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HESTIA3: Effect of Ticagrelor vs. Placebo in the Reduction of Vaso-occlusive Crises in Pediatric Patients With Sickle Cell Disease

Sponsor
AstraZeneca (Industry)
Overall Status
Terminated
CT.gov ID
NCT03615924
Collaborator
Iqvia Pty Ltd (Industry)
193
Enrollment
55
Locations
2
Arms
22.6
Actual Duration (Months)
3.5
Patients Per Site
0.2
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease Intervention/Treatment Phase
Phase 3

Detailed Description

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

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

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

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

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

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

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

Study Design

Study Type:
Interventional
Actual Enrollment :
193 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Triple (Participant, Care Provider, Investigator)
Primary Purpose:
Treatment
Official Title:
A Randomised, Double-Blind, Parallel-Group, Multicentre, Phase III Study to Evaluate the Effect of Ticagrelor Versus Placebo in Reducing the Rate of Vaso-Occlusive Crises in Paediatric Patients With Sickle Cell Disease (HESTIA3)
Actual Study Start Date :
Sep 26, 2018
Actual Primary Completion Date :
Aug 13, 2020
Actual Study Completion Date :
Aug 13, 2020

Arms and Interventions

Arm Intervention/Treatment
Experimental: Ticagrelor

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

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

The double-blinded study drug dose will be weight dependent: ≥12 to ≤24kg: Placebo to match ticagrelor 15 mg, twice a day >24 to ≤48 kg: Placebo to match ticagrelor 30 mg, twice a day >48 kg: Placebo to match ticagrelor 45 mg, twice a day.

Drug: Placebo
The double-blinded study drug dose will be weight dependent: ≥12 to ≤24kg: Placebo to match ticagrelor 15 mg, twice a day >24 to ≤48 kg: Placebo to match ticagrelor 30 mg, twice a day >48 kg: Placebo to match ticagrelor 45 mg, twice a day.

Outcome Measures

Primary Outcome Measures

  1. Number of Vaso-Occlusive Crisis Events [From randomization (Day 0) up to end of study (EOS) visit or date of premature study discontinuation, up to approximately 20 months]

    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.

Secondary Outcome Measures

  1. Number of Painful Crisis Events [From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months]

    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.

  2. Number of Acute Chest Syndrome Events [From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months]

    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.

  3. Duration of Painful Crises [From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months]

    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.

  4. Number of Vaso-Occlusive Crisis Events Requiring Hospitalization or Emergency Department Visits [From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months]

    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.

  5. Number of Days Hospitalized for Vaso-Occlusive Crisis Events [From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months]

    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.

  6. Number of Acute Sickle Cell Disease Complications [From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months]

    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.

  7. Number of Days Hospitalized for Acute Sickle Cell Disease Complications [From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months]

    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.

  8. Number of Sickle Cell-Related Red Blood Cell (RBC) Transfusions [From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months]

    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.

  9. Health-Related Quality of Life Total Score Using the Pediatric Quality of Life Inventory (PedsQL) Sickle Cell Disease Module [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]

    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.

  10. Fatigue Total Score Using Pediatric Quality of Life Inventory Multidimensional Fatigue Scale [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]

    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.

  11. Percentage of Days of Absence From School or Work Due to Sickle Cell Disease [From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months]

    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).

  12. Average Intensity of Worst Pain Daily During Vaso-Occlusive Crisis Events in Participants <5 Years of Age [From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months]

    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.

  13. Average Intensity of Worst Pain Daily During Vaso-Occlusive Crisis Events in Participants ≥5 Years of Age [From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months]

    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.

  14. Type of Analgesics Used by Participants During Vaso-Occlusive Crisis Events [From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months]

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

  15. Palatability of the Study Treatment Assessed by Study Medication Palatability Assessment (SMPA) in Participants ≤4 Years of Age [Baseline (randomization visit) and Month 6]

    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.

  16. Swallowability of the Study Treatment Assessed by Study Medication Palatability Assessment in Participants ≤4 Years of Age [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.

