significance level, provided that 
the efficacy analysis set contains at least 30 patients, otherwise only descriptive statistics 
will be used. The p-value and a 95% confidence interval for the difference between ticagrelor 
and placebo will be reported. There will be no adjustment for multiple comparisons. If it is 
inappropriate to assume a normal distribution, a Wilcoxon rank sum test may be performed. 
Number of VOC requiring hospitalization and intensity of pain will be summarized 
descriptively. 


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
6 
 
Section of protocol affected: 
1.1.1 Disease under treatment 
Previous text: 
A small double-blind, placebo controlled, Phase II trial with prasugrel administered for 30 
days in adult patients with SCD demonstrated a trend toward fewer days with pain and 
decreased pain intensity in the prasugrel arm relative to placebo (Wun et al 2013). Platelet 
surface P-selectin and plasma soluble P-selectin, biomarkers of in vivo platelet activation, 
were significantly reduced in the patients randomised to prasugrel. 
Revised text: 
A small double-blind, placebo controlled, Phase II trial with prasugrel administered for 30 
days in adult patients with SCD demonstrated a trend toward fewer days with pain and 
decreased pain intensity in the prasugrel arm relative to placebo (Wun et al 2013). Platelet 
surface P-selectin and plasma soluble P-selectin, biomarkers of in vivo platelet activation, 
were significantly reduced in the patients randomised to prasugrel. A low level of platelet 
inhibition with prasugrel for at least 9 months in children with SCD showed numerical 
reductions in rate of VOC’s and pain crises, but differences were not statistically 
significant compared to placebo (Heeney et al 2015). 
Section of protocol affected: 
1.2.2 Study design 
Previous text: 
The current study will randomise a minimum of 36 patients with SCD aged ≥2 years to 
<18 years. An open-label, randomised pharmacokinetic (PK) and pharmacodynamic (PD) 
evaluation of 2 single doses will be followed by one week of treatment with ticagrelor twice 
daily to determine tolerability. This will be followed by a 4-week randomised, double blind 
placebo-controlled treatment with twice-daily ticagrelor or placebo. There is no washout 
period between Part A and Part B. All patients will receive 2 single open-label doses of 
ticagrelor separated by at least 7 days, with determination of PK parameters and PD 
(inhibition of platelet activation) after each dose, to support modelling-based selection of a 
weight-based dose for the subsequent Phase III study. The current study is designed to provide 
PK and PD data on ticagrelor in children, and to provide initial experience with chronic daily 
dosing.  
Revised text: 
The current study will randomise a minimum of 36 patients with SCD aged ≥2 years to 
<18 years. An open-label, randomised pharmacokinetic (PK) and pharmacodynamic (PD) 
evaluation of 2 single doses will be followed by one week of treatment with ticagrelor twice 
daily to determine tolerability. This will be followed by an optional 4-week randomised, 


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
7 
 
double blind placebo-controlled treatment with twice-daily ticagrelor or placebo. There is no 
washout period between Part A and Part B. All patients will receive 2 single open-label doses 
of ticagrelor separated by at least 7 days, with determination of PK parameters and PD 
(inhibition of platelet activation) after each dose, to support modelling-based selection of a 
weight-based dose for the subsequent Phase III study. The current study is designed to provide 
PK and PD data on ticagrelor in children, and to provide initial experience with chronic daily 
dosing.  
Section of protocol affected: 
1.2.3 Primary and secondary outcome measures; 1.2.4 Dose and study duration 
Previous text: 
1.2.3 Primary and secondary outcome measures 
The primary study endpoint is the evaluation of the PK and PD properties of ticagrelor and its 
active metabolite in children after each of 3 dose strengths given as single doses (0.125 
mg/kg, 0.375 mg/kg or 0.563 mg/kg) and after attainment of steady-state following twice-
daily administration of 0.125 mg/kg. PK will be determined using standard methodologies. 
The PD measure employed will be the VerifyNow P2Y12 assay (Jeong et al 2012) that is a 
well-validated and commercially available point-of-care assay to assess inhibition of the 
P2Y12 platelet receptor.  
1.2.4 Dose and study duration 
This is the first study in paediatric patients, and thus therapy will be initiated with a 
single low dose of ticagrelor with assessment of PK properties and PD effect. The initial 
dose will be a 0.125mg/kg (weight-based dose equivalent to 10 mg in adults), which is 11% 
of the approved dose for adults with ACS. The second dose of ticagrelor will be 0.375 
mg/kg or 0.563 mg/kg (weight-based dose equivalent to 30 or 45 mg in adults). The chronic 
dose of 0.125 mg/kg to be administered during the repeated treatment phase of the study 
is a very low and thus conservative dose equivalent to 11% of the approved chronic dose 
for adults with ACS.  
For safety reasons the dosing schedule will be modified for individual patients as follows: If 
PRU at 2 hr following dosing of 0.125 mg/kg is <95, subsequent maximum dose for this 
patient will be 0.0625 mg/kg throughout the study. If PRU is <95 on any two dosing 
occasions following dosing of 0.0625 mg/kg, the patient will be discontinued from further 
study drug. 
Dose selection in this study is informed by the substantial clinical pharmacology programme 
for ticagrelor in adults, which included 41 studies in approximately 1000 subjects examining 
the exposure-response relationship, safety, and drug interactions. The dose range of ticagrelor 
administered during these studies was 0.1 to 1260 mg, and 900 mg was established as the 
maximum tolerated dose (MTD) in healthy volunteers. The approved dose regimen in adults 
with ACS consists of a loading dose of 180 mg followed by 90 mg twice daily for up to one 
year. 


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
8 
 
The 4-week duration of the second part of the study is intended to provide preliminary data on 
tolerability of daily dosing in children, without imposing a large burden on the patients but 
providing a period of potential benefit.  
For doses after interim analysis please see Appendix E. 
Revised text: 
1.2.3 Primary and secondary outcome measures 
The primary study endpoint is the evaluation of the PK and PD properties of ticagrelor and its 
active metabolite in children after administration as single doses and after attainment of 
steady-state following twice-daily administration of ticagrelor. PK will be determined using 
standard methodologies. The PD measure employed will be the VerifyNow P2Y12 assay 
(Jeong et al 2012) that is a well-validated and commercially available point-of-care assay to 
assess inhibition of the P2Y12 platelet receptor.  
1.2.4 Dose and study duration 
Assessment of the first 12 randomised patients indicates that higher doses are needed in 
order to accomplish the primary study objective of characterising the relationship 
between ticagrelor dose and inhibition of platelet aggregation to support dose selection 
for Phase III. This amendment provides for the following revised doses: The initial single 
dose will be a 0.75 mg/kg (weight-based dose equivalent to 60 mg in adults). The second 
single dose of ticagrelor will be 1.125 mg/kg or 2.25 mg/kg (weight-based dose equivalent to 
90 or 180 mg in adults).  
For safety reasons the dosing schedule will be modified for individual patients as follows: If 
PRU at 2 hr following dosing of 0.75 mg/kg is <95, subsequent maximum dose for this patient 
will be 0.563 mg/kg throughout the study. If PRU is <95 following dosing of 0.563 mg/kg, the 
patient will be discontinued from further study drug. 
Dose selection in this study is informed by the interim data from the 12 first patients in 
this study as well as the substantial clinical pharmacology programme for ticagrelor in adults, 
which included 41 studies in approximately 1000 subjects examining the exposure-response 
relationship, safety, and drug interactions. The dose range of ticagrelor administered during 
these studies was 0.1 to 1260 mg, and 900 mg was established as the maximum tolerated dose 
(MTD) in healthy volunteers. The approved dose regimen in adults with ACS consists of a 
loading dose of 180 mg followed by 90 mg twice daily for up to one year. In adult patients 
with prior myocardial infarction, a dose of 60 mg twice daily is approved by the US FDA 
and is under review in Europe and additional countries. 
The 4-week duration of the second part of the study is intended to provide preliminary data on 
tolerability of daily dosing in children, without imposing a large burden on the patients but 
providing a period of potential benefit.  
For potential further dose adjustments after monitoring of PK and PD please see 
Appendix E. 


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
9 
 
Section of protocol affected: 
1.3 Benefit/risk and ethical assessment 
Previous text: 
Two randomised studies of clopidogrel in paediatric patients have been performed in infants 
with cyanotic congenital heart disease palliated with a systemic-to-pulmonary artery shunt, 
with the objective of prevention of shunt thrombosis. The largest study, CLARINET, was a 
randomised, double-blind, study in 906 infants aged 92 days or younger randomised to receive 
clopidogrel 0.2 mg/kg/day versus placebo for a median duration of 5.8 months, in addition to 
standard of care (Wessel et al 2013). This dose provides a level of platelet inhibition similar to 
that provided by a 75 mg dose in an adult (30% to 50% inhibition after stimulation with 5 μM 
ADP). Aspirin was administered concomitantly to 88.7% of patients in the clopidogrel group 
and 87.0% of patients randomised to placebo. Serious bleeding occurred in 6.5% in the 
clopidogrel group and 7.3% in the placebo group. These data provide substantial reassurance 
that 30%-50% IPA produced by treatment with a P2Y12 inhibitor is well tolerated even in a 
very young and vulnerable paediatric population.  
The FDA Office of Surveillance and Epidemiology (OSE) recently evaluated post-market 
reports of AEs in paediatric patients (ages 0-17 years) treated with clopidogrel (FDA Office 
Surveillance end Epidemiology report, 2013). The report concludes that there was no new 
safety concerns identified with the use of clopidogrel in paediatric patients.  
To date, there are no safety data regarding ticagrelor treatment in patients younger than 
18 years. However, more than 11,000 adult healthy subjects or patients have been exposed to 
ticagrelor in the completed Phase I, II, and III studies and the overall conclusion based on 
these studies is that ticagrelor has generally been well tolerated.  
Revised text: 
Two randomised studies of clopidogrel in paediatric patients have been performed in infants 
with cyanotic congenital heart disease palliated with a systemic-to-pulmonary artery shunt, 
with the objective of prevention of shunt thrombosis. The largest study, CLARINET, was a 
randomised, double-blind, study in 906 infants aged 92 days or younger randomised to receive 
clopidogrel 0.2 mg/kg/day versus placebo for a median duration of 5.8 months, in addition to 
standard of care (Wessel et al 2013). This dose provides a level of platelet inhibition similar to 
that provided by a 75 mg dose in an adult (30% to 50% inhibition after stimulation with 5 μM 
ADP). Aspirin was administered concomitantly to 88.7% of patients in the clopidogrel group 
and 87.0% of patients randomised to placebo. Serious bleeding occurred in 6.5% in the 
clopidogrel group and 7.3% in the placebo group. These data provide substantial reassurance 
that 30%-50% IPA produced by treatment with a P2Y12 inhibitor is well tolerated even in a 
very young and vulnerable paediatric population. The DOVE study was a randomised, 
placebo controlled study of the P2Y12 inhibitor prasugrel in children with sickle cell 
disease evaluating doses of prasugrel providing a mean platelet inhibition of 
approximately 25%. This treatment was well tolerated with no significant differences in 
safety results compared to placebo, and numerical reduction in rate of pain crises 


