Trial Outcomes & Findings for Effect of Ticagrelor vs. Placebo in the Reduction of Vaso-occlusive Crises in Pediatric Patients With Sickle Cell Disease (NCT NCT03615924)

Last Updated: 2021-04-09

Results Overview

A VOC is the composite of a painful crisis and/or an acute chest syndrome (ACS) event. The number of VOC events is defined as the count of VOC events experienced by a participant throughout the treatment period.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

193 participants

Primary outcome timeframe

From randomization (Day 0) up to end of study (EOS) visit or date of premature study discontinuation, up to approximately 20 months

Results posted on

2021-04-09

Participant Flow

This Phase III study was conducted in pediatric participants with sickle cell disease (SCD) at 53 sites in 16 countries (Kenya, India, Uganda, Egypt, Lebanon, Ghana, South Africa, Tanzania, United Kingdom, Turkey, Spain, Italy, Belgium, Greece, Brazil and United States) between 26 September 2018 and 13 August 2020.

Pediatric participants who experienced at least two vaso-occlusive crisis (VOC) events in the past 12 months prior to screening and who fulfilled the eligibility criteria were enrolled. Participants randomized to ticagrelor received doses based on weight band (at randomization): ≥12 to ≤24 kilogram (kg)=15 milligram (mg), \>24 to ≤48 kg=30 mg, \>48 kg=45 mg. A total of 193 participants were randomized in this study.

Participant milestones

Participant milestones
Measure	Ticagrelor 15/30/45 mg bd Pediatric participants received ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally twice daily (bd) for at least 12 months but no longer than 24 months. The dose of ticagrelor was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of ticagrelor 15 mg (1x15 mg) bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of ticagrelor 15 mg (2x15 mg) bd. * Participants with a body weight \>48 kg received 3 tablets of ticagrelor 15 mg (3x15 mg) bd.	Placebo Pediatric participants received placebo matching with ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The number of placebo tablets was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of placebo matching with ticagrelor 15 mg bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of placebo matching with ticagrelor 30 mg bd. * Participants with a body weight \>48 kg received 3 tablets of placebo matching with ticagrelor 45 mg bd.
Overall Study STARTED	101	92
Overall Study Received Treatment	101	92
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	101	92

Reasons for withdrawal

Reasons for withdrawal
Measure	Ticagrelor 15/30/45 mg bd Pediatric participants received ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally twice daily (bd) for at least 12 months but no longer than 24 months. The dose of ticagrelor was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of ticagrelor 15 mg (1x15 mg) bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of ticagrelor 15 mg (2x15 mg) bd. * Participants with a body weight \>48 kg received 3 tablets of ticagrelor 15 mg (3x15 mg) bd.	Placebo Pediatric participants received placebo matching with ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The number of placebo tablets was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of placebo matching with ticagrelor 15 mg bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of placebo matching with ticagrelor 30 mg bd. * Participants with a body weight \>48 kg received 3 tablets of placebo matching with ticagrelor 45 mg bd.
Overall Study Withdrawal by Subject	2	5
Overall Study Death	3	1
Overall Study Lost to Follow-up	1	0
Overall Study Randomized in error	1	0
Overall Study Study termination by Sponsor	94	86

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Ticagrelor 15/30/45 mg bd n=101 Participants Pediatric participants received ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The dose of ticagrelor was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of ticagrelor 15 mg (1x15 mg) bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of ticagrelor 15 mg (2x15 mg) bd. * Participants with a body weight \>48 kg received 3 tablets of ticagrelor 15 mg (3x15 mg) bd.	Placebo n=92 Participants Pediatric participants received placebo matching with ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The number of placebo tablets was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of placebo matching with ticagrelor 15 mg bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of placebo matching with ticagrelor 30 mg bd. * Participants with a body weight \>48 kg received 3 tablets of placebo matching with ticagrelor 45 mg bd.	Total n=193 Participants Total of all reporting groups
Age, Continuous	10.40 years STANDARD_DEVIATION 4.128 • n=5 Participants	10.12 years STANDARD_DEVIATION 3.799 • n=7 Participants	10.26 years STANDARD_DEVIATION 3.967 • n=5 Participants
Age, Customized ≥2 to <12 years	61 Participants n=5 Participants	54 Participants n=7 Participants	115 Participants n=5 Participants
Age, Customized >=12 to <18 years	40 Participants n=5 Participants	38 Participants n=7 Participants	78 Participants n=5 Participants
Sex: Female, Male Female	48 Participants n=5 Participants	43 Participants n=7 Participants	91 Participants n=5 Participants
Sex: Female, Male Male	53 Participants n=5 Participants	49 Participants n=7 Participants	102 Participants n=5 Participants
Race/Ethnicity, Customized White	25 Participants n=5 Participants	21 Participants n=7 Participants	46 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	60 Participants n=5 Participants	51 Participants n=7 Participants	111 Participants n=5 Participants
Race/Ethnicity, Customized Asian	15 Participants n=5 Participants	15 Participants n=7 Participants	30 Participants n=5 Participants
Race/Ethnicity, Customized Other	1 Participants n=5 Participants	5 Participants n=7 Participants	6 Participants n=5 Participants
Race/Ethnicity, Customized Hispanic or Latino	7 Participants n=5 Participants	5 Participants n=7 Participants	12 Participants n=5 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	94 Participants n=5 Participants	87 Participants n=7 Participants	181 Participants n=5 Participants

PRIMARY outcome

Timeframe: From randomization (Day 0) up to end of study (EOS) visit or date of premature study discontinuation, up to approximately 20 months

Population: The FAS included all randomized participants regardless of treatment received.

Outcome measures

Outcome measures
Measure	Ticagrelor 15/30/45 mg bd n=101 Participants Pediatric participants received ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The dose of ticagrelor was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of ticagrelor 15 mg (1x15 mg) bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of ticagrelor 15 mg (2x15 mg) bd. * Participants with a body weight \>48 kg received 3 tablets of ticagrelor 15 mg (3x15 mg) bd.	Placebo n=92 Participants Pediatric participants received placebo matching with ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The number of placebo tablets was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of placebo matching with ticagrelor 15 mg bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of placebo matching with ticagrelor 30 mg bd. * Participants with a body weight \>48 kg received 3 tablets of placebo matching with ticagrelor 45 mg bd.
Number of Vaso-Occlusive Crisis Events	249 VOC events	202 VOC events

SECONDARY outcome

Timeframe: From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months

Population: The FAS included all randomized participants regardless of treatment received.