  17. Palatability of the Study Treatment Assessed by Facial Hedonic Scale (FHS) in Participants ≥5 Years of Age [Baseline (randomization visit) and Month 6]

    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.

Eligibility Criteria

Criteria

Ages Eligible for Study:
2 Years to 17 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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.

  1. 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.

  2. 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.

  3. 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.

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

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

  6. 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.

  7. 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.

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

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

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

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

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

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

  7. 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).

  8. Renal failure requiring dialysis

  9. 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.

  10. 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.

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

  12. Known hypersensitivity or contraindication to ticagrelor

  13. 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)

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

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

  16. Previous randomisation in the present study.

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

  18. 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).

Contacts and Locations

Locations

Site City State Country Postal Code
1 Research Site Fort Lauderdale Florida United States 33316
2 Research Site Miami Florida United States 33155
3 Research Site Chicago Illinois United States 60612
4 Research Site Oak Lawn Illinois United States 60453
5 Research Site Las Vegas Nevada United States 89135
6 Research Site Brooklyn New York United States 11212
7 Research Site Charleston South Carolina United States 29425
8 Research Site Brussel Belgium 1200
9 Research Site Edegem Belgium 2650
10 Research Site Porto Alegre Brazil 90035-903
11 Research Site Rio de Janeiro Brazil 20211-080
12 Research Site Salvador Brazil 41253-190
13 Research Site São Paulo Brazil 01221010
14 Research Site São Paulo Brazil 08270-070
15 Research Site Al Sharkeya Egypt 44519
16 Research Site Alexandria Egypt 21131
17 Research Site Cairo Egypt 11521
18 Research Site Cairo Egypt 11566
19 Research Site Cairo Egypt 12655
20 Research Site Dakahlia Egypt 35516
21 Research Site Accra Ghana 233
22 Research Site Ho Ghana 0
23 Research Site Kumasi Ghana 1934
24 Research Site Athens Greece 11521
25 Research Site Mumbai India 400053
26 Research Site Nagpur India 440003
27 Research Site Nagpur India 440012
28 Research Site Pune India 411001
29 Research Site Pune India 411004
30 Research Site Wardha India 442004
31 Research Site Catania Italy 95123
32 Research Site Naples Italy 80138
33 Research Site Padova Italy 35128
34 Research Site Verona Italy 37126
35 Research Site Kisumu Kenya 40100
36 Research Site Nairobi Kenya 00200
37 Research Site Siaya Kenya 40600
38 Research Site Beirut Lebanon 11-0236
39 Research Site Tripoli Lebanon 961
40 Research Site Cape Town South Africa 7700
41 Research Site Soweto South Africa 2013
42 Research Site Barakaldo Spain 48903
43 Research Site Barcelona Spain 08035
44 Research Site Madrid Spain 28007
45 Research Site Madrid Spain 28009
46 Research Site Mbeya Tanzania 2410
47 Research Site Antalya Turkey 7070
48 Research Site Mersin Turkey 33343
49 Research Site Seyhan Turkey 01130
50 Research Site Kampala Uganda 10005
51 Research Site Masaka Uganda 0000
52 Research Site Cardiff United Kingdom CF14 4XW
53 Research Site Glasgow United Kingdom G51 4TF
54 Research Site London United Kingdom E1 1BB
55 Research Site London United Kingdom SE1 7EH

Sponsors and Collaborators

  • AstraZeneca
  • Iqvia Pty Ltd

Investigators

  • Study Director: Anders Berggren, MD, PhD, AstraZeneca
  • Principal Investigator: Matthew Heeney, MD, Harvard Medical School (HMS and HSDM)

Study Documents (Full-Text)

More Information

Additional Information:

