Clinical Trial Results:
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)
Summary
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EudraCT number |
2017-002421-38 |
Trial protocol |
GB ES BE GR IT |
Global end of trial date |
13 Aug 2020
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Results information
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Results version number |
v2(current) |
This version publication date |
09 May 2021
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First version publication date |
22 Feb 2021
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Other versions |
v1 |
Version creation reason |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
D5136C00009
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03615924 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
AstraZeneca
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Sponsor organisation address |
Karlebyhusentren, B674 Astraallen, Södertälje, Sweden, SE-151 85
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Public contact |
Global Clinical Lead, AstraZeneca, +1 877-240-9479, information.center@astrazeneca.com
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Scientific contact |
Global Clinical Lead, AstraZeneca, +1 877-240-9479, information.center@astrazeneca.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-000480-PIP01-08 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
23 Sep 2020
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
13 Aug 2020
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
To compare the effect of ticagrelor versus (Vs) placebo for the reduction of vaso-occlusive crisis (VOC), which is the composite of painful crisis and/or acute chest syndrome (ACS), in paediatric participants with sickle cell disease (SCD).
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Protection of trial subjects |
This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Council for Harmonisation/Good Clinical Practice, applicable regulatory requirements (including those for conducting trials with paediatric populations) and the AstraZeneca policy on Bioethics. The data monitoring committee was responsible for safeguarding the interests of the participants in the study by assessing the safety of the intervention during the study, and for reviewing the overall conduct of the clinical study.
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Background therapy |
Participants were to receive standard of care for SCD adjusted to the individual participant at the discretion of the Investigator. If a participant was treated with hydroxyurea, the weight-adjusted dose had to be stable for 3 months before enrolment. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
26 Sep 2018
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Kenya: 55
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Country: Number of subjects enrolled |
India: 30
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Country: Number of subjects enrolled |
Uganda: 26
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Country: Number of subjects enrolled |
Egypt: 18
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Country: Number of subjects enrolled |
Lebanon: 15
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Country: Number of subjects enrolled |
Ghana: 5
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Country: Number of subjects enrolled |
South Africa: 2
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Country: Number of subjects enrolled |
Tanzania, United Republic of: 1
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Country: Number of subjects enrolled |
United Kingdom: 7
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Country: Number of subjects enrolled |
Turkey: 6
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Country: Number of subjects enrolled |
Spain: 5
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Country: Number of subjects enrolled |
Italy: 4
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Country: Number of subjects enrolled |
Belgium: 2
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Country: Number of subjects enrolled |
Greece: 1
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Country: Number of subjects enrolled |
Brazil: 8
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Country: Number of subjects enrolled |
United States: 8
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Worldwide total number of subjects |
193
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EEA total number of subjects |
12
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
115
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Adolescents (12-17 years) |
78
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
This Phase III study was conducted in paediatric participants with SCD at 53 sites in 16 countries between 26 September 2018 and 13 August 2020. Paediatric participants who experienced at least two VOC events in the past 12 months prior to screening and who fulfilled the eligibility criteria were enrolled. | ||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
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. | ||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Carer, Monitor, Data analyst, Assessor | ||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Ticagrelor 15/30/45 mg bd | ||||||||||||||||||||||||||||||
Arm description |
Paediatric 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. | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Ticagrelor
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Investigational medicinal product code |
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Other name |
BRILINTA™, BRILIQUE™
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Participants with a body weight ≥12 to ≤24 kg: 1 tablet of ticagrelor 15 mg orally bd.
Participants with a body weight >24 to ≤48 kg: 2 tablets of ticagrelor 15 mg orally bd.
Participants with a body weight >48 kg: 3 tablets of ticagrelor 15 mg orally bd.
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Arm title
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Placebo | ||||||||||||||||||||||||||||||
Arm description |
Paediatric 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. | ||||||||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Participants with a body weight ≥12 to ≤24 kg: 1 tablet of placebo matching with ticagrelor 15 mg orally bd.
Participants with a body weight >24 to ≤48 kg: 2 tablets of placebo matching with ticagrelor 30 mg orally bd.
Participants with a body weight >48 kg: 3 tablets of placebo matching with ticagrelor 45 mg orally bd.
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Baseline characteristics reporting groups
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Reporting group title |
Ticagrelor 15/30/45 mg bd
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Reporting group description |
Paediatric 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Paediatric 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Ticagrelor 15/30/45 mg bd
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Reporting group description |
Paediatric 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. | ||
Reporting group title |
Placebo
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Reporting group description |
Paediatric 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. |
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End point title |
Number of Vaso-Occlusive Crisis Events | |||||||||
End point 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. The FAS included all randomized participants regardless of treatment received.
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End point type |
Primary
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End point timeframe |
From randomization (Day 0) up to end of study (EOS) visit or date of premature study discontinuation, up to approximately 20 months
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Statistical analysis title |
Treatment comparison: Ticagrelor Vs Placebo | |||||||||
Statistical analysis description |
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.