A painful crisis is an onset or worsening of pain that lasts at least 2 hours, for which there is no explanation other than vaso-occlusion and which requires therapy with oral or parenteral opioids, parenteral non-steroidal anti-inflammatory drugs, or other analgesics prescribed by a healthcare provider in a medical setting (such as a hospital, clinic or emergency room visit) or at home. Events with an onset date \<=7 days of the previous event onset date are not counted as new events.

Outcome measures

Outcome measures
Measure	Ticagrelor 15/30/45 mg bd n=101 Participants Pediatric participants received ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The dose of ticagrelor was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of ticagrelor 15 mg (1x15 mg) bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of ticagrelor 15 mg (2x15 mg) bd. * Participants with a body weight \>48 kg received 3 tablets of ticagrelor 15 mg (3x15 mg) bd.	Placebo n=92 Participants Pediatric participants received placebo matching with ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The number of placebo tablets was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of placebo matching with ticagrelor 15 mg bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of placebo matching with ticagrelor 30 mg bd. * Participants with a body weight \>48 kg received 3 tablets of placebo matching with ticagrelor 45 mg bd.
Number of Painful Crisis Events	248 painful crisis events	209 painful crisis events

SECONDARY outcome

Timeframe: From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months

Population: The FAS included all randomized participants regardless of treatment received.

The ACS is an acute illness characterized by fever and/or respiratory symptoms, accompanied by a new pulmonary infiltrate on a chest X-ray. Events with an onset date \<=7 days of the previous event onset date are not counted as new events.

Outcome measures

Outcome measures
Measure	Ticagrelor 15/30/45 mg bd n=101 Participants Pediatric participants received ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The dose of ticagrelor was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of ticagrelor 15 mg (1x15 mg) bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of ticagrelor 15 mg (2x15 mg) bd. * Participants with a body weight \>48 kg received 3 tablets of ticagrelor 15 mg (3x15 mg) bd.	Placebo n=92 Participants Pediatric participants received placebo matching with ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The number of placebo tablets was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of placebo matching with ticagrelor 15 mg bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of placebo matching with ticagrelor 30 mg bd. * Participants with a body weight \>48 kg received 3 tablets of placebo matching with ticagrelor 45 mg bd.
Number of Acute Chest Syndrome Events	6 ACS events	6 ACS events

SECONDARY outcome

Timeframe: From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months

Population: The FAS included all randomized participants regardless of treatment received.

The duration of painful crises is defined as the sum of the duration of painful crises experienced by a participant over the defined treatment period. If two or more events have overlapping durations, the overlapping days were counted only once.

Outcome measures

Outcome measures
Measure	Ticagrelor 15/30/45 mg bd n=101 Participants Pediatric participants received ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The dose of ticagrelor was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of ticagrelor 15 mg (1x15 mg) bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of ticagrelor 15 mg (2x15 mg) bd. * Participants with a body weight \>48 kg received 3 tablets of ticagrelor 15 mg (3x15 mg) bd.	Placebo n=92 Participants Pediatric participants received placebo matching with ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The number of placebo tablets was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of placebo matching with ticagrelor 15 mg bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of placebo matching with ticagrelor 30 mg bd. * Participants with a body weight \>48 kg received 3 tablets of placebo matching with ticagrelor 45 mg bd.
Duration of Painful Crises	1476 days	1441 days

SECONDARY outcome

Timeframe: From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months

Population: The FAS included all randomized participants regardless of treatment received.

The number of VOC events requiring hospitalization or emergency department visits is defined as the count of VOC events experienced by a participant over the treatment period, for which the primary setting for VOC treatment was in-patient hospitalization or emergency department. Events with an onset date \<=7 days of the previous event onset date are not counted as new events.

Outcome measures

Outcome measures
Measure	Ticagrelor 15/30/45 mg bd n=101 Participants Pediatric participants received ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The dose of ticagrelor was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of ticagrelor 15 mg (1x15 mg) bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of ticagrelor 15 mg (2x15 mg) bd. * Participants with a body weight \>48 kg received 3 tablets of ticagrelor 15 mg (3x15 mg) bd.	Placebo n=92 Participants Pediatric participants received placebo matching with ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The number of placebo tablets was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of placebo matching with ticagrelor 15 mg bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of placebo matching with ticagrelor 30 mg bd. * Participants with a body weight \>48 kg received 3 tablets of placebo matching with ticagrelor 45 mg bd.
Number of Vaso-Occlusive Crisis Events Requiring Hospitalization or Emergency Department Visits	87 VOC events requiring hospitalization	51 VOC events requiring hospitalization

SECONDARY outcome

Timeframe: From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months

Population: The FAS included all randomized participants regardless of treatment received.

The number of days hospitalized for all individual VOC events experienced by a participant during the treatment period is defined as the sum of the duration of all individual hospitalizations (taking into account potential overlapping hospitalization days of VOC components) during VOC events experienced by a participant over the treatment period for which the primary setting for VOC treatment was in-patient hospitalization.

Outcome measures

Outcome measures
Measure	Ticagrelor 15/30/45 mg bd n=101 Participants Pediatric participants received ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The dose of ticagrelor was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of ticagrelor 15 mg (1x15 mg) bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of ticagrelor 15 mg (2x15 mg) bd. * Participants with a body weight \>48 kg received 3 tablets of ticagrelor 15 mg (3x15 mg) bd.	Placebo n=92 Participants Pediatric participants received placebo matching with ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The number of placebo tablets was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of placebo matching with ticagrelor 15 mg bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of placebo matching with ticagrelor 30 mg bd. * Participants with a body weight \>48 kg received 3 tablets of placebo matching with ticagrelor 45 mg bd.
Number of Days Hospitalized for Vaso-Occlusive Crisis Events	526 days	256 days

SECONDARY outcome

Timeframe: From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months

Population: The FAS included all randomized participants regardless of treatment received.