Publications

None provided.
Responsible Party:
AstraZeneca
ClinicalTrials.gov Identifier:
NCT03615924
Other Study ID Numbers:
  • D5136C00009
First Posted:
Aug 6, 2018
Last Update Posted:
Apr 9, 2021
Last Verified:
Mar 1, 2021
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Product Manufactured in and Exported from the U.S.:
No
Keywords provided by AstraZeneca
Sickle Cell Disease
Sickle Cell Anemia
SCD
Platelet aggregation
Ticagrelor
Brilinta
VOC
Vaso-Occlusive Crises
ACS
painful crisis
Additional relevant MeSH terms:
Anemia, Sickle Cell
Ticagrelor

Study Results

Participant Flow

Recruitment Details 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.
Pre-assignment Detail 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.
Arm/Group Title Ticagrelor 15/30/45 mg bd Placebo
Arm/Group Description 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. 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.
Period Title: Overall Study
STARTED 101 92
Received Treatment 101 92
COMPLETED 0 0
NOT COMPLETED 101 92

Baseline Characteristics

Arm/Group Title Ticagrelor 15/30/45 mg bd Placebo Total
Arm/Group Description 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. 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 of all reporting groups
Overall Participants 101 92 193
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
10.40
(4.128)
10.12
(3.799)
10.26
(3.967)
Age, Customized (Count of Participants)
≥2 to <12 years
61
60.4%
54
58.7%
115
59.6%
>=12 to <18 years
40
39.6%
38
41.3%
78
40.4%
Sex: Female, Male (Count of Participants)
Female
48
47.5%
43
46.7%
91
47.2%
Male
53
52.5%
49
53.3%
102
52.8%
Race/Ethnicity, Customized (Count of Participants)
White
25
24.8%
21
22.8%
46
23.8%
Black or African American
60
59.4%
51
55.4%
111
57.5%
Asian
15
14.9%
15
16.3%
30
15.5%
Other
1
1%
5
5.4%
6
3.1%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino
7
6.9%
5
5.4%
12
6.2%
Not Hispanic or Latino
94
93.1%
87
94.6%
181
93.8%

Outcome Measures

1. Primary Outcome
Title Number of Vaso-Occlusive Crisis Events
Description 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.
Time Frame From randomization (Day 0) up to end of study (EOS) visit or date of premature study discontinuation, up to approximately 20 months

Outcome Measure Data

Analysis Population Description
The FAS included all randomized participants regardless of treatment received.
Arm/Group Title Ticagrelor 15/30/45 mg bd Placebo
Arm/Group Description 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. 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.
Measure Participants 101 92
Number [VOC events]
249
202
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ticagrelor 15/30/45 mg bd, Placebo
Comments Incidence rates, incidence rate ratios, and p-values are from a negative binomial model analysis, with treatment group and baseline hydroxyurea use included in the model as covariates.
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.7597
Comments
Method Negative binomial model
Comments
Method of Estimation Estimation Parameter Incidence rate ratio
Estimated Value 1.06
Confidence Interval (2-Sided) 95%
0.75 to 1.50
Parameter Dispersion Type:
Value:
Estimation Comments
2. Secondary Outcome
Title Number of Painful Crisis Events
Description 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.
Time Frame From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months

Outcome Measure Data

Analysis Population Description
The FAS included all randomized participants regardless of treatment received.
Arm/Group Title Ticagrelor 15/30/45 mg bd Placebo
Arm/Group Description 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. 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.
Measure Participants 101 92
Number [painful crisis events]
248
209
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ticagrelor 15/30/45 mg bd, Placebo
Comments Incidence rates, incidence rate ratios, and p-values are from a negative binomial model analysis, with treatment group and baseline hydroxyurea use included in the model as covariates.
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.9037
Comments
Method Negative binomial model
Comments
Method of Estimation Estimation Parameter Incidence rate ratio
Estimated Value 1.02
Confidence Interval (2-Sided) 95%
0.72 to 1.45
Parameter Dispersion Type:
Value:
Estimation Comments
3. Secondary Outcome
Title Number of Acute Chest Syndrome Events
Description 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.
Time Frame From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months