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
10 
 
although differences were not statistically significant compared to placebo (Heeney et al 
2015) 
The FDA Office of Surveillance and Epidemiology (OSE) recently evaluated post-market 
reports of AEs in paediatric patients (ages 0-17 years) treated with clopidogrel (FDA Office 
Surveillance end Epidemiology report, 2013). The report concludes that there was no new 
safety concerns identified with the use of clopidogrel in paediatric patients.  
Prior to the current study, there are no safety data regarding ticagrelor treatment in patients 
younger than 18 years. However, more than 25,000 adult healthy subjects or patients have 
been exposed to ticagrelor in the completed Phase I, II, and III studies and the overall 
conclusion based on these studies is that ticagrelor has generally been well tolerated.  
Section of protocol affected: 
1.4 Study design  
Previous text: 
Figure 1 
Study flow chart before interim analysis 
 
R = randomisation; PRO = patient reported outcome 
For study flow chart after the interim analysis please see Appendix E. 


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
11 
 
Revised text: 
Figure 1 
Study flow chart  
 
R = randomisation; PRO = patient reported outcome 
For study flow chart after the interim analysis please see Appendix E. 
Section of protocol affected: 
3.1 Inclusion criteria 
Previous text: 
2. Experienced at least 2 VOC requiring medical intervention during the past 12 
months** 
**VOC is defined as a painful sickle cell crisis requiring medical intervention 
including any of the following (1) hospitalization (2) emergency department or 
clinic visit (3) medically supervised outpatient treatment with escalated doses 
of drugs for management of painful crisis (may include oral or parenteral 
opioids or non-steroidal anti-inflammatory drugs). 
5. If treated with an anti-sickling agent such as hydroxyurea, the weight-adjusted 
dose must be stable for 3 months before enrolment 
Revised text: 
Inclusion criteria 2 concerning VOC in the prior 12 months has been removed. 
4. If treated with an anti-sickling agent such as hydroxyurea, the weight-adjusted 
dose must be stable for 1 months before enrolment 


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
12 
 
Section of protocol affected: 
3.2 Exclusion criteria 
Previous text: 
16. Previous enrolment in the present study  
Revised text: 
16. Previous randomisation in the present study***  
*** As the eligibility criteria have been changed with this amendment, patients 
previously enrolled but not randomised may be reassessed for eligibility. Patients 
fulfilling all inclusion criteria and no exclusion criteria can be re-enrolled. 
Section of protocol affected: 
3.3 Patient enrolment and randomisation 
Previous text: 
Investigator(s) should keep a record, the patient screening log, of patients who entered pre-
study screening. 
The Investigator(s) will: 
1. 
Obtain signed informed consent from the parent/both parents/legal guardian 
(according to local regulations) and assent or consent from the child/adolescent 
(where required by local regulations) before any study specific procedures are 
performed. Patient is considered enrolled in the study after she/he has signed the 
informed consent form 
2. 
Assign potential patient a unique enrolment number, beginning with E+4-digit site 
number +3-digit patient number starting with 001. For example, the first patient at 
site 9999 would be assigned the patient number: E9999001 
3. 
Determine patient eligibility. See Section 3.1 and 3.2. Patient who does not meet the 
eligibility criteria is considered as screening failure 
4. 
Assign eligible patient unique randomisation code. Patient will be randomised 
twice, both in Part A and Part B and will receive 2 unique randomisation codes 
If a patient withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused. 
Part A will be performed in open label fashion i.e. the patient as well as members of the study 
team, at investigational centres or third party vendors conducting the study or handling data, 
AstraZeneca R&D Supply Chain (including packaging and distribution vendors on their 
behalf) and bio analysis personnel analysing the PK samples will all have access to the 
randomisation schedule. Part B will be double blind i.e. no member of the study team at 


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
13 
 
AstraZeneca, the Steering Committee (SC), personnel at investigational centres or any 
contract Research Organization (CRO) handling data will have access to the randomisation 
scheme during the conduct of the study, with the exception of the Supply Chain Study 
Management department, CRO unblinded team and the Patient Safety department at 
AstraZeneca. 
Randomisation codes will be assigned strictly sequentially as patients become eligible for 
randomisation for both Part A and Part B. 
Revised text: 
Investigator(s) should keep a record, the patient screening log, of patients who entered pre-
study screening. 
The Investigator(s) will: 
1. 
Obtain signed informed consent from the parent/both parents/legal guardian 
(according to local regulations) and assent or consent from the child/adolescent 
(where required by local regulations) before any study specific procedures are 
performed. Patient is considered enrolled in the study after she/he has signed the 
informed consent form. If a patient was previously enrolled into the present 
study but not randomised, a new informed consent document should be signed 
by the parent/both parents/legal guardian (according to local legislation) and 
assent or consent from the child/adolescent (where required by local 
regulations) before any study specific procedures are performed. The patient 
must receive a new unique enrolment number. 
2. 
Assign potential patient a unique enrolment number, beginning with E+4-digit site 
number +3-digit patient number starting with 001. For example, the first patient at 
site 9999 would be assigned the patient number: E9999001 
3. 
Determine patient eligibility. See Section 3.1 and 3.2. Patient who does not meet the 
eligibility criteria is considered as screening failure 
4. 
Assign eligible patient unique randomisation code. Patient will be randomised once 
or twice, both in Part A and Part B and will receive 2 unique randomisation codes 
If a patient withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused. 
Part A will be performed in open label fashion i.e. the patient as well as members of the study 
team, at investigational centres or third party vendors conducting the study or handling data, 
AstraZeneca R&D Supply Chain (including packaging and distribution vendors on their 
behalf) and bio analysis personnel analysing the PK samples will all have access to the 
randomisation schedule. Part B will be double blind i.e. no member of the study team at 
AstraZeneca, the Steering Committee (SC), personnel at investigational centres or any 
contract Research Organization (CRO) handling data will have access to the randomisation 


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
14 
 
scheme during the conduct of the study, with the exception of the Supply Chain Study 
Management department, CRO unblinded team and the Patient Safety department at 
AstraZeneca. 
Randomisation codes will be assigned strictly sequentially as patients become eligible for 
randomisation for both Part A and/or Part B. 
Section of protocol affected: 
3.9.2 Permanent discontinuation from investigational product (active and placebo) 
Previous text: 
x 
If PRU is <95 on any two dosing occasions following dosing of 0.0625 mg/kg, the 
patient will be discontinued from further study drug for safety reasons 
Revised text: 
x 
If PRU is <95 despite an individual dose reduction having already been made, the 
patient will be discontinued from further study drug for safety reasons. 


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
15 
 
Section of protocol affected: 
4. STUDY PLAN AND TIMING OF PROCEDURES 
Previous text: 
Table 1 
Study Plan detailing the procedures  
 
Part A 
Part B 
Assessment 
Enrolment 
Dose 1 
Dose 2 
Repeated treatment phase 
End of 
treatment 
Follow-up 
Visit 
Visit window: 
 
1m 
Days -30 to -7 
for Visit 1 
2m 
 ±0 day for 
Visit 2 
3 
+ 7 days 
4 
+7 days 
5r 
+ 7 days 
6 
+ 7 days 
7r 
+ 7 days 
8 
+ 7 days 
9 
30-35 days 
following last dose 
for Visit 8d 
Week 
 
0 
1 
2 
3 
4 
5 
6  
10 
Day 
 
0 
7 
14 
21 
28 
35 
42 
72-77 
Signed Informed Assent/Consent 
X 
 
 
 
 
 
 
 
 
Randomisation 
 
X 
 
X 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
Xa 
 
 
 
 
 
 
 
Relevant Medical and Surgical history, SCD 
characteristics and history 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Vital signs (BP, pulse) 
X 
X 
X 
X 
Xr 
X 
Xr 
X 
X 
Physical examination  
X 
 
 
 
 
 
 
 
X 
Weight, heighte 
X 
X 
X 
 
 
 
 
X 
 
Transcranial Doppler examo 
X 
 
 
 
 
 
 
 
 
Ophthalmological (Eye) examo 
X 
 
 
 
 
 
 
 
 
12-lead ECGp 
Xp 
 
 
X 
 
 
 
 
 
Daily pain assessmentg 
X 
X 
X 
X 
X 
X 
X 
X 
 
FLACC assessmentq 
X 
 
 
X 
 
 
 
