Effect of Ticagrelor vs. Placebo in the Reduction of Vaso-occlusive Crises in Pediatric Patients With Sickle Cell Disease

Hestia3 will evaluate the efficacy, safety and tolerability of ticagrelor versus placebo in
children with SCD during treatment for at least 12 months and up to approximately 24 months.

- The target population are children aged ≥2 to <18 years of age and body weight of ≥12 kg
diagnosed with HbSS or HbS/β0 confirmed by high-performance liquid chromatography or
hemoglobin electrophoresis. At least 50 evaluable patients should be recruited in each
of the age groups, ≥2 years to <12 years and ≥12 years to <18 years.

- To be eligible for the study, patients must have experienced at least 2 VOCs (defined as
painful crisis and/or ACS) events in the past 12 months prior to Visit 1, indicating
that the severity of the patient's disease justifies preventive chronic long-term
treatment. The intent is to enroll only children aged 2 years or above, since VOCs
become more frequent with age.

- Study participants should receive standard of care for SCD, adjusted to the individual
patient at the discretion of the investigator, including routine health care screening
examinations and immunizations according to local guidelines and health care
programmers. Study drug will be given on the background of standard treatments for SCD.
Study participants are not withheld from any other treatments that may be used in SCD
(eg., hydroxyurea) during the trial, which is important considering the use of a placebo
control group. However, restrictions apply to some medications and interventions that
may be necessary for the patient's health and well-being during the study.

- Patients are to be followed up to 24 months or until a common study end date is reached
defined as 12 months after the last patient is randomised. The expected average
follow-up is 18 months. Considering inclusion of patients with at least 2 VOC events in
the past year, this treatment duration is considered long enough to evaluate effects on
VOC events as well as to capture safety and tolerability data supporting a potential
future long term use of ticagrelor.

- Due to ticagrelor mechanism of action and the potential to reduce symptoms caused by
ischemia during a vaso-occlusion, a composite endpoint with painful crises and/or ACS
has been selected for the primary endpoint. Painful crisis is the most common reason for
emergency department visits for patients with SCD with a significant impact on young
patients' lives, affecting them physically and emotionally. Secondary endpoints are
included to broaden the understanding of effects in patients with SCD and to also assess
potential benefits on symptomatic disease burden and health-related quality of life
(HRQL).

- Patients will be treated with 15, 30 and 45 mg bd or matching placebo, depending on body
weight.

Inclusion Criteria:

1. Provision of signed and dated informed consent prior to any study specific procedures
not part of standard medical care (local regulations and international guidelines are
to be followed in determining the assent/consent requirements for children).

2. Male or female paediatric patients aged ≥2 to <18 years and body weight of ≥12 kg (at
Visit 1), diagnosed with HbSS or HbS/β0 as confirmed by high-performance liquid
chromatography or haemoglobin electrophoresis.

Note: Diagnosis of SCD (if not confirmed prior to screening and records available on
the medical file) should be confirmed for HbSS or HbS/β0 by high-performance liquid
chromatography or haemoglobin electrophoresis, performed at the site's local lab, in
order to confirm the type of mutation.

3. Have experienced at least 2 VOCs (painful crisis and/or ACS) as judged by the
Investigator in the past 12 months prior to Visit 1. These VOCs need to be documented
in the patient's medical records or in other documents that can be reconciled.

4. If ≤16 years old, must have had transcranial Doppler (TCD) within the past year prior
to Visit 1. If this is not the case, a TCD examination must be done before proceeding
in the study.

5. If ≥10 years old, must have had an ophthalmological examination within the past year
prior to Visit 1. If this is not the case, the patient must be examined by an
ophthalmologist before proceeding in the study. If local guidelines dictate
ophthalmological examination at younger ages, those local guidelines should be
followed.

6. If treated with hydroxyurea, the weight-adjusted dose must be stable for 3 months
before screening.

7. Suitable venous access for the study-related blood sampling

8. Prior to dosing on day of randomisation (Visit 2), a negative urine (dipstick)
pregnancy test performed at Screening (Visit 1) and at Visit 2 must be available for
female patients of childbearing potential.

9. Females of childbearing potential (after menarche) must not become pregnant during
study. Sexually active females must use a highly effective method of contraception
which results in a low failure rate (ie, less than 1% per year). If use of effective
contraception cannot be secured in sexually active females, the patient cannot be
included in this study.

Exclusion Criteria:

1. History of transient ischaemic attack (TIA) or cerebrovascular accident (ischaemic or
haemorrhagic), severe head trauma, intracranial haemorrhage, intracranial neoplasm,
arteriovenous malformation, aneurysm, or proliferative retinopathy.

2. Findings on TCD: Current or previous values for time averaged mean of the maximum
velocity (TAMMV) that are Conditional or Abnormal. Patients with Conditional TAMMV
values or higher (≥153 cm/sec using TCD imaging technique [TCDi] which is
corresponding to ≥170 cm/sec by the non-imaging technique). Both the middle cerebral
artery and the internal carotid artery should be considered.

Any other criteria that would locally be considered as TCD indications for chronic
transfusion would also exclude the patient.

3. Active pathological bleeding or increased risk of bleeding complications according to
Investigator

4. Haemoglobin <6 g/dL from test performed at Screening (Visit 1)

5. Platelets <100 x 10^9/L from test performed at Screening (Visit 1) Undergoing
treatment with chronic red blood cell transfusion therapy.

6. Undergoing treatment with chronic red blood cell transfusion therapy.

7. Chronic use of NSAIDs defined as continuous intake >3 days per week that cannot be
discontinued

8. Receiving chronic treatment with anticoagulants or antiplatelet drugs that cannot be
discontinued

9. Moderate or severe hepatic impairment defined as laboratory values of alanine
aminotransferase (ALT) >2 × upper limits of normal (ULN), total bilirubin >2 × ULN
(unless judged by the Investigator to be caused by haemolysis), albumin <35 g/L (3.5
g/dL) and International normalised ratio (INR) >1.4, or symptoms of liver disease (eg,
ascites) from test performed at Screening (Visit 1).

10. Renal failure requiring dialysis

11. Patient considered to be at risk of bradycardic events (eg, known sick sinus syndrome
or second or third degree atrioventricular block) unless already treated with a
permanent pacemaker.

12. Concomitant oral or intravenous therapy with strong or moderate cytochrome P450 3A
(CYP3A) inhibitors, CYP3A substrates with narrow therapeutic indices, or strong CYP3A
inducers, which cannot be stopped at least 5 half-lives before randomisation.

13. Active untreated malaria. Patients with suspected malaria at Screening (Visit 1) will
be tested.

14. Known hypersensitivity or contraindication to ticagrelor

15. Patients who are currently pregnant or breastfeeding, or planning to become pregnant
during the study or have given birth less than 3 months prior to Screening (Visit 1)

16. Any condition which, in the opinion of the Investigator, would make it unsafe or
unsuitable for the patient to participate in this study

17. Concern for the inability of the patient or caregiver (defined as legally authorized
representative) to comply with study procedures and/or follow-up

18. Previous randomisation in the present study.

19. Participation in another clinical study with an IP or device during the last 30 days
preceding screening.

20. Involvement of member of patient's family, or patient self, in the planning and/or
conduct of the study (applies to both AstraZeneca staff and/or staff at the study
site).