Outcome Measure Data

Analysis Population Description
The FAS included all randomized participants regardless of treatment received.
Arm/Group Title Ticagrelor 15/30/45 mg bd Placebo
Arm/Group Description 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. 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.
Measure Participants 101 92
Number [ACS events]
6
6
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ticagrelor 15/30/45 mg bd, Placebo
Comments Incidence rates, incidence rate ratios, and p-values are from a negative binomial model analysis, with treatment group and baseline hydroxyurea use included in the model as covariates.
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.7136
Comments
Method Negative binomial model
Comments
Method of Estimation Estimation Parameter Incidence rate ratio
Estimated Value 0.76
Confidence Interval (2-Sided) 95%
0.17 to 3.30
Parameter Dispersion Type:
Value:
Estimation Comments
4. Secondary Outcome
Title Duration of Painful Crises
Description 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.
Time Frame From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months

Outcome Measure Data

Analysis Population Description
The FAS included all randomized participants regardless of treatment received.
Arm/Group Title Ticagrelor 15/30/45 mg bd Placebo
Arm/Group Description 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. 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.
Measure Participants 101 92
Number [days]
1476
1441
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ticagrelor 15/30/45 mg bd, Placebo
Comments Incidence rates, incidence rate ratios, and p-values are from a negative binomial model analysis, with treatment group and baseline hydroxyurea use included in the model as covariates.
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.4970
Comments
Method Negative binomial model
Comments
Method of Estimation Estimation Parameter Incidence rate ratio
Estimated Value 0.84
Confidence Interval (2-Sided) 95%
0.50 to 1.40
Parameter Dispersion Type:
Value:
Estimation Comments
5. Secondary Outcome
Title Number of Vaso-Occlusive Crisis Events Requiring Hospitalization or Emergency Department Visits
Description 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.
Time Frame From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months

Outcome Measure Data

Analysis Population Description
The FAS included all randomized participants regardless of treatment received.
Arm/Group Title Ticagrelor 15/30/45 mg bd Placebo
Arm/Group Description 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. 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.
Measure Participants 101 92
Number [VOC events requiring hospitalization]
87
51
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ticagrelor 15/30/45 mg bd, Placebo
Comments Incidence rates, incidence rate ratios, and p-values are from a negative binomial model analysis, with treatment group and baseline hydroxyurea use included in the model as covariates.
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.1636
Comments
Method Negative binomial model
Comments
Method of Estimation Estimation Parameter Incidence rate ratio
Estimated Value 1.43
Confidence Interval (2-Sided) 95%
0.87 to 2.36
Parameter Dispersion Type:
Value:
Estimation Comments
6. Secondary Outcome
Title Number of Days Hospitalized for Vaso-Occlusive Crisis Events
Description 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.
Time Frame From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months

Outcome Measure Data

Analysis Population Description
The FAS included all randomized participants regardless of treatment received.
Arm/Group Title Ticagrelor 15/30/45 mg bd Placebo
Arm/Group Description 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. 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.
Measure Participants 101 92
Number [days]
526
256
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ticagrelor 15/30/45 mg bd, Placebo
Comments Incidence rates, incidence rate ratios, and p-values are from a negative binomial model analysis, with treatment group and baseline hydroxyurea use included in the model as covariates.
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.2011
Comments
Method Negative binomial model
Comments
Method of Estimation Estimation Parameter Incidence rate ratio
Estimated Value 1.68
Confidence Interval (2-Sided) 95%
0.76 to 3.75
Parameter Dispersion Type:
Value:
Estimation Comments
7. Secondary Outcome
Title Number of Acute Sickle Cell Disease Complications
Description 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.
Time Frame From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months

Outcome Measure Data

Analysis Population Description
The FAS included all randomized participants regardless of treatment received.
Arm/Group Title Ticagrelor 15/30/45 mg bd Placebo
Arm/Group Description 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. 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.
Measure Participants 101 92
Number [acute SCD complications]
6
3
8. Secondary Outcome
Title Number of Days Hospitalized for Acute Sickle Cell Disease Complications
Description 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.
Time Frame From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months