The number of acute SCD complications is defined as the count of all individual acute SCD complications experienced by a participant over the treatment period. Acute SCD complications are defined as any one or more of the following individual complications: Transient ischaemic attack/ischaemic stroke, hepatic sequestration, splenic sequestration, priapism, and dactylitis.

Outcome measures

Outcome measures
Measure	Ticagrelor 15/30/45 mg bd n=101 Participants Pediatric participants received ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The dose of ticagrelor was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of ticagrelor 15 mg (1x15 mg) bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of ticagrelor 15 mg (2x15 mg) bd. * Participants with a body weight \>48 kg received 3 tablets of ticagrelor 15 mg (3x15 mg) bd.	Placebo n=92 Participants Pediatric participants received placebo matching with ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The number of placebo tablets was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of placebo matching with ticagrelor 15 mg bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of placebo matching with ticagrelor 30 mg bd. * Participants with a body weight \>48 kg received 3 tablets of placebo matching with ticagrelor 45 mg bd.
Number of Acute Sickle Cell Disease Complications	6 acute SCD complications	3 acute SCD complications

SECONDARY outcome

Timeframe: From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months

Population: The FAS included all randomized participants regardless of treatment received.

The number of days hospitalized for acute SCD complications is defined as the sum of the duration of all individual hospitalizations (taking into account potential overlapping hospitalization days) due to acute SCD complications experienced by a participant over the treatment period, for which hospitalization was reported.

Outcome measures

Outcome measures
Measure	Ticagrelor 15/30/45 mg bd n=101 Participants Pediatric participants received ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The dose of ticagrelor was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of ticagrelor 15 mg (1x15 mg) bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of ticagrelor 15 mg (2x15 mg) bd. * Participants with a body weight \>48 kg received 3 tablets of ticagrelor 15 mg (3x15 mg) bd.	Placebo n=92 Participants Pediatric participants received placebo matching with ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The number of placebo tablets was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of placebo matching with ticagrelor 15 mg bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of placebo matching with ticagrelor 30 mg bd. * Participants with a body weight \>48 kg received 3 tablets of placebo matching with ticagrelor 45 mg bd.
Number of Days Hospitalized for Acute Sickle Cell Disease Complications	0 days	6 days

SECONDARY outcome

Timeframe: From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months

Population: The FAS included all randomized participants regardless of treatment received.

The number of participants with at least one sickle cell-related RBC transfusion reported. Adverse events resulting in the need for RBC transfusions were captured prior to database lock to determine if the transfusion was sickle cell-related or not.

Outcome measures

Outcome measures
Measure	Ticagrelor 15/30/45 mg bd n=101 Participants Pediatric participants received ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The dose of ticagrelor was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of ticagrelor 15 mg (1x15 mg) bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of ticagrelor 15 mg (2x15 mg) bd. * Participants with a body weight \>48 kg received 3 tablets of ticagrelor 15 mg (3x15 mg) bd.	Placebo n=92 Participants Pediatric participants received placebo matching with ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The number of placebo tablets was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of placebo matching with ticagrelor 15 mg bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of placebo matching with ticagrelor 30 mg bd. * Participants with a body weight \>48 kg received 3 tablets of placebo matching with ticagrelor 45 mg bd.
Number of Sickle Cell-Related Red Blood Cell (RBC) Transfusions	39 RBC transfusions	49 RBC transfusions

SECONDARY outcome

Timeframe: For ages ≥2 to <5 years and ≥5 to <8 years: Baseline (observation prior to and including the randomization visit) and Months 6, and 12; For ages ≥8 to <13 years and ≥13 to ≤18 years: Baseline and Months 6, 12, and 18

Population: The FAS included all randomized participants regardless of treatment received. Only number of participants included in analysis at each time point are reported.

The PedsQL SCD module instrument developed using a 5-point Likert scale (where 0= never and 4= almost always) for the participant self-report forms for ages ≥5 to \<8 years, ≥8 to \<13 years, and ≥13 to ≤18 years and the caregiver proxy-report form specific for ≥2 to \<5 years was used. The PedsQL SCD module measures problems in the following categories: * Pain: 3 sub-scales * Worry: 2 sub-scales * Emotions: 1 sub-scale * Treatment: 1 sub-scale * Communication: 2 sub-scales * Total score PedsQL SCD module items were reverse-scored and linearly transformed to a 0 to 100 scale (0= 100, 1= 75, 2= 50, 3= 25, 4= 0) so that higher scores indicate better quality of life. To create the PedsQL SCD module total score (43/42/40 items - depending on version completed) the arithmetic mean of the transformed scores was computed as the sum of the items transformed scores divided by the number of items answered. Baseline values are the closest observation prior to and including the randomization visit.