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Comparison groups |
Ticagrelor 15/30/45 mg bd v Placebo
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Number of subjects included in analysis |
193
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
= 0.7597 | |||||||||
Method |
Negative binomial model | |||||||||
Parameter type |
Incidence rate ratio | |||||||||
Point estimate |
1.06
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.75 | |||||||||
upper limit |
1.5 |
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End point title |
Number of Painful Crisis Events | |||||||||
End point 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. The FAS included all randomized participants regardless of treatment received.
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End point type |
Secondary
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End point timeframe |
From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months
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Statistical analysis title |
Treatment comparison: Ticagrelor Vs Placebo | |||||||||
Statistical analysis description |
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.
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Comparison groups |
Ticagrelor 15/30/45 mg bd v Placebo
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Number of subjects included in analysis |
193
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
= 0.9037 | |||||||||
Method |
Negative binomial model | |||||||||
Parameter type |
Incidence rate ratio | |||||||||
Point estimate |
1.02
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.72 | |||||||||
upper limit |
1.45 |
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End point title |
Number of Acute Chest Syndrome Events | |||||||||
End point 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. The FAS included all randomized participants regardless of treatment received.
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End point type |
Secondary
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End point timeframe |
From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months
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Statistical analysis title |
Treatment comparison: Ticagrelor Vs Placebo | |||||||||
Statistical analysis description |
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.
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Comparison groups |
Ticagrelor 15/30/45 mg bd v Placebo
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Number of subjects included in analysis |
193
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
= 0.7136 | |||||||||
Method |
Negative binomial model | |||||||||
Parameter type |
Incidence rate ratio | |||||||||
Point estimate |
0.76
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.17 | |||||||||
upper limit |
3.3 |
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End point title |
Duration of Painful Crises | |||||||||
End point 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. The FAS included all randomized participants regardless of treatment received.
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End point type |
Secondary
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End point timeframe |
From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months
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Statistical analysis title |
Treatment comparison: Ticagrelor Vs Placebo | |||||||||
Statistical analysis description |
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.
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Comparison groups |
Ticagrelor 15/30/45 mg bd v Placebo
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Number of subjects included in analysis |
193
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
= 0.497 | |||||||||
Method |
Negative binomial model | |||||||||
Parameter type |
Incidence rate ratio | |||||||||
Point estimate |
0.84
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.5 | |||||||||
upper limit |
1.4 |
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End point title |
Number of Vaso-Occlusive Crisis Events Requiring Hospitalization or Emergency Department Visits | |||||||||
End point 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. The FAS included all randomized participants regardless of treatment received.
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End point type |
Secondary
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End point timeframe |
From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months
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Statistical analysis title |
Treatment comparison: Ticagrelor Vs Placebo | |||||||||
Statistical analysis description |
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.
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Comparison groups |
Ticagrelor 15/30/45 mg bd v Placebo
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Number of subjects included in analysis |
193
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
= 0.1636 | |||||||||
Method |
Negative binomial model | |||||||||
Parameter type |
Incidence rate ratio | |||||||||
Point estimate |
1.43
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.87 | |||||||||
upper limit |
2.36 |
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End point title |
Number of Days Hospitalized for Vaso-Occlusive Crisis Events | |||||||||
End point 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. The FAS included all randomized participants regardless of treatment received.
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End point type |
Secondary
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End point timeframe |
From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months
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Statistical analysis title |
Treatment comparison: Ticagrelor Vs Placebo | |||||||||
Statistical analysis description |
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.
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Comparison groups |
Ticagrelor 15/30/45 mg bd v Placebo
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Number of subjects included in analysis |
193
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
= 0.2011 | |||||||||
Method |
Negative binomial model | |||||||||
Parameter type |
Incidence rate ratio | |||||||||
Point estimate |
1.68
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.76 | |||||||||
upper limit |
3.75 |
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End point title |
Number of Acute Sickle Cell Disease Complications | |||||||||
End point 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. The FAS included all randomized participants regardless of treatment received.
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End point type |
Secondary
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End point timeframe |
From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months
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No statistical analyses for this end point |
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End point title |
Number of Days Hospitalized for Acute Sickle Cell Disease Complications | |||||||||
End point 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. The FAS included all randomized participants regardless of treatment received. Here, 9999 = Upper limit of confidence interval was not calculable due to 0 events in Ticagrelor 15/30/45 mg bd reporting group.
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End point type |
Secondary
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End point timeframe |
From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months
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Statistical analysis title |
Treatment comparison: Ticagrelor Vs Placebo | |||||||||
Statistical analysis description |
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.
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Comparison groups |
Ticagrelor 15/30/45 mg bd v Placebo
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Number of subjects included in analysis |
193
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
= 0.994 | |||||||||
Method |
Negative binomial model | |||||||||
Parameter type |
Incidence rate ratio | |||||||||
Point estimate |
0
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0 | |||||||||
upper limit |
9999 |
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End point title |
Number of Sickle Cell-Related Red Blood Cell (RBC) Transfusions | |||||||||
End point 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. The FAS included all randomized participants regardless of treatment received.