 
 
Daily recording of analgesic useg 
X 
X 
X 
X 
X 
X 
X 
X 
 
Days absent from school/workg 
X 
X 
X 
X 
X 
X 
X 
X 
 
Administration of IP at clinici 
 
X 
X 
X 
 
 
 
X 
 
Treatment dispensed/returneds 
 
 
X 
Xj 
X 
X 
X 
Xj 
 
Compliance/ Drug accountability 
 
X 
X 
X 
X 
X 
X 
X 
 


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
16 
 
Table 1 
Study Plan detailing the procedures  
 
Part A 
Part B 
Assessment 
Enrolment 
Dose 1 
Dose 2 
Repeated treatment phase 
End of 
treatment 
Follow-up 
Visit 
Visit window: 
 
1m 
Days -30 to -7 
for Visit 1 
2m 
 ±0 day for 
Visit 2 
3 
+ 7 days 
4 
+7 days 
5r 
+ 7 days 
6 
+ 7 days 
7r 
+ 7 days 
8 
+ 7 days 
9 
30-35 days 
following last dose 
for Visit 8d 
Week 
 
0 
1 
2 
3 
4 
5 
6  
10 
Day 
 
0 
7 
14 
21 
28 
35 
42 
72-77 
Acceptability/Palatabilityh 
 
X 
 
 
 
 
 
 
 
Concomitant medication  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event review (AEs and SAEs) 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 
Blood samples for haematology and clinical 
chemistry (incl uric acid) 
Xn 
 
 
Xk 
 
 
 
X 
 
Blood samples for coagulation (INR and PTT) 
Xn 
 
 
 
 
 
 
 
 
VerifyNow™ PRUc 
 
X 
X 
Xl 
 
 
 
X 
 
Pregnancy test (dipstick)b 
X 
 
X 
 
 
 
 
X 
 
Collection of VOC in CRF 
 
X 
X 
X 
X 
X 
X 
X 
X 
Collection of transfusion data in CRF 
 
X 
X 
X 
X 
X 
X 
X 
X 
Collection of bleeding events in CRF 
 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
Xn 
 
 
X 
 
 
 
X 
 
Blood sampling for pharmacokineticsc 
 
X 
X 
Xl 
 
 
 
X 
 
Abbreviations: AE = adverse event; BP = blood pressure; CRF = Case Report Form; ECG = electrocardiogram; eCRF = electronic Case Report Form; 
FLACC = Face, Legs, Activity, Cry, Consolability form; INR = International Normalised Ratio; PK = pharmacokinetics; PRU = P2Y12 reaction units; 
PTT = Partial Thromboplastin Time; SAE = serious adverse event; SCD = Sickle Cell Disease; VOC = vaso-occlusive crisis 
a 
Results from local laboratory must have been received before first dose to check eligibility criteria. 
b 
In patient after menarche. 
c 
Actual time of PK and PRU sampling should be recorded in the eCRF. 
d 
May occur following earlier visits than Visit 9. 
e 
Height only at enrolment. 
f 
Only SAE assessed at this time. 
g 
Electronic diary recording by patient ≥4 years (when needed with parent/guardian help). 
h 
Questions assessed by nurse in children <6 years, Hedonic Faces Scale (HFS) for children ≥6 years 
i 
Actual time of dosing should be recorded in the eCRF. 


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
17 
 
j 
The time of drug administration in the morning and evening before Visit 4 and 8 will be registered in a patient diary. 
k Blood sample for haematology and clinical chemistry (including uric acid) at Visit 4 will be collected 2h post-dose together with PK and PRU. 
l 
PK and PRU sampling at Visit 4 will be performed at 2 hours post-dose ONLY. 
m Visit 2 should be at least 7 days apart from Visit 1. 
n Laboratory testing performed prior to Visit 1 as part of usual clinical care does not need to be repeated as long as the values were obtained within 30 days 
prior to Visit 2. 
o The most recent examination must be performed within 12 months before Visit 1. If this is not the case, the examination must be done before proceeding 
in the study. 
p 12-lead ECG must be performed within 6 months before Visit 1. If this is not the case, the examination must be done before proceeding in the study. 
q FLACC for patients aged from 2 to <4 years only to be collected between Visit 1 and Visit 2, and between Visit 4 and Visit 5. 
r 
Visit 5 and Visit 7 may be performed as telephone contacts, based on the opinion of the Investigator.  Vital signs (BP and pulse) will only be measured if 
the patient visits the site. 
s 
If Visit 5 and/or Visit 7 are performed as telephone contacts, doubles kits of study treatment will be dispended on Visit 4 and/or Visit 6 to cover the 
whole period. 
During visits when investigational product is administered at clinic perform the following protocol procedures prior to 
administration of study drug (if applicable to the visit):  
Review of AEs and concomitant medications, vital signs, weight, ECG, urine sampling (including pregnancy test if applicable), and 
pre-dose blood sampling (safety, PK, PD). 
Table 2 
Blood sampling in patients with a weight of >21 kg 
Assessment 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Coagulation (INR and PTT) 
X 
 
 
 
 
 
 
 
 
Haematology and clinical 
chemistry (incl uric acid) 
X 
 
 
2h post-dose 
 
 
 
X 
 
VerifyNow™ PRU 
 
Pre-dose, 2, 6h 
post-dose 
Pre-dose, 2, 6h 
post-dose 
2h post-dose 
 
 
 
Pre-dose, 2h 
post-dose 
 
Blood sampling for 
pharmacokinetics 
 
1, 2, 4, 6h 
post-dose 
1, 2, 4, 6h 
post-dose 
2h 
post-dose 
 
 
 
Pre-dose, 1, 2, 
4h post-dose 
 
Abbreviations: INR = International Normalised Ratio; PK = pharmacokinetics; PRU = P2Y12 reaction units; PTT = Partial Thromboplastin Time 
The 1, 2, 4, and 6 hour samples can be collected ±15 minutes from actual post-dose time point. 
If applicable, PRU and PK sampling should be arranged at the same time to avoid repeated venipuncture. 
A peripheral catheter can be used for blood sampling. 


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
18 
 
Table 3 
Blood sampling in patients with a weight of 16-21 kg 
Assessment 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Coagulation (INR and PTT) 
X 
 
 
 
 
Haematology and clinical 
chemistry (incl uric acid) 
X 
 
 
2h post-dose 
X 
 
VerifyNow™ PRU 
 
Pre-dose, 2h 
post-dose 
Pre-dose, 2h 
post-dose 
2h post-dose 
Pre-dose, 2h 
post-dose 
 
Blood sampling for 
pharmacokinetics 
 
1, 2, 4, 6h 
post-dose 
1, 2, 4, 6h 
post-dose 
2h 
post-dose 
Pre-dose, 2h 
post-dose 
 
Abbreviations: INR = International Normalised Ratio; PK = pharmacokinetics; PRU = P2Y12 reaction units; PTT = Partial Thromboplastin Time 
The 1, 2 and 4 and 6 hour samples can be collected ±15 minutes from actual post-dose time point. 
If applicable, PRU and PK sampling should be arranged at the same time to avoid repeated venipuncture. 
A peripheral catheter can be used for blood sampling. 


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
19 
 
Revised text: 
Table 1 
Study Plan detailing the procedures  
 
Part A 
Part B 
Assessment 
Enrolment 
Dose 1 
Dose 2 
Repeated treatment phase 
End of 
treatment 
Follow-up 
Visit 
 
 
1m 
 
2m 
 
3 
 
4l 
 
5r 
 
6 
 
7r 
 
8 
 
9 l 
Week 
 
0 
1 
2 
3 
4 
5 
6 
10 
Day (Visit window) 
-30 - -14 
0 
7 (+3) 
14 (+7) 
21 (+3) 
28 (+3) 
35 (+3) 
42 (+3) 
72-77 
30-35 days 
following last 
dose for Visit 8 
(or Visit 4)d 
Signed Informed Assent/Consent 
X 
 
 
 
 
 
 
 
 
Randomisation 
 
X 
 
X 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
Xa 
 
 
 
 
 
 
 
Relevant Medical and Surgical history, SCD 
characteristics and history 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Vital signs (BP, pulse) 
X 
X 
X 
X 
Xr 
X 
Xr 
X 
X 
Physical examination 
X 
 
 
 
 
 
 
 
X 
Weight, heighte 
X 
X 
X 
 
 
 
 
X 
 
Transcranial Doppler examo 
X 
 
 
 
 
 
 
 
 
Ophthalmological (Eye) examo 
X 
 
 
 
 
 
 
 
 
12-lead ECGp 
Xp 
 
 
X 
 
 
 
 
 
Daily pain assessmentg 
X 
X 
X 
X 
X 
X 
X 
X 
 
FLACC assessmentq 
X 
 
 
X 
 
 
 
 
 
Daily recording of analgesic useg 
X 
X 
X 
X 
X 
X 
X 
X 
 
Days absent from school/workg 
X 
X 
X 
X 
X 
X 
X 
X 
 
Administration of IP at clinici 
 
X 
X 
X 
 
 
 
X 
 
Treatment dispensed/returneds 
 
 
X 
Xj 
X 
X 
X 
Xj 
 
Compliance/ Drug accountability 
 
X 
X 
X 
X 
X 
X 
X 
 
Acceptability/Palatabilityh 
 
X 
 
 
 
 
 
 
 


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
20 
 
Table 1 
Study Plan detailing the procedures  
 
Part A 
Part B 
Assessment 
Enrolment 
Dose 1 
Dose 2 
Repeated treatment phase 
End of 
treatment 
Follow-up 
Visit 
 