Outcome measures

Outcome measures
Measure	Ticagrelor 15/30/45 mg bd n=101 Participants Pediatric participants received ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The dose of ticagrelor was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of ticagrelor 15 mg (1x15 mg) bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of ticagrelor 15 mg (2x15 mg) bd. * Participants with a body weight \>48 kg received 3 tablets of ticagrelor 15 mg (3x15 mg) bd.	Placebo n=92 Participants Pediatric participants received placebo matching with ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The number of placebo tablets was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of placebo matching with ticagrelor 15 mg bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of placebo matching with ticagrelor 30 mg bd. * Participants with a body weight \>48 kg received 3 tablets of placebo matching with ticagrelor 45 mg bd.
Health-Related Quality of Life Total Score Using the Pediatric Quality of Life Inventory (PedsQL) Sickle Cell Disease Module >=13 to <=18 years: Baseline	64.45 score on a scale Standard Deviation 18.746	60.81 score on a scale Standard Deviation 24.979
Health-Related Quality of Life Total Score Using the Pediatric Quality of Life Inventory (PedsQL) Sickle Cell Disease Module >=2 to <5 years: Baseline	88.81 score on a scale Standard Deviation 14.107	67.02 score on a scale Standard Deviation 20.041
Health-Related Quality of Life Total Score Using the Pediatric Quality of Life Inventory (PedsQL) Sickle Cell Disease Module >=2 to <5 years: Month 6	80.75 score on a scale Standard Deviation 20.779	81.37 score on a scale Standard Deviation 14.125
Health-Related Quality of Life Total Score Using the Pediatric Quality of Life Inventory (PedsQL) Sickle Cell Disease Module >=2 to <5 years: Month 12	—	88.10 score on a scale Standard Deviation NA Standard deviation could not be calculated as only 1 participant had analyzable data.
Health-Related Quality of Life Total Score Using the Pediatric Quality of Life Inventory (PedsQL) Sickle Cell Disease Module >=5 to <8 years: Baseline	75.05 score on a scale Standard Deviation 20.147	74.04 score on a scale Standard Deviation 21.646
Health-Related Quality of Life Total Score Using the Pediatric Quality of Life Inventory (PedsQL) Sickle Cell Disease Module >=5 to <8 years: Month 6	83.04 score on a scale Standard Deviation 15.332	84.91 score on a scale Standard Deviation 18.117
Health-Related Quality of Life Total Score Using the Pediatric Quality of Life Inventory (PedsQL) Sickle Cell Disease Module >=5 to <8 years: Month 12	65.63 score on a scale Standard Deviation 48.614	97.50 score on a scale Standard Deviation NA Standard deviation could not be calculated as only 1 participant had analyzable data.
Health-Related Quality of Life Total Score Using the Pediatric Quality of Life Inventory (PedsQL) Sickle Cell Disease Module >=8 to <13 years: Baseline	62.35 score on a scale Standard Deviation 24.725	67.98 score on a scale Standard Deviation 24.338
Health-Related Quality of Life Total Score Using the Pediatric Quality of Life Inventory (PedsQL) Sickle Cell Disease Module >=8 to <13 years: Month 6	76.52 score on a scale Standard Deviation 17.189	75.76 score on a scale Standard Deviation 21.749
Health-Related Quality of Life Total Score Using the Pediatric Quality of Life Inventory (PedsQL) Sickle Cell Disease Module >=8 to <13 years: Month 12	83.20 score on a scale Standard Deviation 13.479	64.12 score on a scale Standard Deviation 27.253
Health-Related Quality of Life Total Score Using the Pediatric Quality of Life Inventory (PedsQL) Sickle Cell Disease Module >=8 to <13 years: Month 18	86.05 score on a scale Standard Deviation NA Standard deviation could not be calculated as only 1 participant had analyzable data.	—
Health-Related Quality of Life Total Score Using the Pediatric Quality of Life Inventory (PedsQL) Sickle Cell Disease Module >=13 to <=18 years: Month 6	68.13 score on a scale Standard Deviation 16.811	74.42 score on a scale Standard Deviation 19.146
Health-Related Quality of Life Total Score Using the Pediatric Quality of Life Inventory (PedsQL) Sickle Cell Disease Module >=13 to <=18 years: Month 12	63.05 score on a scale Standard Deviation 19.810	73.26 score on a scale Standard Deviation 22.589
Health-Related Quality of Life Total Score Using the Pediatric Quality of Life Inventory (PedsQL) Sickle Cell Disease Module >=13 to <=18 years: Month 18	65.12 score on a scale Standard Deviation NA Standard deviation could not be calculated as only 1 participant had analyzable data.	—

SECONDARY outcome

Population: The FAS included all randomized participants regardless of treatment received. Only number of participants included in analysis at each time point are reported.

The PedsQL multidimensional fatigue scale instrument developed using a 5-point Likert scale (where 0= never and 4= almost always) for the participant self-report forms for ages ≥5 to \<8 years, ≥8 to \<13 years, and ≥13 to ≤18 years and the caregiver proxy-report form specific for ≥2 to \<5 years was used. The PedsQL multidimensional fatigue scale measures problems in the following categories: * General (6 items) * Sleep/rest (6 items) * Cognitive fatigue (6 items) * Total score (18 items) PedsQL multidimensional fatigue scale items were reverse-scored and linearly transformed to a 0 to 100 scale (0= 100, 1= 75, 2= 50, 3= 25, 4= 0) so that higher scores indicate better quality of life. To create the PedsQL multidimensional fatigue scale total score (18 items), the arithmetic mean of the transformed scores was computed as the sum of the items transformed scores divided by the number of items answered. Baseline values are closest observation prior to and including randomization visit.