Outcome Measure Data

Analysis Population Description
The FAS included all randomized participants regardless of treatment received.
Arm/Group Title Ticagrelor 15/30/45 mg bd Placebo
Arm/Group Description 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. 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.
Measure Participants 101 92
Number [days]
0
6
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ticagrelor 15/30/45 mg bd, Placebo
Comments Incidence rates, incidence rate ratios, and p-values are from a negative binomial model analysis, with treatment group and baseline hydroxyurea use included in the model as covariates.
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.9940
Comments
Method Negative binomial model
Comments
Method of Estimation Estimation Parameter Incidence rate ratio
Estimated Value 0.00
Confidence Interval (2-Sided) 95%
0.00 to
Parameter Dispersion Type:
Value:
Estimation Comments
9. Secondary Outcome
Title Number of Sickle Cell-Related Red Blood Cell (RBC) Transfusions
Description 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.
Time Frame From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months

Outcome Measure Data

Analysis Population Description
The FAS included all randomized participants regardless of treatment received.
Arm/Group Title Ticagrelor 15/30/45 mg bd Placebo
Arm/Group Description 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. 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.
Measure Participants 101 92
Number [RBC transfusions]
39
49
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ticagrelor 15/30/45 mg bd, Placebo
Comments Incidence rates, incidence rate ratios, and p-values are from a negative binomial model analysis, with treatment group and baseline hydroxyurea use included in the model as covariates.
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.4822
Comments
Method Negative binomial model
Comments
Method of Estimation Estimation Parameter Incidence rate ratio
Estimated Value 0.77
Confidence Interval (2-Sided) 95%
0.38 to 1.58
Parameter Dispersion Type:
Value:
Estimation Comments
10. Secondary Outcome
Title Health-Related Quality of Life Total Score Using the Pediatric Quality of Life Inventory (PedsQL) Sickle Cell Disease Module
Description 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.
Time Frame 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

Outcome Measure Data

Analysis Population Description
The FAS included all randomized participants regardless of treatment received. Only number of participants included in analysis at each time point are reported.
Arm/Group Title Ticagrelor 15/30/45 mg bd Placebo
Arm/Group Description 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. 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.
Measure Participants 101 92
>=2 to <5 years: Baseline
88.81
(14.107)
67.02
(20.041)
>=2 to <5 years: Month 6
80.75
(20.779)
81.37
(14.125)
>=2 to <5 years: Month 12
88.10
(NA)
>=5 to <8 years: Baseline
75.05
(20.147)
74.04
(21.646)
>=5 to <8 years: Month 6
83.04
(15.332)
84.91
(18.117)
>=5 to <8 years: Month 12
65.63
(48.614)
97.50
(NA)
>=8 to <13 years: Baseline
62.35
(24.725)
67.98
(24.338)
>=8 to <13 years: Month 6
76.52
(17.189)
75.76
(21.749)
>=8 to <13 years: Month 12
83.20
(13.479)
64.12
(27.253)
>=8 to <13 years: Month 18
86.05
(NA)
>=13 to <=18 years: Baseline
64.45
(18.746)
60.81
(24.979)
>=13 to <=18 years: Month 6
68.13
(16.811)
74.42
(19.146)
>=13 to <=18 years: Month 12
63.05
(19.810)
73.26
(22.589)
>=13 to <=18 years: Month 18
65.12
(NA)
11. Secondary Outcome
Title Fatigue Total Score Using Pediatric Quality of Life Inventory Multidimensional Fatigue Scale
Description 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.
Time Frame 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