 
1m 
 
2m 
 
3 
 
4l 
 
5r 
 
6 
 
7r 
 
8 
 
9 l 
Week 
 
0 
1 
2 
3 
4 
5 
6 
10 
Day (Visit window) 
-30 - -14 
0 
7 (+3) 
14 (+7) 
21 (+3) 
28 (+3) 
35 (+3) 
42 (+3) 
72-77 
30-35 days 
following last 
dose for Visit 8 
(or Visit 4)d 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event review (AEs and SAEs) 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 
Blood samples for haematology and clinical 
chemistry (incl uric acid) 
Xn 
 
 
Xk 
 
 
 
X 
 
Blood samples for coagulation (INR and PTT) 
Xn 
 
 
 
 
 
 
 
 
VerifyNow™ PRUc 
 
X 
X 
X 
 
 
 
 
 
Pregnancy test (dipstick)b 
X 
X 
 
Xb 
 
 
 
X 
 
Collection of VOC in CRF 
 
X 
X 
X 
X 
X 
X 
X 
X 
Collection of transfusion data in CRF 
 
X 
X 
X 
X 
X 
X 
X 
X 
Collection of bleeding events in CRF 
 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
Xn 
 
 
X 
 
 
 
X 
 
Blood sampling for pharmacokineticsc 
 
X 
X 
X 
 
 
 
 
 
Abbreviations: AE = adverse event; BP = blood pressure; CRF = Case Report Form; ECG = electrocardiogram; eCRF = electronic Case Report Form; 
FLACC = Face, Legs, Activity, Cry, Consolability form; INR = International Normalised Ratio; PK = pharmacokinetics; PRU = P2Y12 reaction units; 
PTT = Partial Thromboplastin Time; SAE = serious adverse event; SCD = Sickle Cell Disease; VOC = vaso-occlusive crisis 
a 
Results from local laboratory must have been received before first dose to check eligibility criteria. 
b 
In patient after menarche. Pregnancy testing at Visit 4 is only applicable for patients NOT performing Part B. 
c 
Actual time of PK and PRU sampling should be recorded in the eCRF. See Table 2 and Table 3 for PK sampling time points. 
d 
May occur following earlier visits than Visit 9. 
 
e 
Height only at enrolment. 
f 
Only SAE assessed at this time. 
g 
Electronic diary recording by patient ≥4 years (when needed with parent/guardian help). 


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
21 
 
h 
Questions assessed by nurse in children <6 years, Hedonic Faces Scale (HFS) for children ≥6 years 
i 
Actual time of dosing should be recorded in the eCRF. 
j 
The time of drug administration in the morning and evening before Visit 4 and 8 will be registered in a patient diary. 
k Blood sample for haematology and clinical chemistry (including uric acid) at Visit 4 will be collected 2h post-dose together with PK and PRU. 
l 
If patient only participates in Part A, the follow-up Visit 9 should be performed after Visit 4 according to schedule. 
m Visit 2 should be at least 14 days apart from Visit 1. 
n Laboratory testing performed prior to Visit 1 as part of usual clinical care does not need to be repeated as long as the values were obtained within 30 days 
prior to Visit 2. 
o The most recent examination must be performed within 12 months before Visit 1. If this is not the case, the examination must be done before proceeding 
in the study. 
p 12-lead ECG must be performed within 6 months before Visit 1. If this is not the case, the examination must be done before proceeding in the study. 
q FLACC for patients aged from 2 to <4 years only to be collected between Visit 1 and Visit 2, and between Visit 4 and Visit 5. 
r 
Visit 5 and Visit 7 may be performed as telephone contacts, based on the opinion of the Investigator.  Vital signs (BP and pulse) will only be measured if 
the patient visits the site. 
s 
If Visit 5 and/or Visit 7 are performed as telephone contacts, doubles kits of study treatment will be dispended on Visit 4 and/or Visit 6 to cover the 
whole period. 
During visits when investigational product is administered at clinic perform the following protocol procedures prior to 
administration of study drug (if applicable to the visit):  
Review of AEs and concomitant medications, vital signs, weight, ECG, urine sampling (including pregnancy test if applicable), and 
pre-dose blood sampling (safety, PK, PD). 
Table 2 
Blood sampling in patients with a weight of >21 kg 
Assessment 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Coagulation (INR and PTT) 
X 
 
 
 
 
 
 
 
 
Haematology and clinical 
chemistry (incl uric acid) 
X 
 
 
2h post-dose 
 
 
 
X 
 
VerifyNow™ PRU 
 
Pre-dose, 2h, 6h 
post-dose 
Pre-dose, 2, 6h 
post-dose 
Pre-dose, 
2h post-dose 
 
 
 
 
 
Blood sampling for 
pharmacokinetics 
 
1, 2, 4, 6h 
post-dose 
1, 2, 4, 6h 
post-dose 
Pre-dose, 1, 
2h 
post-dose 
 
 
 
 
 
Abbreviations: INR = International Normalised Ratio; PK = pharmacokinetics; PRU = P2Y12 reaction units; PTT = Partial Thromboplastin Time 
The 1, 2, 4, and 6 hour samples can be collected ±15 minutes from actual post-dose time point. 
If applicable, PRU and PK sampling should be arranged at the same time to avoid repeated venipuncture. 


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
22 
 
A peripheral catheter can be used for blood sampling. 
Table 3 
Blood sampling in patients with a weight of 16-21 kg 
Assessment 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Coagulation (INR and PTT) 
X 
 
 
 
 
Haematology and clinical 
chemistry (incl uric acid) 
X 
 
 
2h post-dose 
X 
 
VerifyNow™ PRU 
 
Pre-dose, 2h 
post-dose 
Pre-dose, 2h 
post-dose 
Pre-dose, 
2h post-dose 
 
Blood sampling for 
pharmacokinetics 
 
1, 2, 4, 6h 
post-dose 
1, 2, 4, 6h 
post-dose 
Pre-dose, 1, 
2h post-dose
 
Abbreviations: INR = International Normalised Ratio; PK = pharmacokinetics; PRU = P2Y12 reaction units; PTT = Partial Thromboplastin Time 
The 1, 2 and 4 and 6 hour samples can be collected ±15 minutes from actual post-dose time point. 
If applicable, PRU and PK sampling should be arranged at the same time to avoid repeated venipuncture. 
A peripheral catheter can be used for blood sampling. 
Section of protocol affected: 
4.1 Treatment period 
Previous text: 
At least a 7-day interval is needed between Visit 1 and Visit 2 to allow for the recording of the baseline data on patient diary (see 
Section 5.1.2) 
Revised text: 
At least a 14-day interval is needed between Visit 1 and Visit 2 to allow for the recording of the baseline data on patient diary (see 
section 5.1.2) and to separate the blood sampling in time considering total blood sampling volume recommendations in 
children.


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
23 
 
Section of protocol affected: 
4.2 Treatment period 
Previous text: 
Part A: 
Visit 2 & 3: Randomisation will take place 7 to 30 days after enrolment. Patients will be 
randomised 1:1 to receive one of two dosing schedules, with each dose separated by 7 days. 
Platelet aggregation will be measured using the VerifyNow™ P2Y12 assay and reported as 
PRU. PRU will determine continued dosing. Patients are not allowed to eat 2 hours before and 
1 hour after dosing at these visits. Palatability assessment will be performed (Visit 2). A study 
nurse will assess palatability directly after administration of dose (for more information see 
Section 5.3). The patients will be allowed to leave the clinic after all sampling has been 
completed. Following the 2 single doses, all patients will receive open-label one-week 
treatment with ticagrelor twice daily to determine tolerability prior to randomisation into 
Part B. Dose to be administered twice daily within a 9-12 hours interval (starting in the 
evening the same day as Visit 3). For assessments performed during the visits see Table 1. 
For dosing before interim analysis see Figure 2 and for dosing after interim analysis see 
Appendix E. 
Part B:  
Visit 4, 5, 6, 7 & 8: The patient will register actual date and time of drug administration the 
morning and evening before Visit 4 in a Dosing Diary. He/she will be instructed to not take 
their dose at home in the morning of Visit 4. Study drug will be administered at the clinic and 
actual time of dosing should be recorded in the eCRF at Visit 4. Patients will be randomised 
(2:1 ratio) to ticagrelor twice daily or placebo for a 4-week treatment phase and will return to 
the clinic on a weekly basis for study related procedures. Visit 5 and Visit 7 may optionally be 
performed as telephone contacts, based on the opinion of the Investigator (See Table 1, Visit 
4-8). The patient will register actual date and time of drug administration the morning 
and evening before Visit 8 in a Dosing Diary. He/she will be instructed to not take their 
dose at home in the morning of Visit 8. Study drug will be administered at the clinic and 
actual time of dosing should be recorded in the eCRF at Visit 8. For dosing before 
interim analysis see Figure 2 and for dosing after interim analysis see Appendix E. 
Patients will be followed for the occurrence of VOC events and for other disease 
manifestations such as daily pain, analgesic use, and complications of SCD throughout the 
study. Daily pain (ages ≥4 years only) and analgesic use will be reported by the patient (or if 
needed with the help of parent/guardian) using an electronic diary (for more information see 
Section 5.3). Specification of whether analgesics have been opiod or non-opiod will be done 
at follow-up site visit. Days of absence from school or work (ages ≥6 years only) will be 
collected weekly using the same electronic device. 
For safety reasons the dosing schedule will be modified for individual patients based on their 
PRU at Visit 2, 3 and 4 (see Figure 2). The dose modifications may occur at Visit 2, 3 and 4. 