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End point type |
Secondary
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End point timeframe |
From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months
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|||||||||
|
||||||||||
Statistical analysis title |
Treatment comparison: Ticagrelor Vs Placebo | |||||||||
Statistical analysis description |
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.
|
|||||||||
Comparison groups |
Ticagrelor 15/30/45 mg bd v Placebo
|
|||||||||
Number of subjects included in analysis |
193
|
|||||||||
Analysis specification |
Pre-specified
|
|||||||||
Analysis type |
superiority | |||||||||
P-value |
= 0.4822 | |||||||||
Method |
Negative binomial model | |||||||||
Parameter type |
Incidence rate ratio | |||||||||
Point estimate |
0.77
|
|||||||||
Confidence interval |
||||||||||
level |
95% | |||||||||
sides |
2-sided
|
|||||||||
lower limit |
0.38 | |||||||||
upper limit |
1.58 |
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End point title |
Health-Related Quality of Life Total Score Using the Paediatric Quality of Life Inventory (PedsQL) Sickle Cell Disease Module | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point 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. Baseline values are closest observation prior to and including randomization visit. The FAS population. Here, n= number of participants analyzed at specific time point; 9999= Standard deviation could not be calculated as only 1 participant had analyzable data; 99999= No participants were analyzed at that specific time point.
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End point type |
Secondary
|
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End point 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
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|
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No statistical analyses for this end point |
|
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End point title |
Fatigue Total Score Using Paediatric Quality of Life Inventory Multidimensional Fatigue Scale | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The PedsQL multidimensional fatigue scale instrument developed using a 5-point Likert scale (where 0= never and 4= almost always) for participant self-report forms for ages ≥5 to <8 years, ≥8 to <13 years, and ≥13 to ≤18 years and caregiver proxy-report form specific for ≥2 to <5 years was used. PedsQL multidimensional fatigue scale measures problems in 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. Baseline values are closest observation prior to and including randomization visit. FAS population. Here, n= number of participants analyzed at specific time point; 9999= Standard deviation could not be calculated as only 1 participant had analyzable data; 99999= No participants were analyzed at that specific time point.
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End point type |
Secondary
|
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End point 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
|
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|
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No statistical analyses for this end point |
|
|||||||||||||
End point title |
Percentage of Days of Absence From School or Work due to Sickle Cell Disease | ||||||||||||
End point 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). The FAS included all randomized participants regardless of treatment received. Only participants going to school or work at randomization are reported.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Average Intensity of Worst Pain Daily During Vaso-Occlusive Crisis Events in Participants <5 years of Age | ||||||||||||
End point 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. 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.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Average Intensity of Worst Pain Daily During Vaso-Occlusive Crisis Events in Participants ≥5 years of Age | ||||||||||||
End point 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. 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.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||
End point title |
Type of Analgesics Used by Participants During Vaso-Occlusive Crisis Events | |||||||||||||||||||||
End point description |
Analgesics use (opioid and non-opioid) during VOC events. The FAS included all randomized participants regardless of treatment received. Only participants who had at least one VOC and took an analgesic are reported.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
From randomization (Day 0) up to EOS visit or date of premature study discontinuation, up to approximately 20 months
|
|||||||||||||||||||||
|
||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||
End point title |
Palatability of the Study Treatment Assessed by Study Medication Palatability Assessment (SMPA) in Participants ≤4 years of Age | |||||||||||||||||||||||||||||||||
End point 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. Participants included in the Safety Analysis Set were analyzed for this endpoint. Here, n= number of participants ≤4 years of age who completed the assessment for study treatment palatability at the specific time point. NRP= Negative response to palatability.
|
|||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||
End point timeframe |
Baseline (randomization visit) and Month 6
|
|||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Swallowability of the Study Treatment Assessed by Study Medication Palatability Assessment in Participants ≤4 years of Age | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point 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. 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. Here, n= number of participants ≤4 years of age who completed the assessment for study treatment swallowability at the specific time point. WT= Whole tablet and DT= Dispersed tablet.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline (randomization visit) and Month 6
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Palatability of the Study Treatment Assessed by Facial Hedonic Scale (FHS) in Participants ≥5 years of Age | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point 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. 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. Here, n= number of participants ≥5 years of age who completed the assessment for study treatment palatability at the specific time point.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline (randomization visit) and Month 6
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
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Timeframe for reporting adverse events |
From first dose of study treatment (Day 0) up to 7 days after last dose of study treatment, approximately 20 months.
|
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Adverse event reporting additional 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.
|
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
23.0
|
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Reporting groups
|
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Reporting group title |
Ticagrelor 15/30/45 mg bd
|
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Reporting group description |
Paediatric 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
|
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Reporting group description |
Paediatric 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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|
|||
Substantial protocol amendments (globally) |
|||
Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
20 Apr 2020 |
New subsection was added to allow modification of study conduct during COVID-19 pandemic including visits, Investigational Product administration, and procedures. |
||
Interruptions (globally) |
|||
Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
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. |