Outcome measures

Outcome measures
Measure	Ticagrelor 15/30/45 mg bd n=101 Participants Pediatric participants received ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The dose of ticagrelor was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of ticagrelor 15 mg (1x15 mg) bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of ticagrelor 15 mg (2x15 mg) bd. * Participants with a body weight \>48 kg received 3 tablets of ticagrelor 15 mg (3x15 mg) bd.	Placebo n=92 Participants Pediatric participants received placebo matching with ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The number of placebo tablets was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of placebo matching with ticagrelor 15 mg bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of placebo matching with ticagrelor 30 mg bd. * Participants with a body weight \>48 kg received 3 tablets of placebo matching with ticagrelor 45 mg bd.
Fatigue Total Score Using Pediatric Quality of Life Inventory Multidimensional Fatigue Scale >=2 to <5 years: Month 12	—	94.44 score on a scale Standard Deviation NA Standard deviation could not be calculated as only 1 participant had analyzable data.
Fatigue Total Score Using Pediatric Quality of Life Inventory Multidimensional Fatigue Scale >=8 to <13 years: Baseline	64.72 score on a scale Standard Deviation 26.779	69.51 score on a scale Standard Deviation 25.261
Fatigue Total Score Using Pediatric Quality of Life Inventory Multidimensional Fatigue Scale >=2 to <5 years: Baseline	88.06 score on a scale Standard Deviation 16.304	70.56 score on a scale Standard Deviation 23.220
Fatigue Total Score Using Pediatric Quality of Life Inventory Multidimensional Fatigue Scale >=2 to <5 years: Month 6	84.44 score on a scale Standard Deviation 15.541	81.94 score on a scale Standard Deviation 22.775
Fatigue Total Score Using Pediatric Quality of Life Inventory Multidimensional Fatigue Scale >=5 to <8 years: Baseline	82.33 score on a scale Standard Deviation 11.450	84.13 score on a scale Standard Deviation 16.139
Fatigue Total Score Using Pediatric Quality of Life Inventory Multidimensional Fatigue Scale >=5 to <8 years: Month 6	87.12 score on a scale Standard Deviation 10.553	87.70 score on a scale Standard Deviation 16.076
Fatigue Total Score Using Pediatric Quality of Life Inventory Multidimensional Fatigue Scale >=5 to <8 years: Month 12	95.83 score on a scale Standard Deviation 5.893	100.00 score on a scale Standard Deviation NA Standard deviation could not be calculated as only 1 participant had analyzable data.
Fatigue Total Score Using Pediatric Quality of Life Inventory Multidimensional Fatigue Scale >=8 to <13 years: Month 6	75.65 score on a scale Standard Deviation 18.571	77.89 score on a scale Standard Deviation 22.283
Fatigue Total Score Using Pediatric Quality of Life Inventory Multidimensional Fatigue Scale >=8 to <13 years: Month 12	81.48 score on a scale Standard Deviation 17.866	65.87 score on a scale Standard Deviation 25.495
Fatigue Total Score Using Pediatric Quality of Life Inventory Multidimensional Fatigue Scale >=8 to <13 years: Month 18	73.61 score on a scale Standard Deviation NA Standard deviation could not be calculated as only 1 participant had analyzable data.	—
Fatigue Total Score Using Pediatric Quality of Life Inventory Multidimensional Fatigue Scale >=13 to <=18 years: Baseline	68.06 score on a scale Standard Deviation 21.781	67.17 score on a scale Standard Deviation 18.223
Fatigue Total Score Using Pediatric Quality of Life Inventory Multidimensional Fatigue Scale >=13 to <=18 years: Month 6	73.53 score on a scale Standard Deviation 19.138	75.21 score on a scale Standard Deviation 14.913
Fatigue Total Score Using Pediatric Quality of Life Inventory Multidimensional Fatigue Scale >=13 to <=18 years: Month 12	67.13 score on a scale Standard Deviation 22.556	60.28 score on a scale Standard Deviation 23.664
Fatigue Total Score Using Pediatric Quality of Life Inventory Multidimensional Fatigue Scale >=13 to <=18 years: Month 18	72.22 score on a scale Standard Deviation NA Standard deviation could not be calculated as only 1 participant had analyzable data.	—

SECONDARY outcome

Timeframe: From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months

Population: The FAS included all randomized participants regardless of treatment received. Only participants going to school or work at randomization are reported.

For participants attending school/work at randomization, absence from school/work due to SCD was recorded weekly by the participant in the eDevice with the help of the caregiver if needed. The percentage of days absent from school/work due to SCD in the defined treatment period was calculated as follows: Percentage of absent days = (total number of days reported)/(total number of questionnaires answered ×7).

Outcome measures

Outcome measures
Measure	Ticagrelor 15/30/45 mg bd n=94 Participants Pediatric participants received ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The dose of ticagrelor was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of ticagrelor 15 mg (1x15 mg) bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of ticagrelor 15 mg (2x15 mg) bd. * Participants with a body weight \>48 kg received 3 tablets of ticagrelor 15 mg (3x15 mg) bd.	Placebo n=82 Participants Pediatric participants received placebo matching with ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The number of placebo tablets was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of placebo matching with ticagrelor 15 mg bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of placebo matching with ticagrelor 30 mg bd. * Participants with a body weight \>48 kg received 3 tablets of placebo matching with ticagrelor 45 mg bd.
Percentage of Days of Absence From School or Work Due to Sickle Cell Disease	5.24 percentage of days Standard Deviation 8.942	4.24 percentage of days Standard Deviation 4.964

SECONDARY outcome

Timeframe: From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months

Population: The FAS included all randomized participants regardless of treatment received. Only participants \<5 years of age who had experienced at least one individual VOC event and analyzed for pain assessment are reported.

The Face, Legs, Activity, Cry, Consolability (FLACC) scale is caregiver-reported and used to assess pain daily during the VOC event for those participants \<5 years of age as determined at randomization. Each of the 5 behaviours observed are assigned a score of 0, 1 or 2. The total FLACC score ranges between 0 and 10, with 0 representing "no pain" and 10 representing "very much pain". Lower score indicate better outcome. Worst pain ratings were collected once daily throughout the duration of the VOC event using an eDevice.

Outcome measures

Outcome measures
Measure	Ticagrelor 15/30/45 mg bd n=3 Participants Pediatric participants received ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The dose of ticagrelor was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of ticagrelor 15 mg (1x15 mg) bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of ticagrelor 15 mg (2x15 mg) bd. * Participants with a body weight \>48 kg received 3 tablets of ticagrelor 15 mg (3x15 mg) bd.	Placebo n=5 Participants Pediatric participants received placebo matching with ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The number of placebo tablets was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of placebo matching with ticagrelor 15 mg bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of placebo matching with ticagrelor 30 mg bd. * Participants with a body weight \>48 kg received 3 tablets of placebo matching with ticagrelor 45 mg bd.
Average Intensity of Worst Pain Daily During Vaso-Occlusive Crisis Events in Participants <5 Years of Age	3.4 score on a scale Standard Deviation 2.51	2.9 score on a scale Standard Deviation 1.99

SECONDARY outcome

Timeframe: From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months

Population: The FAS included all randomized participants regardless of treatment received. Only participants ≥5 years of age who had experienced at least one individual VOC event and analyzed for pain assessment are reported.

The Faces Pain Scale-revised (FPS-R) was administered to assess pain daily during the VOC event by those participants aged ≥5 years as determined at randomization. The FPS-R consists of 6 faces and scoring ranges between 0 and 10 (with an increase in numeric value by 2), where 0 is "no pain" and 10 is "very much pain". Lower score indicate better outcome. Worst pain ratings were collected once daily throughout the duration of the VOC event using an eDevice.