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
24 
 
After 12 patients have completed dosing in Part A, a PK/PD evaluation (interim 
analysis) of the data will be conducted and the dose for the repeated dosing in both Part 
A and B for the remaining patients may be adjusted (aiming for a mean reduction in 
PRU 2 hour post-dose of 45%) see Section 8.6.  
Enrolment into the study will not be stopped during the interim analysis. For dosing of 
ticagrelor see Figure 2. 
Figure 2 
Dosing schedule before interim analysis 
0.125 mg/kg
0.0625 mg/kg
0.375 or 
0.563 mg/kg
0.125 mg/kg
0.0625 mg/kg
0.0625 mg/kg
0.125 mg/kg
0.0625 mg/kg
0.0625 mg/kg
0.0625 mg/kg
Single 
dose 1
Single 
dose 2
PRU 2 hr 
at Visit 2
PRU 2 hr 
at Visit 4
PRU 2 hr 
at Visit 3
Open-label 
1 week 
treatment
Double-blind 
4 week treatment
>95
<95
>95
<95
Discontinue
>95
>95
<95
<95
 
 
Revised text: 
Part A: 
Visit 2, 3 &4: Randomisation will take place 14 to 30 days after enrolment. Patients will be 
randomised 1:1 to receive one of two dosing schedules, with each dose separated by 7 days. 
Platelet aggregation will be measured using the VerifyNow™ P2Y12 assay and reported as 
PRU. PRU will determine continued dosing. Patients are not allowed to eat 2 hours before and 
1 hour after dosing at these visits. Palatability assessment will be performed (Visit 2). A study 
nurse will assess palatability directly after administration of dose (for more information see 
Section 5.3). The patients will be allowed to leave the clinic after all sampling has been 
completed. Following the 2 single doses, all patients will receive open-label one-week 
treatment with ticagrelor twice daily to determine tolerability prior to randomisation into 
Part B. Dose to be administered twice daily within a 9-12 hours interval (starting in the 
evening the same day as Visit 3). For assessments performed during the visits see Table 1. 
For dosing see Figure 2, and Appendix E in case of potential change to dosing schedule.  


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
25 
 
Patients only participating in Part A will complete Visit 4, see below, which will be their 
last visit on treatment and after Visit 4 perform Visit 9 (30-35 days following last dose 
for Visit 4). 
Part B:  
Visit 4, 5, 6, 7 & 8: Visit 4 will be performed in all patients, including those not 
continuing to Part B. Participation in Part B is optional. The patient will register actual 
date and time of drug administration the morning and evening before Visit 4 in a Dosing 
Diary. He/she will be instructed to not take their dose at home in the morning of Visit 4. Study 
drug will be administered at the clinic and actual time of dosing should be recorded in the 
eCRF at Visit 4. For patients not participating in Part B, visit 4 will be the last visit on 
treatment. For patients continuing into Part B, patients will be randomised (2:1 ratio) to 
ticagrelor twice daily or placebo for a 4-week treatment phase and will return to the clinic on a 
weekly basis for study related procedures. Visit 5 and Visit 7 may optionally be performed as 
telephone contacts, based on the opinion of the Investigator (See Table 1, Visit 4-8). The 
patient will register actual date and time of drug administration the morning and evening 
before Visit 8 in a Dosing Diary. He/she will be instructed to not take their dose at home in 
the morning of Visit 8. Study drug will be administered at the clinic and actual time of dosing 
should be recorded in the eCRF at Visit 8. For dosing see Figure 2, and Appendix E in case 
of potential change to dosing schedule. For dosing before interim analysis see Figure 2 and 
for dosing after interim analysis see Appendix E. 
Patients will be followed for the occurrence of VOC events and for other disease 
manifestations such as daily pain, analgesic use, and complications of SCD throughout the 
study. Daily pain (ages ≥4 years only) and analgesic use will be reported by the patient (or if 
needed with the help of parent/guardian) using an electronic diary (for more information see 
Section 5.3) Specification of whether analgesics have been opiod or non-opiod will be done at 
follow-up site visit. Days of absence from school or work (ages ≥6 years only) will be 
collected weekly using the same electronic device. 
For safety reasons the dosing schedule will be modified for individual patients based on their 
PRU at Visit 2, 3 and 4 (see Figure 2). The dose modifications may occur at Visit 2, 3 and 4. 
After 12 patients have completed dosing in Part A, a PK/PD evaluation (interim analysis) of 
the data will be conducted and the dose for the repeated dosing in both Part A and B for the 
remaining patients may be adjusted (aiming for a mean reduction in PRU 2 hour post-dose of 
45%) see Section 8.6.  
Enrolment into the study will not be stopped during the interim analysis. For dosing of 
ticagrelor see Figure 2 


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
26 
 
Figure 2 
Dosing schedule 
0.75 mg/kg
0.563 mg/kg
1.125 or
2.25 mg/kg
0.75 mg/kg
0.563 mg/kg
Discontinue
0.75 mg/kg
or placebo
0.563 mg/kg
or placebo
0.563 mg/kg
or placebo
Single
dose 1
Single
dose 2
PRU 2 hr
at Visit 2
PRU 2 hr
at Visit 4
PRU 2 hr
at Visit 3
Open-label
1 week
treatment
Double-blind
4 week treatment
>95
<95
>95
<95
>95
<95
> 95
 
 
Section of protocol affected: 
5.2.1 Laboratory safety assessments 
Previous text: 
Urinalysis is to be performed at the investigational site by dipstick. A urine pregnancy test (U-
HCG) will be taken at Visit 1 and repeated at Visit 3 and Visit 8 in 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 visit. 
Revised text: 
Urinalysis is to be performed at the investigational site by dipstick. A urine pregnancy test (U-
HCG) will be taken at Visit 1, Visit 2 and repeated at Visit 4 (for patients only completing 
Part A) or Visit 8 (for patients completing Part B) in 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 visit. 


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
27 
 
Section of protocol affected: 
5.8 Volume of blood 
Previous text: 
Table 6  
Volume of blood to be drawn from patients with a weight >21 kg 
Assessment 
Sample 
volume 
(mL) 
No. of 
samples 
Visit 1 
Total 
volume 
Visit 1 
(mL) 
No. of 
samples 
Visit 2 
Total 
volume 
Visit 2 
(mL) 
No. of 
samples 
Visit 3 
Total 
volume 
Visit 3 
(mL) 
No. of 
samples 
Visit 4 
Total 
volume 
Visit 4 
(mL) 
No. of 
samples 
Visit 8 
Total 
volume 
Visit 8 
(mL) 
Total 
(mL) 
Haematology 
1.2 
1 
1.2 
0 
0 
0 
0 
1 
1.2 
1 
1.2 
 
Clinical 
Chemistry 
1.1 
1 
1.1 
0 
0 
0 
0 
1 
1.1 
1 
1.1 
 
Coagulation 
1.2 
1 
1.2 
0 
0 
0 
0 
0 
0 
0 
0 
 
Pharmacokinetic 
1.2 
0 
0 
4 
4.8 
4 
4.8 
1 
1.2 
4 
4.8 
 
PRU* 
4.0 
0 
0 
3 
12.0 
3 
12 
1 
4 
2 
8 
 
Total 
 
 
3.5 
 
16.8 
 
16.8 
 
7.5 
 
15.1 
59.7 
* PRU sampling via a central catheter may require up to an additional 3 mL at each PRU sampling timepoint. 
Table 7 
Volume of blood to be drawn from patient with a weight of 16-21 kg 
Assessment 
Sample 
volume 
(mL) 
No. of 
samples 
Visit 1 
Total 
volume 
Visit 1 
(mL) 
No. of 
samples 
Visit 2 
Total 
volume 
Visit 2 
(mL) 
No. of 
samples 
Visit 3 
Total 
volume 
Visit 3 
(mL) 
No. of 
samples 
Visit 4 
Total 
volume 
Visit 4 
(mL) 
No. of 
samples 
Visit 8 
Total 
volume 
Visit 8 
(mL) 
Total 
(mL) 
Haematology 
1.2 
1 
1.2 
0 
0 
0 
0 
1 
1.2 
1 
1.2 
 
Clinical 
Chemistry 
1.1 
1 
1.1 
0 
0 
0 
0 
1 
1.1 
1 
1.1 
 
Coagulation 
1.2 
1 
1.2 
0 
0 
0 
0 
0 
0 
0 
0 
 
Pharmacokinetic 
1.2 
0 
0 
4 
4.8 
4 
4.8 
1 
1.2 
2 
2.4 
 
PRU* 
4.0 
0 
0 
2 
8 
2 
8 
1 
4 
2 
8 
 
Total 
 
 
3.5 
 
12.8 
 
12.8 
 
7.5 
 
12.7 
49.3 
* PRU sampling via a central catheter may require up to an additional 3 mL at each PRU sampling timepoint. 


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
28 
 
Revised text: 
Table 6 
Volume of blood to be drawn from patients with a weight >21 kg 
Assessment 
Sample 
volume 
(mL) 
No. of 
samples 
Visit 1 
Total 
volume 
Visit 1 
(mL) 
No. of 
samples 
Visit 2 
Total 
volume 
Visit 2 
(mL) 
No. of 
samples 
Visit 3 
Total 
volume 
Visit 3 
(mL) 
No. of 
samples 
Visit 4 
Total 
volume 
Visit 4 
(mL) 
No. of 
samples 
Visit 8 
Total 
volume 
Visit 8 
(mL) 
Total 
(mL) 
Haematology 
1.2 
1 
1.2 
0 
0 
0 
0 
1 
1.2 
1 
1.2 
 
Clinical 
Chemistry 
1.1 
1 
1.1 
0 
0 
0 
0 
1 
1.1 
1 
1.1 
 
Coagulation 
1.2 
1 
1.2 
0 
0 
0 
0 
0 
0 
0 
0 
 
Pharmacokinetic 
1.2 
0 
0 
2 
2.4 
2 
2.4 
1 
1.2 
0 
0 
 
PRU* 
4.0 
0 
0 
1 
4.0 
1 
4.0 
0 
0 
0 
0 
 
Pharmacokinetic 
+ PRU** 
4.2 
0 
0 
2 
8.4 
2 
8.4 
2 
8.4 
0 
0 
 
Total 
 
 
3.5 
 
14.8 
 
14.8 
 
11.9 
 
2.3 
47.3 
* PRU sampling via a central catheter may require up to an additional 3 mL at each PRU sampling timepoint. 
** Timepoint with both PRU + PK required volume is 4.2 mL total for both. 