Outcome Measure Data

Analysis Population Description
The FAS included all randomized participants regardless of treatment received. Only number of participants included in analysis at each time point are reported.
Arm/Group Title Ticagrelor 15/30/45 mg bd Placebo
Arm/Group Description 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. 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.
Measure Participants 101 92
>=2 to <5 years: Baseline
88.06
(16.304)
70.56
(23.220)
>=2 to <5 years: Month 6
84.44
(15.541)
81.94
(22.775)
>=2 to <5 years: Month 12
94.44
(NA)
>=5 to <8 years: Baseline
82.33
(11.450)
84.13
(16.139)
>=5 to <8 years: Month 6
87.12
(10.553)
87.70
(16.076)
>=5 to <8 years: Month 12
95.83
(5.893)
100.00
(NA)
>=8 to <13 years: Baseline
64.72
(26.779)
69.51
(25.261)
>=8 to <13 years: Month 6
75.65
(18.571)
77.89
(22.283)
>=8 to <13 years: Month 12
81.48
(17.866)
65.87
(25.495)
>=8 to <13 years: Month 18
73.61
(NA)
>=13 to <=18 years: Baseline
68.06
(21.781)
67.17
(18.223)
>=13 to <=18 years: Month 6
73.53
(19.138)
75.21
(14.913)
>=13 to <=18 years: Month 12
67.13
(22.556)
60.28
(23.664)
>=13 to <=18 years: Month 18
72.22
(NA)
12. Secondary Outcome
Title Percentage of Days of Absence From School or Work Due to Sickle Cell Disease
Description 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).
Time Frame From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months

Outcome Measure Data

Analysis Population Description
The FAS included all randomized participants regardless of treatment received. Only participants going to school or work at randomization are reported.
Arm/Group Title Ticagrelor 15/30/45 mg bd Placebo
Arm/Group Description 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. 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.
Measure Participants 94 82
Mean (Standard Deviation) [percentage of days]
5.24
(8.942)
4.24
(4.964)
13. Secondary Outcome
Title Average Intensity of Worst Pain Daily During Vaso-Occlusive Crisis Events in Participants <5 Years of Age
Description 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.
Time Frame From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title Ticagrelor 15/30/45 mg bd Placebo
Arm/Group Description 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. 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.
Measure Participants 3 5
Mean (Standard Deviation) [score on a scale]
3.4
(2.51)
2.9
(1.99)
14. Secondary Outcome
Title Average Intensity of Worst Pain Daily During Vaso-Occlusive Crisis Events in Participants ≥5 Years of Age
Description 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.
Time Frame From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title Ticagrelor 15/30/45 mg bd Placebo
Arm/Group Description 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. 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.
Measure Participants 44 40
Mean (Standard Deviation) [score on a scale]
4.5
(2.71)
4.1
(2.02)
15. Secondary Outcome
Title Type of Analgesics Used by Participants During Vaso-Occlusive Crisis Events
Description Analgesics use (opioid and non-opioid) during VOC events.
Time Frame From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months

Outcome Measure Data

Analysis Population Description
The FAS included all randomized participants regardless of treatment received. Only participants who had at least one VOC and took an analgesic are reported.
Arm/Group Title Ticagrelor 15/30/45 mg bd Placebo
Arm/Group Description 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. 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.
Measure Participants 70 58
Opioids: Yes
46
45.5%
22
23.9%
Opioids: No
57
56.4%
50
54.3%
Non-opioids: Yes
69
68.3%
57
62%
Non-opioids: No
14
13.9%
7
7.6%
16. Secondary Outcome
Title Palatability of the Study Treatment Assessed by Study Medication Palatability Assessment (SMPA) in Participants ≤4 Years of Age
Description 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.
Time Frame Baseline (randomization visit) and Month 6

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title Ticagrelor 15/30/45 mg bd Placebo
Arm/Group Description 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. 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.
Measure Participants 6 10
Negative response to palatability - No
5
5%
8
8.7%
Negative response to palatability - Yes
0
0%
0
0%
Negative response to palatability - No
1
1%
2
2.2%
Negative response to palatability - Yes
0
0%
0
0%
Negative response to palatability - No
4
4%
9
9.8%
Negative response to palatability - Yes
0
0%
0
0%
Negative response to palatability - No
1
1%
1
1.1%
Negative response to palatability - Yes
0
0%
0
0%
17. Secondary Outcome
Title Swallowability of the Study Treatment Assessed by Study Medication Palatability Assessment in Participants ≤4 Years of Age
Description 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.
Time Frame Baseline (randomization visit) and Month 6