Outcome measures

Outcome measures
Measure	Ticagrelor 15/30/45 mg bd n=44 Participants Pediatric participants received ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The dose of ticagrelor was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of ticagrelor 15 mg (1x15 mg) bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of ticagrelor 15 mg (2x15 mg) bd. * Participants with a body weight \>48 kg received 3 tablets of ticagrelor 15 mg (3x15 mg) bd.	Placebo n=40 Participants Pediatric participants received placebo matching with ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The number of placebo tablets was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of placebo matching with ticagrelor 15 mg bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of placebo matching with ticagrelor 30 mg bd. * Participants with a body weight \>48 kg received 3 tablets of placebo matching with ticagrelor 45 mg bd.
Average Intensity of Worst Pain Daily During Vaso-Occlusive Crisis Events in Participants ≥5 Years of Age	4.5 score on a scale Standard Deviation 2.71	4.1 score on a scale Standard Deviation 2.02

SECONDARY outcome

Timeframe: From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months

Population: The FAS included all randomized participants regardless of treatment received. Only participants who had at least one VOC and took an analgesic are reported.

Analgesics use (opioid and non-opioid) during VOC events.

Outcome measures

Outcome measures
Measure	Ticagrelor 15/30/45 mg bd n=70 Participants Pediatric participants received ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The dose of ticagrelor was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of ticagrelor 15 mg (1x15 mg) bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of ticagrelor 15 mg (2x15 mg) bd. * Participants with a body weight \>48 kg received 3 tablets of ticagrelor 15 mg (3x15 mg) bd.	Placebo n=58 Participants Pediatric participants received placebo matching with ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The number of placebo tablets was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of placebo matching with ticagrelor 15 mg bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of placebo matching with ticagrelor 30 mg bd. * Participants with a body weight \>48 kg received 3 tablets of placebo matching with ticagrelor 45 mg bd.
Type of Analgesics Used by Participants During Vaso-Occlusive Crisis Events Opioids: Yes	46 participants	22 participants
Type of Analgesics Used by Participants During Vaso-Occlusive Crisis Events Opioids: No	57 participants	50 participants
Type of Analgesics Used by Participants During Vaso-Occlusive Crisis Events Non-opioids: Yes	69 participants	57 participants
Type of Analgesics Used by Participants During Vaso-Occlusive Crisis Events Non-opioids: No	14 participants	7 participants

SECONDARY outcome

Timeframe: Baseline (randomization visit) and Month 6

Population: The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available. Only participants ≤4 years of age who completed the assessment for study treatment palatability are reported.

Response to palatability was assessed through the SMPA question "Was any behaviour observed when the study medication was given to this participant that would be indicative of a negative response to the palatability of the study medication?". This was presented as a binary outcome (that is, where "No" is no negative response and "Yes" is negative response). No negative response was considered as a positive outcome.

Outcome measures

Outcome measures
Measure	Ticagrelor 15/30/45 mg bd n=6 Participants Pediatric participants received ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The dose of ticagrelor was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of ticagrelor 15 mg (1x15 mg) bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of ticagrelor 15 mg (2x15 mg) bd. * Participants with a body weight \>48 kg received 3 tablets of ticagrelor 15 mg (3x15 mg) bd.	Placebo n=10 Participants Pediatric participants received placebo matching with ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The number of placebo tablets was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of placebo matching with ticagrelor 15 mg bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of placebo matching with ticagrelor 30 mg bd. * Participants with a body weight \>48 kg received 3 tablets of placebo matching with ticagrelor 45 mg bd.
Palatability of the Study Treatment Assessed by Study Medication Palatability Assessment (SMPA) in Participants ≤4 Years of Age Baseline: Whole tablet · Negative response to palatability - No	5 Participants	8 Participants
Palatability of the Study Treatment Assessed by Study Medication Palatability Assessment (SMPA) in Participants ≤4 Years of Age Baseline: Whole tablet · Negative response to palatability - Yes	0 Participants	0 Participants
Palatability of the Study Treatment Assessed by Study Medication Palatability Assessment (SMPA) in Participants ≤4 Years of Age Baseline: Dispersed tablet · Negative response to palatability - No	1 Participants	2 Participants
Palatability of the Study Treatment Assessed by Study Medication Palatability Assessment (SMPA) in Participants ≤4 Years of Age Baseline: Dispersed tablet · Negative response to palatability - Yes	0 Participants	0 Participants
Palatability of the Study Treatment Assessed by Study Medication Palatability Assessment (SMPA) in Participants ≤4 Years of Age Month 6: Whole tablet · Negative response to palatability - No	4 Participants	9 Participants
Palatability of the Study Treatment Assessed by Study Medication Palatability Assessment (SMPA) in Participants ≤4 Years of Age Month 6: Whole tablet · Negative response to palatability - Yes	0 Participants	0 Participants
Palatability of the Study Treatment Assessed by Study Medication Palatability Assessment (SMPA) in Participants ≤4 Years of Age Month 6: Dispersed tablet · Negative response to palatability - No	1 Participants	1 Participants
Palatability of the Study Treatment Assessed by Study Medication Palatability Assessment (SMPA) in Participants ≤4 Years of Age Month 6: Dispersed tablet · Negative response to palatability - Yes	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline (randomization visit) and Month 6

An observer's assessment of the participant's behaviour using the SMPA was performed for all participants taking the study treatment who are 2 to 4 years of age. Willingness to swallow was assessed and categorized as follows: * Swallowed without a problem * Some resistance but did swallow * Spit out some/all of the medication * Vomited up the medication. The category "swallowed without a problem" was considered as positive outcome.