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
29 
 
 
Table 7 
Volume of blood to be drawn from patient with a weight of 16-21 kg 
Assessment 
Sample 
volume 
(mL) 
No. of 
samples 
Visit 1 
Total 
volume 
Visit 1 
(mL) 
No. of 
samples 
Visit 2 
Total 
volume 
Visit 2 
(mL) 
No. of 
samples 
Visit 3 
Total 
volume 
Visit 3 
(mL) 
No. of 
samples 
Visit 4 
Total 
volume 
Visit 4 
(mL) 
No. of 
samples 
Visit 8 
Total 
volume 
Visit 8 
(mL) 
Total 
(mL) 
Haematology 
1.2 
1 
1.2 
0 
0 
0 
0 
1 
1.2 
1 
1.2 
 
Clinical 
Chemistry 
1.1 
1 
1.1 
0 
0 
0 
0 
1 
1.1 
1 
1.1 
 
Coagulation 
1.2 
1 
1.2 
0 
0 
0 
0 
0 
0 
0 
0 
 
Pharmacokinetic 
1.2 
0 
0 
3 
3.6 
3 
3.6 
1 
1.2 
0 
0 
 
PRU* 
4.0 
0 
0 
1 
4.0 
1 
4.0 
0 
0 
0 
0 
 
Pharmacokinetic 
+ PRU** 
4.2 
0 
0 
1 
4.2 
1 
4.2 
2 
8.4 
0 
0 
 
Total 
 
 
3.5 
 
11.8 
 
11.8 
 
11.9 
 
2.3 
41.3 
* PRU sampling via a central catheter may require up to an additional 3 mL at each PRU sampling timepoint. 
** Timepoint with both PRU + PK required volume is 4.2 mL total for both. 
The maximum blood withdrawal during any 4 week period is 41.5 mL for patients weighing >21 kg and 35.5 mL for 
patients weighing 16-21 kg. 


 
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Date 22 December 2015 
 
 
30 
 
Section of protocol affected: 
7.1 Identity of investigational product(s) 
Previous text: 
Investigational product 
Dosage form and strength 
Manufacturer 
Ticagrelor  
Granules for oral suspension 10 mg 
Almac Pharma Services 
Ticagrelor  
Granules for oral suspension 45 mg 
Almac Pharma Services 
Matching placebo for Ticagrelor  
Granules for oral suspension 
Almac Pharma Services 
Revised text: 
Investigational product 
Dosage form and strength 
Manufacturer 
Ticagrelor  
Granules for oral suspension 10 mg 
Almac Pharma Services 
Ticagrelor  
Granules for oral suspension 45 mg 
Almac Pharma Services 
Matching placebo for Ticagrelor  
Granules for oral suspension 
Almac Pharma Services 
 
Section of protocol affected: 
7.2 Dose and treatment regimens 
Previous text: 
Part A: 
Open-label single doses (Visit 2 and 3):  
All patients will receive 0.125 mg/kg as their initial dose, followed 7 days later by 0.375 mg/kg 
or 0.563 mg/kg. Single doses will be administered at the clinic by site staff. Patients are not 
allowed to eat 2 hours before and 1 hour after dosing at Visit 2 and 3. 
Repeated dosing (Visit 3-4): 
Patients will self-administer 0.125 mg/kg of open label ticagrelor for 1 week. Dose to be 
administered twice daily within a 9-12 hours interval. The first dose will be administered in the 
evening the same day as Visit 3.  
Following an evaluation of the first 12 patients, the repeated treatment dose may be 
adjusted to 0.0625 mg/kg, 0.125 mg/kg or 0.25 mg/kg (see Section 8.6). 
Part B: 
Repeated dosing (Visit 4-8): 
Randomisation to twice daily treatment with ticagrelor or placebo will occur at Visit 4. Patients 
will self-administer 0.125 mg/kg of ticagrelor dose or placebo for 4 weeks. Dose will be 


 
Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
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Date 22 December 2015 
 
 
31 
 
administered twice daily within a 9-12 hours interval. The first dose will be administered in the 
evening the same day as Visit 4.  
Revised text: 
Part A: 
Open-label single doses (Visit 2 and 3):  
All patients will receive 0.75 mg/kg as their initial single dose, followed 7 days later by 
1.125mg/kg or 2.25 mg/kg. Single doses will be administered at the clinic by site staff. Patients 
are not allowed to eat 2 hours before and 1 hour after dosing at Visit 2 and 3. 
Repeated dosing (Visit 3-4): 
Patients will self-administer 0.75 mg/kg of open label ticagrelor for 1 week. Dose to be 
administered twice daily within a 9-12 hours interval. The first dose will be administered in the 
evening the same day as Visit 3.  
Doses may be adjusted following assessment by AstraZeneca and the Steering Committee 
of open label Part A results in the first 6-12 patients. Dose adjustment decisions will be 
based upon a review of PK, PD and adverse events (see Section 8.6). 
Part B: 
Repeated dosing (Visit 4-8): 
Randomisation to twice daily treatment with ticagrelor or placebo will occur at Visit 4. Patients 
will self-administer 0.75 mg/kg of ticagrelor dose or placebo for 4 weeks. Dose will be 
administered twice daily within a 9-12 hours interval. The first dose will be administered in the 
evening the same day as Visit 4.  
Doses may be adjusted following assessment by AstraZeneca and the Steering Committee 
of open label Part A results in the first 6-12 patients. Dose adjustment decisions will be 
based upon a review of PK, PD and adverse events (see Section 8.6). 
Section of protocol affected: 
7.5 Compliance 
Previous text: 
Compliance will also be checked by measurement of PRU at Visit 8. 
Revised text: 
Compliance will also be checked by measurement of PRU at Visit 4 and Visit 8 (if applicable). 
Section of protocol affected: 
8.5 Statistical analyses 


 
Clinical Study Protocol Amendment 3 
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Study Code D5136C00007 
Date 22 December 2015 
 
 
32 
 
Previous text: 
A t-test will be performed for each of these variables at 5% significance level. The p-value and a 
95% confidence interval for the difference between ticagrelor and placebo will be reported. 
There will be no adjustment for multiple comparisons. If it is inappropriate to assume a normal 
distribution, a Wilcoxon rank sum test may be performed. In case more than one adult 
equivalent dose is studied in Part B, the analysis will be repeated both for all ticagrelor doses 
versus placebo and for the dose the majority of patients received versus placebo. 
Revised text: 
A t-test will be performed for each of these variables at 5% significance level, provided that 
the efficacy analysis set contains at least 30 patients, otherwise only descriptive statistics 
will be used. The p-value and a 95% confidence interval for the difference between ticagrelor 
and placebo will be reported. There will be no adjustment for multiple comparisons. If it is 
inappropriate to assume a normal distribution, a Wilcoxon rank sum test may be performed. In 
case more than one adult equivalent dose is studied in Part B, the analysis will be repeated both 
for all ticagrelor doses versus placebo and for the dose the majority of patients received versus 
placebo. 
Section of protocol affected: 
8.6 Interim analysis 
Previous text: 
8.6 Interim analysis 
An interim analysis will be conducted after 12 patients have completed Part A. The 
average PRU reduction from baseline at 2 hours post-dose at Visit 4 will be used for a 
potential adjustment of the dose in the 7 days repeated dosing in Part A and in Part B for 
subsequent patients. PRU values from patients on 0.0625 mg/kg will not be included in the 
average. The new dose will be determined as follows: 
x 
If mean PRU reduction >60% and ≤80%, a ticagrelor dose of 0.0625 mg/kg will 
be administered to the remaining patients 
x 
If mean PRU reduction ≥30% and ≤60%, a ticagrelor dose of 0.125 mg/kg will 
be administered to the remaining patients 
x 
If mean PRU reduction <30% and ≥20%, a ticagrelor dose equivalent to 0.25 
mg/kg in adults will be administered to the remaining patients 
x 
If mean PRU reduction <20% or >80%, an analysis integrating all data from the 
single doses and the repeated dosing in Part A will be used to adjust the dose. An 
amendment will be submitted with the new dose 
For more details on dose adjustment see Appendix E. 
Revised text: 


 
Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
 
33 
 
8.6 Interim analysis and potential further dose adjustments 
An interim analysis was conducted per protocol after 12 patients had completed dosing in 
part A. The mean PRU reduction 2 hours post-dose at Visit 4 was <20%, and plasma 
ticagrelor concentrations were lower than expected. This triggered a protocol amendment 
to increase the weight-adjusted dosing in order to achieve a higher level of platelet 
inhibition. 
Doses may be further adjusted following assessment by AstraZeneca and the Steering 
Committee of Part A results in the first 6-12 patients randomised under this amendment. 
Dose adjustment decisions will be based upon a review of PK, PD and adverse events and 
will apply only to patients randomised subsequent to the dose change decision. 
For more details on potential dose adjustment see Appendix E. 
 
Section of protocol affected: 
9.3 Study timeline and end of study 
Previous text: 
The study is expected to start in Q3 2014 and to end by Q2 to Q3 2015. 
Revised text: 
The study is expected to start in Q3 2014 and to end by Q1 2017. 