Outcome Measure Data

Analysis Population Description
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 swallowability are reported.
Arm/Group Title Ticagrelor 15/30/45 mg bd Placebo
Arm/Group Description 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. 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.
Measure Participants 6 10
Swallow without problem
5
5%
8
8.7%
Some resistance but did swallow
0
0%
0
0%
Spit out some/all medication
0
0%
0
0%
Vomited up medication
0
0%
0
0%
Swallow without problem
1
1%
2
2.2%
Some resistance but did swallow
0
0%
0
0%
Spit out some/all medication
0
0%
0
0%
Vomited up medication
0
0%
0
0%
Swallow without problem
4
4%
9
9.8%
Some resistance but did swallow
0
0%
0
0%
Spit out some/all medication
0
0%
0
0%
Vomited up medication
0
0%
0
0%
Swallow without problem
1
1%
1
1.1%
Some resistance but did swallow
0
0%
0
0%
Spit out some/all medication
0
0%
0
0%
Vomited up medication
0
0%
0
0%
18. Secondary Outcome
Title Palatability of the Study Treatment Assessed by Facial Hedonic Scale (FHS) in Participants ≥5 Years of Age
Description 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.
Time Frame Baseline (randomization visit) and Month 6

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title Ticagrelor 15/30/45 mg bd Placebo
Arm/Group Description 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. 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.
Measure Participants 93 82
Dislike very much
3
3%
2
2.2%
Dislike a little
4
4%
2
2.2%
Not sure
12
11.9%
8
8.7%
Like a little
25
24.8%
23
25%
Like very much
48
47.5%
45
48.9%
Dislike very much
0
0%
0
0%
Dislike a little
0
0%
0
0%
Not sure
1
1%
0
0%
Like a little
0
0%
1
1.1%
Like very much
0
0%
1
1.1%
Dislike very much
0
0%
0
0%
Dislike a little
5
5%
3
3.3%
Not sure
4
4%
4
4.3%
Like a little
30
29.7%
20
21.7%
Like very much
44
43.6%
47
51.1%
Dislike very much
0
0%
Dislike a little
0
0%
Not sure
1
1%
Like a little
0
0%
Like very much
0
0%