Outcome measures

Outcome measures
Measure	Ticagrelor 15/30/45 mg bd n=6 Participants Pediatric participants received ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The dose of ticagrelor was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of ticagrelor 15 mg (1x15 mg) bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of ticagrelor 15 mg (2x15 mg) bd. * Participants with a body weight \>48 kg received 3 tablets of ticagrelor 15 mg (3x15 mg) bd.	Placebo n=10 Participants Pediatric participants received placebo matching with ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The number of placebo tablets was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of placebo matching with ticagrelor 15 mg bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of placebo matching with ticagrelor 30 mg bd. * Participants with a body weight \>48 kg received 3 tablets of placebo matching with ticagrelor 45 mg bd.
Swallowability of the Study Treatment Assessed by Study Medication Palatability Assessment in Participants ≤4 Years of Age Baseline: Whole tablet · Vomited up medication	0 Participants	0 Participants
Swallowability of the Study Treatment Assessed by Study Medication Palatability Assessment in Participants ≤4 Years of Age Baseline: Whole tablet · Swallow without problem	5 Participants	8 Participants
Swallowability of the Study Treatment Assessed by Study Medication Palatability Assessment in Participants ≤4 Years of Age Baseline: Whole tablet · Some resistance but did swallow	0 Participants	0 Participants
Swallowability of the Study Treatment Assessed by Study Medication Palatability Assessment in Participants ≤4 Years of Age Baseline: Whole tablet · Spit out some/all medication	0 Participants	0 Participants
Swallowability of the Study Treatment Assessed by Study Medication Palatability Assessment in Participants ≤4 Years of Age Baseline: Dispersed tablet · Swallow without problem	1 Participants	2 Participants
Swallowability of the Study Treatment Assessed by Study Medication Palatability Assessment in Participants ≤4 Years of Age Baseline: Dispersed tablet · Some resistance but did swallow	0 Participants	0 Participants
Swallowability of the Study Treatment Assessed by Study Medication Palatability Assessment in Participants ≤4 Years of Age Baseline: Dispersed tablet · Spit out some/all medication	0 Participants	0 Participants
Swallowability of the Study Treatment Assessed by Study Medication Palatability Assessment in Participants ≤4 Years of Age Baseline: Dispersed tablet · Vomited up medication	0 Participants	0 Participants
Swallowability of the Study Treatment Assessed by Study Medication Palatability Assessment in Participants ≤4 Years of Age Month 6: Whole tablet · Swallow without problem	4 Participants	9 Participants
Swallowability of the Study Treatment Assessed by Study Medication Palatability Assessment in Participants ≤4 Years of Age Month 6: Whole tablet · Some resistance but did swallow	0 Participants	0 Participants
Swallowability of the Study Treatment Assessed by Study Medication Palatability Assessment in Participants ≤4 Years of Age Month 6: Whole tablet · Spit out some/all medication	0 Participants	0 Participants
Swallowability of the Study Treatment Assessed by Study Medication Palatability Assessment in Participants ≤4 Years of Age Month 6: Whole tablet · Vomited up medication	0 Participants	0 Participants
Swallowability of the Study Treatment Assessed by Study Medication Palatability Assessment in Participants ≤4 Years of Age Month 6: Dispersed tablet · Swallow without problem	1 Participants	1 Participants
Swallowability of the Study Treatment Assessed by Study Medication Palatability Assessment in Participants ≤4 Years of Age Month 6: Dispersed tablet · Some resistance but did swallow	0 Participants	0 Participants
Swallowability of the Study Treatment Assessed by Study Medication Palatability Assessment in Participants ≤4 Years of Age Month 6: Dispersed tablet · Spit out some/all medication	0 Participants	0 Participants
Swallowability of the Study Treatment Assessed by Study Medication Palatability Assessment in Participants ≤4 Years of Age Month 6: Dispersed tablet · Vomited up medication	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline (randomization visit) and Month 6

Population: The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available. Only participants ≥5 years of age who completed the assessment for study treatment palatability are reported.

The FHS method was used for all participants taking the study treatment who are ≥5 years of age. The FHS consists of 5 faces with descriptions ranging from "Dislike very much" to "Like very much". The face with description "Like very much" was considered as positive outcome. The way in which the study treatment was taken, that is, whether the tablet is whole or dispersed, was captured.

Outcome measures

Outcome measures
Measure	Ticagrelor 15/30/45 mg bd n=93 Participants Pediatric participants received ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The dose of ticagrelor was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of ticagrelor 15 mg (1x15 mg) bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of ticagrelor 15 mg (2x15 mg) bd. * Participants with a body weight \>48 kg received 3 tablets of ticagrelor 15 mg (3x15 mg) bd.	Placebo n=82 Participants Pediatric participants received placebo matching with ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The number of placebo tablets was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of placebo matching with ticagrelor 15 mg bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of placebo matching with ticagrelor 30 mg bd. * Participants with a body weight \>48 kg received 3 tablets of placebo matching with ticagrelor 45 mg bd.
Palatability of the Study Treatment Assessed by Facial Hedonic Scale (FHS) in Participants ≥5 Years of Age Baseline: Dispersed tablet · Not sure	1 Participants	0 Participants
Palatability of the Study Treatment Assessed by Facial Hedonic Scale (FHS) in Participants ≥5 Years of Age Baseline: Dispersed tablet · Like a little	0 Participants	1 Participants
Palatability of the Study Treatment Assessed by Facial Hedonic Scale (FHS) in Participants ≥5 Years of Age Month 6: Whole tablet · Like a little	30 Participants	20 Participants
Palatability of the Study Treatment Assessed by Facial Hedonic Scale (FHS) in Participants ≥5 Years of Age Month 6: Whole tablet · Like very much	44 Participants	47 Participants
Palatability of the Study Treatment Assessed by Facial Hedonic Scale (FHS) in Participants ≥5 Years of Age Month 6: Dispersed tablet · Dislike very much	0 Participants	—
Palatability of the Study Treatment Assessed by Facial Hedonic Scale (FHS) in Participants ≥5 Years of Age Baseline: Whole tablet · Dislike very much	3 Participants	2 Participants
Palatability of the Study Treatment Assessed by Facial Hedonic Scale (FHS) in Participants ≥5 Years of Age Baseline: Whole tablet · Dislike a little	4 Participants	2 Participants
Palatability of the Study Treatment Assessed by Facial Hedonic Scale (FHS) in Participants ≥5 Years of Age Baseline: Whole tablet · Not sure	12 Participants	8 Participants
Palatability of the Study Treatment Assessed by Facial Hedonic Scale (FHS) in Participants ≥5 Years of Age Baseline: Whole tablet · Like a little	25 Participants	23 Participants
Palatability of the Study Treatment Assessed by Facial Hedonic Scale (FHS) in Participants ≥5 Years of Age Baseline: Whole tablet · Like very much	48 Participants	45 Participants
Palatability of the Study Treatment Assessed by Facial Hedonic Scale (FHS) in Participants ≥5 Years of Age Baseline: Dispersed tablet · Dislike very much	0 Participants	0 Participants
Palatability of the Study Treatment Assessed by Facial Hedonic Scale (FHS) in Participants ≥5 Years of Age Baseline: Dispersed tablet · Dislike a little	0 Participants	0 Participants
Palatability of the Study Treatment Assessed by Facial Hedonic Scale (FHS) in Participants ≥5 Years of Age Baseline: Dispersed tablet · Like very much	0 Participants	1 Participants
Palatability of the Study Treatment Assessed by Facial Hedonic Scale (FHS) in Participants ≥5 Years of Age Month 6: Whole tablet · Dislike very much	0 Participants	0 Participants
Palatability of the Study Treatment Assessed by Facial Hedonic Scale (FHS) in Participants ≥5 Years of Age Month 6: Whole tablet · Dislike a little	5 Participants	3 Participants
Palatability of the Study Treatment Assessed by Facial Hedonic Scale (FHS) in Participants ≥5 Years of Age Month 6: Whole tablet · Not sure	4 Participants	4 Participants
Palatability of the Study Treatment Assessed by Facial Hedonic Scale (FHS) in Participants ≥5 Years of Age Month 6: Dispersed tablet · Dislike a little	0 Participants	—
Palatability of the Study Treatment Assessed by Facial Hedonic Scale (FHS) in Participants ≥5 Years of Age Month 6: Dispersed tablet · Not sure	1 Participants	—
Palatability of the Study Treatment Assessed by Facial Hedonic Scale (FHS) in Participants ≥5 Years of Age Month 6: Dispersed tablet · Like a little	0 Participants	—
Palatability of the Study Treatment Assessed by Facial Hedonic Scale (FHS) in Participants ≥5 Years of Age Month 6: Dispersed tablet · Like very much	0 Participants	—