 
Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
 
34 
 
Section of protocol affected: 
Appendix E 
Previous text: 
An interim analysis will be conducted after 12 patients have completed part A. The 
average PRU reduction from baseline at 2 hours post-dose at Visit 4 will be used for a 
potential adjustment of the dose in the 7 days repeated dosing in part A and in part B for 
subsequent patients. PRU values from patients on 0.0625 mg/kg will not be included in 
the average. The new dose and will be determined as follows: 
 
• 
If mean PRU reduction >60% and ≤80%, a ticagrelor dose of 0.0625 mg/kg 
will be administered to the remaining patients 
 
• 
If mean PRU reduction ≥30% and ≤60%, a ticagrelor dose of 0.125 mg/kg 
will be administered to the remaining patients 
 
• 
If mean PRU reduction <30% and ≥20%, a ticagrelor dose equivalent to 0.25 
mg/kg in adults will be administered to the remaining patients 
 
• 
If mean PRU reduction <20% or >80%, an analysis integrating all data from 
the single doses and the repeated dosing in part A will be used to adjust the 
dose. An amendment will be submitted with the new dose 
 


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
 
35 
 
Figure 1 in this Appendix will replace Figure 1 in the main body of the Clinical Study Protocol after the interim analysis, see 
Section 1.4. 
 
Figure 1 
Study flow chart after interim analysis 
 
 


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
 
36 
 
 
Patients enrolled subsequent to the interim analysis will follow the dosing schedule shown in Figure 2 if mean PRU reduction 
in the interim analysis is >60% and ≤80%. 
 
Figure 2 in this Appendix will replace Figure 2 in the main body of the Clinical Study Protocol after the interim analysis, see 
Section 4.2. 
 
Figure 2 
Dosing schedule after interim analysis, Repeated dose 0.0625 mg/kg 
 
Single 
PRU 2 hr 
Single 
PRU 2 hr 
Open-label 
PRU 2 hr 
Double-blind 
dose 1 
at Visit 2 
dose 2 
at Visit 3 
1 week 
treatment 
at Visit 4 
4 week treatment 
 
0.375 or 
0.563 mg/kg 
0.0625 mg/kg 
 
0.0625 mg/kg 
 
 
 
 
 
0.125 mg/kg 
 
 
0.0625 mg/kg 
0.0625 mg/kg 
 
 
0.0625 mg/kg 
 
 
 
 
0.0625 mg/kg 
0.0625 mg/kg 
 
 
Discontinue 


Clinical Study Protocol Amendment 3
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
 
37 
 
 
Patients enrolled subsequent to the interim analysis will follow the dosing schedule shown in Figure 3 if mean PRU reduction 
in the interim analysis is ≥30% and ≤60%. 
 
Figure 3 in this Appendix will replace Figure 2 in the main body of the Clinical Study Protocol after the interim analysis, see 
Section 4.2. 
 
Figure 3 
Dosing schedule after interim analysis, Repeated dose 0.125 mg/kg 
 
Single 
dose 1 
PRU 2 hr 
at Visit 2 
Single 
dose 2 
PRU 2 hr 
at Visit 3 
Open-label 
1 week 
treatment 
PRU 2 hr 
at Visit 4 
Double-blind 
4 week treatment 
 
 
 
 
0.375 or 
0.563 mg/kg 
 
 
 
 
0.125 mg/kg 
0.125 mg/kg 
 
0.0625 mg/kg 
 
 
0.125 mg/kg 
 
 
0.0625 mg/kg 
0.0625 mg/kg 
 
 
0.0625 mg/kg 
 
 
 
 
0.0625 mg/kg 
0.0625 mg/kg 
 
 
Discontinue 


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
 
38 
 
 
Patients enrolled subsequent to the interim analysis will follow the dosing schedule shown in Figure 4 if mean PRU reduction 
in the interim analysis is <30% and ≥20%. 
 
Figure 4 in this Appendix will replace Figure 2 in the main body of the Clinical Study Protocol after the interim analysis, see 
Section 4.2. 
 
Figure 4 
Dosing schedule after interim analysis, Repeated dose 0.25 mg/kg 
 


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
 
39 
 
0.125 mg/kg
0.0625 mg/kg
0.375 or
0.563 mg/kg
0.25 mg/kg
0.0625 mg/kg
0.0625 mg/kg
0.25 mg/kg
0.125 mg/kg
0.0625 mg/kg
0.0625 mg/kg
Single
dose 1
Single
dose 2
PRU 2 hr
at Visit 2
PRU 2 hr
at Visit 4
PRU 2 hr
at Visit 3
Open-label
1 week
treatment
Double-blind
4 week treatment
>95
<95
>95
<95
Discontinue
>95
>95
<95
<95


 
Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
 
40 
 
Revised text: 
An interim analysis was conducted per protocol after 12 patients had completed dosing 
in part A. The mean PRU reduction 2 hours post-dose at Visit 4 was <20%, and plasma 
ticagrelor concentrations were lower than expected. This triggered a protocol 
amendment to increase the weight-adjusted dosing in order to achieve a higher level of 
platelet inhibition. 
Doses may be further adjusted following assessment by AstraZeneca and the Steering 
Committee of results in the first 6-12 patients randomised under this amendment. Dose 
adjustment decisions will be based upon a review of PK, PD and adverse events and will 
apply only to patients randomised subsequent to the dose change decision. 
Alternative Dosing Schedule 1: 
The dose for Visit 2, Part A and Part B may be reduced from 0.75 mg/kg to 0.563 
mg/kg and the highest dose administered on Visit 3 may be reduced from 2.25 
mg/kg to 1.69 mg/kg.  
Refer to Figure 1: Alternative dosing schedule 1, reduced doses in Appendix E  
 
Alternative Dosing Schedule 2: 
 
If two or more patients exceed the paediatric exposure limit (Cmax 2000 ng/mL) 
after receiving 2.25 mg/kg as single dose on visit 3, this dose will be reduced from 
2.25 mg/kg to 1.69 mg/kg.  
 
Refer to Figure 2: Alternative dosing schedule 2, reduced top dose in Appendix E  
 
Alternative Dosing Schedule 3: 
 
The dose at visit 2 and during repeated dosing in Part A and Part B may be 
increased from 0.75 mg/kg to 1.125 mg/kg, and the single doses at visit 3 may be 
increased to 1.69 mg/kg and 2.25 mg/kg  
 
Refer to Figure 3:  Alternative dosing schedule 3, increased doses in Appendix E


 
Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
 
41 
 
 
 
Table 1 
Adult equivalents of doses in the alternative dosing schedules 
Weight-based Dose (mg/kg) 
Adult equivalent dose (mg) 
0.375 
30 
0.563 
45 
0.75 
60 
1.125 
90 
1.69 
135 
2.25 
180 


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
 
42 
 
Figure 1 in this Appendix will replace Figure 2 in the main body of the Clinical Study Protocol if the doses are reduced, see 
Section 4.2 
Figure 1 
Alternative dosing schedule 1, reduced doses 
0.563 mg/kg
or placebo
0.375 mg/kg
or placebo
Double-blind
4 week treatment
0.375 mg/kg
or placebo
0.563 mg/kg
0.375 mg/kg
1.125 or
1.69 mg/kg
0.563 mg/kg
0.375 mg/kg
Discontinue
Single
dose 1
Single
dose 2
PRU 2 hr
at Visit 2
PRU 2 hr
at Visit 4
PRU 2 hr
at Visit 3
Open-label
1 week
treatment
>95
<95
>95
<95
<95
> 95
> 95
> 95
 


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
43 
 
Figure 2 in this Appendix will replace Figure 2 in the main body of the Clinical Study Protocol if the top dose is reduced, see Section 
4.2. 
Figure 2 
Alternative dosing schedule 2, reduced top dose: 
 
0.75 mg/kg
0.563 mg/kg
1.125 or
1.69 mg/kg
0.75 mg/kg
0.563 mg/kg
Discontinue
0.75 mg/kg
or placebo
0.563 mg/kg
or placebo
Single
dose 1
Single
dose 2
PRU 2 hr
at Visit 2
PRU 2 hr
at Visit 4
PRU 2 hr
at Visit 3
Open-label
1 week
treatment
Double-blind
4 week treatment
>95
<95
>95
<95
<95
> 95
> 95
> 95
0.563 mg/kg
or placebo
 


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
44 
 
Figure 3 in this Appendix will replace Figure 2 in the main body of the Clinical Study Protocol if the doses are increased, see Section 
4.2. 
Figure 3 
Alternative dosing schedule 3, increased doses: 
 
1.125 mg/kg
0.75 mg/kg
1.69 or
2.25 mg/kg
1.125 mg/kg
0.75 mg/kg
Discontinue
1.125 mg/kg
or placebo
0.75 mg/kg
or placebo
Single
dose 1
Single
dose 2
PRU 2 hr
at Visit 2
PRU 2 hr
at Visit 4
PRU 2 hr
at Visit 3
Open-label
1 week
treatment
Double-blind
4 week treatment
>95
<95
>95
<95
<95
> 95
> 95
> 95
0.75 mg/kg
or placebo


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
45 
 
Section of protocol affected: 
Appendix F 
Previous text: 
Before each dosing occasion the granules will be constituted with a fixed volume of purified 
water to form a homogenous suspension suitable for oral dosing. Dosing will be weight based 
and a suitable volume of suspension should be withdrawn from the bottle using a syringe suitable 
for oral dosing. The dose volume to be given to the patient is defined in Table 1-Table 5. The 
dose tables are based on predefined weight brackets in order to ensure dose accuracy (only whole 
mL to be given) and that the correct treatment strength is given to patient. All patients will 
receive a handling instruction together with study drug at each visit starting at Visit 3. The 
investigator will enter the individual volume to be given in the handling instruction before the 
patient leaves the clinic. For more information, please see Section 7.2 in the Clinical Study 
Protocol.  
Table 1 
0.0625 mg/kg 
 