Adverse Events

Time Frame From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months.
Adverse Event Reporting Description 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.
Arm/Group Title Ticagrelor 15/30/45 mg bd Placebo
Arm/Group Description 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. 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.
All Cause Mortality
Ticagrelor 15/30/45 mg bd Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 3/100 (3%) 1/92 (1.1%)
Serious Adverse Events
Ticagrelor 15/30/45 mg bd Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 44/100 (44%) 29/92 (31.5%)
Blood and lymphatic system disorders
Anaemia 6/100 (6%) 7 7/92 (7.6%) 13
Hypersplenism 0/100 (0%) 0 3/92 (3.3%) 4
Pancytopenia 0/100 (0%) 0 1/92 (1.1%) 1
Sickle cell anaemia with crisis 39/100 (39%) 75 24/92 (26.1%) 41
Gastrointestinal disorders
Abdominal distension 0/100 (0%) 0 1/92 (1.1%) 1
Constipation 2/100 (2%) 2 0/92 (0%) 0
General disorders
Pyrexia 2/100 (2%) 2 3/92 (3.3%) 4
Sudden death 1/100 (1%) 1 0/92 (0%) 0
Infections and infestations
Atypical pneumonia 1/100 (1%) 1 0/92 (0%) 0
Bronchitis 1/100 (1%) 2 1/92 (1.1%) 1
Cellulitis 3/100 (3%) 3 0/92 (0%) 0
Gastroenteritis 0/100 (0%) 0 1/92 (1.1%) 1
Influenza 0/100 (0%) 0 2/92 (2.2%) 3
Malaria 4/100 (4%) 4 1/92 (1.1%) 2
Meningitis 1/100 (1%) 1 0/92 (0%) 0
Nasopharyngitis 1/100 (1%) 1 0/92 (0%) 0
Pharyngotonsillitis 1/100 (1%) 1 0/92 (0%) 0
Pneumonia 4/100 (4%) 4 0/92 (0%) 0
Respiratory syncytial virus infection 0/100 (0%) 0 1/92 (1.1%) 1
Respiratory tract infection viral 1/100 (1%) 1 0/92 (0%) 0
Sepsis 6/100 (6%) 6 1/92 (1.1%) 1
Upper respiratory tract infection 1/100 (1%) 1 0/92 (0%) 0
Urinary tract infection 0/100 (0%) 0 1/92 (1.1%) 1
Viral infection 1/100 (1%) 1 0/92 (0%) 0
Injury, poisoning and procedural complications
Jaw fracture 1/100 (1%) 1 0/92 (0%) 0
Post-traumatic pain 1/100 (1%) 1 0/92 (0%) 0
Road traffic accident 1/100 (1%) 1 0/92 (0%) 0
Investigations
Haemoglobin decreased 0/100 (0%) 0 1/92 (1.1%) 1
Musculoskeletal and connective tissue disorders
Osteonecrosis 2/100 (2%) 2 1/92 (1.1%) 1
Nervous system disorders
Cerebrovascular accident 1/100 (1%) 1 0/92 (0%) 0
Respiratory, thoracic and mediastinal disorders
Atelectasis 1/100 (1%) 1 0/92 (0%) 0
Bronchospasm 1/100 (1%) 1 0/92 (0%) 0
Skin and subcutaneous tissue disorders
Pemphigoid 1/100 (1%) 1 0/92 (0%) 0
Other (Not Including Serious) Adverse Events
Ticagrelor 15/30/45 mg bd Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 82/100 (82%) 71/92 (77.2%)
Blood and lymphatic system disorders
Leukocytosis 6/100 (6%) 6 3/92 (3.3%) 3
Sickle cell anaemia with crisis 60/100 (60%) 190 49/92 (53.3%) 176
Gastrointestinal disorders
Abdominal pain 15/100 (15%) 35 10/92 (10.9%) 16
Diarrhoea 3/100 (3%) 5 5/92 (5.4%) 5
Vomiting 6/100 (6%) 8 2/92 (2.2%) 2
General disorders
Non-cardiac chest pain 7/100 (7%) 10 5/92 (5.4%) 5
Pain 5/100 (5%) 18 8/92 (8.7%) 9
Pyrexia 11/100 (11%) 15 10/92 (10.9%) 12
Infections and infestations
Gastroenteritis 6/100 (6%) 7 4/92 (4.3%) 5
Malaria 12/100 (12%) 15 7/92 (7.6%) 8
Nasopharyngitis 4/100 (4%) 7 6/92 (6.5%) 7
Upper respiratory tract infection 19/100 (19%) 28 24/92 (26.1%) 33
Urinary tract infection 2/100 (2%) 3 5/92 (5.4%) 5
Musculoskeletal and connective tissue disorders
Arthralgia 14/100 (14%) 17 14/92 (15.2%) 21
Back pain 21/100 (21%) 28 12/92 (13%) 16
Pain in extremity 28/100 (28%) 58 23/92 (25%) 39
Nervous system disorders
Headache 24/100 (24%) 44 18/92 (19.6%) 33
Respiratory, thoracic and mediastinal disorders
Cough 17/100 (17%) 22 7/92 (7.6%) 11
Epistaxis 6/100 (6%) 9 8/92 (8.7%) 13

Limitations/Caveats

AstraZeneca took the decision to terminate the study early, following a recommendation from the independent Data Monitoring Committee. This early termination was not considered to have had an impact on the robustness of the study results.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Name/Title Global Clinical Lead
Organization AstraZeneca
Phone 1-877-240-9479
Email information.center@astrazeneca.com
Responsible Party:
AstraZeneca
ClinicalTrials.gov Identifier:
NCT03615924
Other Study ID Numbers:
  • D5136C00009
First Posted:
Aug 6, 2018
Last Update Posted:
Apr 9, 2021
Last Verified:
Mar 1, 2021