Adverse Events

Ticagrelor 15/30/45 mg bd

Serious events: 44 serious events

Other events: 82 other events

Deaths: 3 deaths

Placebo

Serious events: 29 serious events

Other events: 71 other events

Deaths: 1 deaths

Serious adverse events

Other adverse events

Additional Information

Global Clinical Lead

AstraZeneca

Phone: 1-877-240-9479

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Ticagrelor 15/30/45 mg bd n=100 participants at risk Pediatric participants received ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The dose of ticagrelor was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of ticagrelor 15 mg (1x15 mg) bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of ticagrelor 15 mg (2x15 mg) bd. * Participants with a body weight \>48 kg received 3 tablets of ticagrelor 15 mg (3x15 mg) bd.	Placebo n=92 participants at risk Pediatric participants received placebo matching with ticagrelor 15 mg, or 30 mg, or 45 mg tablets orally bd for at least 12 months but no longer than 24 months. The number of placebo tablets was determined based on body weight at randomization: * Participants with a body weight ≥12 to ≤24 kg received 1 tablet of placebo matching with ticagrelor 15 mg bd. * Participants with a body weight \>24 to ≤48 kg received 2 tablets of placebo matching with ticagrelor 30 mg bd. * Participants with a body weight \>48 kg received 3 tablets of placebo matching with ticagrelor 45 mg bd.
Blood and lymphatic system disorders Leukocytosis	6.0% 6/100 • Number of events 6 • From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available.	3.3% 3/92 • Number of events 3 • From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available.
Blood and lymphatic system disorders Sickle cell anaemia with crisis	60.0% 60/100 • Number of events 190 • From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available.	53.3% 49/92 • Number of events 176 • From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available.
Gastrointestinal disorders Abdominal pain	15.0% 15/100 • Number of events 35 • From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available.	10.9% 10/92 • Number of events 16 • From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available.
Gastrointestinal disorders Diarrhoea	3.0% 3/100 • Number of events 5 • From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available.	5.4% 5/92 • Number of events 5 • From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available.
Gastrointestinal disorders Vomiting	6.0% 6/100 • Number of events 8 • From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available.	2.2% 2/92 • Number of events 2 • From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available.
General disorders Non-cardiac chest pain	7.0% 7/100 • Number of events 10 • From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available.	5.4% 5/92 • Number of events 5 • From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available.
General disorders Pain	5.0% 5/100 • Number of events 18 • From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available.	8.7% 8/92 • Number of events 9 • From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available.
General disorders Pyrexia	11.0% 11/100 • Number of events 15 • From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available.	10.9% 10/92 • Number of events 12 • From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available.
Infections and infestations Gastroenteritis	6.0% 6/100 • Number of events 7 • From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available.	4.3% 4/92 • Number of events 5 • From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available.
Infections and infestations Malaria	12.0% 12/100 • Number of events 15 • From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available.	7.6% 7/92 • Number of events 8 • From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available.
Infections and infestations Nasopharyngitis	4.0% 4/100 • Number of events 7 • From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available.	6.5% 6/92 • Number of events 7 • From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available.
Infections and infestations Upper respiratory tract infection	19.0% 19/100 • Number of events 28 • From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available.	26.1% 24/92 • Number of events 33 • From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available.
Infections and infestations Urinary tract infection	2.0% 2/100 • Number of events 3 • From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available.	5.4% 5/92 • Number of events 5 • From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available.
Musculoskeletal and connective tissue disorders Arthralgia	14.0% 14/100 • Number of events 17 • From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available.	15.2% 14/92 • Number of events 21 • From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available.
Musculoskeletal and connective tissue disorders Back pain	21.0% 21/100 • Number of events 28 • From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available.	13.0% 12/92 • Number of events 16 • From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available.
Musculoskeletal and connective tissue disorders Pain in extremity	28.0% 28/100 • Number of events 58 • From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available.	25.0% 23/92 • Number of events 39 • From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available.
Nervous system disorders Headache	24.0% 24/100 • Number of events 44 • From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available.	19.6% 18/92 • Number of events 33 • From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available.
Respiratory, thoracic and mediastinal disorders Cough	17.0% 17/100 • Number of events 22 • From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available.	7.6% 7/92 • Number of events 11 • From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available.
Respiratory, thoracic and mediastinal disorders Epistaxis	6.0% 6/100 • Number of events 9 • From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available.	8.7% 8/92 • Number of events 13 • From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months. The Safety Analysis Set included all participants who received at least 1 single dose of randomized study treatment, ticagrelor or placebo, and for whom any post-dose data were available.