Weight (kg) 
Bottle strength (mg) 
Dose volume (mL) 
Actual dose (mg) 
16-27 
10 
1 
1 
28-41 
10 
2 
2 
42-55 
10 
3 
3 
56-69 
10 
4 
4 
70-120 
10 
5 
5 
 
 
Table 2 
0.125 mg/kg 
 
Weight (kg) 
Bottle strength (mg) 
Dose volume (mL) 
Actual dose (mg) 
16-27 
10 
2 
2 
28-41 
10 
4 
4 
42-55 
10 
6 
6 
56-69 
10 
8 
8 
70-120 
10 
10 
10 
 
 
Table 3 
0.250 mg/kg 
 
Weight (kg) 
Bottle strength (mg) 
Dose volume (mL) 
Actual dose (mg) 
16-27 
10 
4 
4 
28-41 
10 
8 
8 
42-55 
45 
3 
13.5 
56-69 
45 
4 
18 
70-120 
45 
5 
22.5 


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
46 
 
 
Table 4 
0.375 mg/kg 
 
Weight (kg) 
Bottle strength (mg) 
Dose volume (mL) 
Actual dose (mg) 
16-27 
10 
6 
6 
28-41 
45 
3 
13.5 
42-55 
45 
4 
18 
56-69 
45 
5 
22.5 
70-120 
45 
7 
31.5 
 
 
Table 5 
0.563 mg/kg 
 
Weight (kg) 
Bottle strength (mg) 
Dose volume (mL) 
Actual dose (mg) 
16-27 
45 
2 
9 
28-41 
45 
4 
18 
42-55 
45 
6 
27 
56-69 
45 
8 
36 
70-120 
45 
10 
45* 
* The highest dose in this study is 45 mg, even if the patient weight is >120 kg


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
47 
 
Revised text: 
Before each dosing occasion the granules will be constituted with 10 mL of purified water to 
form a homogenous suspension suitable for oral dosing. Dosing will be weight based and a 
suitable volume of suspension should be withdrawn from the bottle using a syringe suitable 
for oral dosing. The dose volume to be given to the patient is defined in Table 1-Table 6. The 
dose tables are based on predefined weight brackets in order to ensure dose accuracy (only 
whole mL to be given, except for the 0.375 mg/kg dose) and that the correct treatment dose 
is given to patient. All patients will receive a handling instruction together with study drug at 
each visit starting at Visit 3. The investigator will enter the individual volume to be given in 
the handling instruction before the patient leaves the clinic. For more information, please see 
Section 7.2 in the Clinical Study Protocol.  
Table 1 
0.375 mg/kg 
Weight (kg) 
Bottle strength (mg) 
Dose volume (mL) 
Actual dose (mg) * 
16-27 
45 
1.3 
6 
28-41 
45 
3 
13.5 
42-55 
45 
4 
18 
56-69 
45 
5 
22.5 
≥70 
45 
7 
31.5 
 
Table 2 
0.563 mg/kg 
Weight (kg) 
Bottle strength (mg) 
Dose volume (mL) 
Actual dose (mg) * 
16-27 
45 
2 
9 
28-41 
45 
4 
18 
42-55 
45 
6 
27 
56-69 
45 
8 
36 
≥70 
45 
10 
45 
 
Table 3 
0.75 mg/kg 
Weight (kg) 
Bottle strength (mg) 
Dose volume (mL) 
Actual dose (mg) * 
16-27 
45 
3 
13.5 
28-41 
45 
6 
27 
42-55 
45 
8 
36 
56-69 
45 
10 
45 
≥70 
45 
13 
58.5 
 


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
48 
 
Table 4 
1.125 mg/kg  
Weight (kg) 
Bottle strength (mg) 
Dose volume (mL) 
Actual dose (mg) * 
16-27 
45 
4 
18 
28-41 
45 
9 
40.5 
42-55 
45 
12 
54 
56-69 
45 
16 
72 
≥70 
45 
20 
90** 
 
Table 5  
1.69 mg/kg  
Weight (kg) 
Bottle strength (mg) 
Dose volume (mL) 
Actual dose (mg) * 
16-27 
45 
6 
27 
28-41 
45 
13 
58.5 
42-55 
45 
18 
81 
56-69 
45 
23 
103.5 
≥70 
45 
30 
135 
 
 
Table 6 
2.25 mg/kg  
Weight (kg) 
Bottle strength (mg) 
Dose volume (mL) 
Actual dose (mg) * 
16-27 
45 
8 
36 
28-41 
45 
17 
76.5 
42-55 
45 
24 
108 
56-69 
45 
31 
139.5 
≥70 
45 
40 
180** 
* Actual doses were calculated using the mean weight in the weight bands ((Upper weight-Lower 
weight)/2+Lower weight) except for the highest and lowest weight bands, where 80kg and the 16kg was used 
respectively.   
** The highest dose in this study is 180 mg for single doses, and 90 mg for repeated doses. 


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
49 
 
Reason for Amendment:  
 
Change in Dosing Scheme:   
Study D5136C00007 (HESTIA1) was initiated with ticagrelor doses ranging from 0.125-
0.563 mg/kg (equivalent to adult doses of 10-45 mg). The protocol provided for an interim 
analyses of PK and PD with protocol-specified criteria for dose adjustments.  Analysis of the 
first 12 randomised patients shows that the exposure to ticagrelor was lower than predicted 
and the platelet inhibitory effect was also lower than intended. The doses administered were 
predicted to result in approximately 10-75% platelet inhibition, but the observed mean 
reductions were 13-30%.  In order to accomplish the primary study objective of characterising 
the relationship between ticagrelor dose and inhibition of platelet aggregation to support dose 
selection for Phase III, the doses studied in the remaining patients will be increased by this 
protocol amendment. 
Moreover, recently published results from a Phase III study in children with SCD with another 
P2Y12 inhibitor, prasugrel, suggest that the low degree of platelet inhibition achieved so far in 
this Phase 2 study with ticagrelor cannot be expected to provide any clinically meaningful 
effect on pain crises (ref Heeney et al, NEJM, online before printed, Dec 8, 2015).  
The interim data from HESTIA1 do not raise any safety concerns, and in fact no bleeding 
adverse events have been reported. The most commonly reported adverse events were sickle 
cell anemia crisis (4 patients), vomiting, arthralgia and pain in extremities (3 patients each). 
Three serious adverse events occurred in 2 patients (acute chest syndrome, sickle cell anemia 
crises). None of the non-serious or serious adverse events were judged as related to study drug 
by the investigator.  
This amendment will provide for higher doses for patients enrolled following this amendment 
in order to fully characterize the dose-response for ticagrelor in children. Doses proposed in 
this amendment on a mg/kg basis are all less than or equivalent to the currently approved 
doses for adult cardiovascular diseases (single loading dose of 180 mg followed by 90 mg 
twice daily) and the predicted highest exposure, taking individual variability into account, are 
well below pediatric exposure limits (Cmax 2000 ng/mL and AUC 19000 ng*hr/mL). 
The 10 mg bottle strength has been removed because this bottle strength is no longer needed 
for the revised dosing schedule. 
Changes in Inclusion and Exclusion Criteria:   
Inclusion criteria #2 concerning the history of VOC in the prior 12 months was removed to 
enable characterization of PK and PD in a broader patient population of patients with SCD. 
The requirement for stable hydroxyurea dosing was changed from 3 months to 1 month since 
this is considered sufficient to establish steady state.  


Clinical Study Protocol Amendment 3 
Drug Substance Ticagrelor 
Study Code D5136C00007 
Date 22 December 2015 
 
50 
 
As the eligibility criteria have been changed with this amendment, previously enrolled but not 
randomized patients may be re-enrolled and evaluated for participation under the new study 
protocol, at the discretion of the investigator. 
Changes to Part B of the study:   
The amended protocol allows for patients to opt out of participation in Part B. HESTIA1 is a 
complex study with a high study burden to paediatric patients and their families. The primary 
objective of the study is to determine the PK/PD relationship, which can be determined in Part 
A of the amended protocol. This change will allow those patients interested in a longer 
double-blind treatment to participate in both parts of the study, but also to enable participation 
in part A only for those patients and families who otherwise would completely deny study 
participation because Part B is too time-consuming and burdensome for them. 
Since Part B is now optional, the PK/PD determinations previously scheduled for Visit 8 have 
been moved to Visit 4 in order to assure that steady state PK/PD is obtained in all study 
patients.  
The pregnancy urine testing has been moved from Visit 3 to Visit 2 to insure that all patients 
are tested prior to first dose. A pregnancy test has been added to Visit 4 for the patients only 
completing Part A to insure that all patients are tested following repeated dosing. 
Changes to the statistical analyses section: 
If most of the remaining patients decline participation in part B, the patients in the efficacy 
analysis set are prone to selection bias. Results of statistical tests conducted under such 
circumstances are not generalizable and hence only descriptive statistics will be used.  
Changes to Visit Schedule:   
The minimum number of days between Visit 1 and Visit 2 was increased from 7 days to 14 
days to ensure that 30 days elapse between Visit 1 and Visit 4.  This ensures that the volume 
of blood to be drawn within 30 days is not higher than 3% of blood volume.  The visit window 
between the treatment visits has been shortened to better fit the visit schedule and to avoid 
requiring patients to bring home large volumes of study medication. 
Changes to List of References: 
Heeney et al 2015 
Heeney MM, Hoppe CC, Abboud MR, Inusa B, Kanter J, Ogutu B et al. A multinational trial 
of prasugrel for sickle cell vaso-occlusive events. 
NEJM, online before print Dec 8, 2015 
Persons who initiated the Amendment: 
AstraZeneca Study Team, with concurrence of study Steering Committee.  
 

SAP_000.pdf: 
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