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Clinical Trial Results:
A Multi-centre, Phase I, Open-label, Single-dose Study to Investigate Pharmacokinetics (PK) of Ticagrelor in Infants and Toddlers, Aged 0 to less than 24 Months, with Sickle Cell Disease (HESTIA4)

Summary
EudraCT number	2017-003641-14
Trial protocol	BE ES GB IT
Global end of trial date	07 May 2019

Results information
Results version number	v1(current)
This version publication date	06 Nov 2019
First version publication date	06 Nov 2019
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

D5136C00010

ISRCTN number

US NCT number

NCT03492931

WHO universal trial number (UTN)

Sponsor organisation name

AstraZeneca

Sponsor organisation address

950 Wind River Ln, Gaithersburg, MD, United States, 20878

Public contact

Global Clinical Lead, AstraZeneca, +1 3028851180, ClinicalTrialTransparency@astrazeneca.com

Scientific contact

Global Clinical Lead, AstraZeneca, +1 3028851180, ClinicalTrialTransparency@astrazeneca.com

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-000480-PIP01-08

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

07 May 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

07 May 2019

Was the trial ended prematurely?

Main objective of the trial

D5136C00010 is part of a paediatric development programme and is the first study with ticagrelor in paediatric patients aged 0 months to <24 months with sickle cell disease (SCD) to characterise pharmacokinetic (PK) properties after single doses.

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 and the AstraZeneca policy on Bioethics.

Background therapy

Evidence for comparator

Actual start date of recruitment

28 Mar 2018

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 3

Country: Number of subjects enrolled

Italy: 1

Country: Number of subjects enrolled

Kenya: 7

Country: Number of subjects enrolled

Lebanon: 7

Country: Number of subjects enrolled

Spain: 1

Country: Number of subjects enrolled

United Kingdom: 2

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Paediatric patients aged 0 to <24 months with SCD were recruited to this Phase I open-label, single-dose study at 8 study centres in Belgium, Italy, Kenya, Lebanon, Spain and the United Kingdom. The first patient started in March 2018 and the last patient completed in May 2019.

Screening details

Patients were diagnosed with homozygous sickle cell anaemia or sickle beta-zero-thalassaemia and had a body weight of at least 5 kilograms (kg) at screening. Patients participating in this study were not withheld from any other standard of care treatments that may be used in SCD.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Ticagrelor 0.1 mg/kg: <6 months old

Arm description

Patients in the age group <6 months old received a single oral dose of 0.1 milligrams per kg (mg/kg) ticagrelor.

Arm type

Experimental

Investigational medicinal product name

Ticagrelor

Investigational medicinal product code

Other name

BRILINTA™

Pharmaceutical forms

Granules for oral suspension

Routes of administration

Oral use

Dosage and administration details

A single oral 0.1 mg/kg dose of ticagrelor. Before administration, ticagrelor granules were constituted with 10 millilitres (mL) of purified water to form a homogenous suspension of 1 mg/mL ticagrelor.

Ticagrelor 0.2 mg/kg: 6 to <12 months old

Arm description

Patients in the age group 6 to <12 months old received a single oral dose of 0.2 mg/kg ticagrelor.

Arm type

Experimental

Investigational medicinal product name

Ticagrelor

Investigational medicinal product code

Other name

BRILINTA™

Pharmaceutical forms

Granules for oral suspension

Routes of administration

Oral use

Dosage and administration details

A single oral 0.2 mg/kg dose of ticagrelor. Before administration, ticagrelor granules were constituted with 10 mL of purified water to form a homogenous suspension of 1 mg/mL ticagrelor.

Ticagrelor 0.2 mg/kg: 12 to <24 months old

Arm description

Patients in the age group 12 to <24 months old received a single oral dose of 0.2 mg/kg ticagrelor.

Arm type

Experimental

Investigational medicinal product name

Ticagrelor

Investigational medicinal product code

Other name

BRILINTA™

Pharmaceutical forms

Granules for oral suspension

Routes of administration

Oral use

Dosage and administration details

A single oral 0.2 mg/kg dose of ticagrelor. Before administration, ticagrelor granules were constituted with 10 mL of purified water to form a homogenous suspension of 1 mg/mL ticagrelor.

Number of subjects in period 1	Ticagrelor 0.1 mg/kg: <6 months old	Ticagrelor 0.2 mg/kg: 6 to <12 months old	Ticagrelor 0.2 mg/kg: 12 to <24 months old
Started	2	6	13
Received ticagrelor	2	6	13
Completed	2	6	13

Baseline characteristics

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Reporting group title

Ticagrelor 0.1 mg/kg: <6 months old

Reporting group description

Patients in the age group <6 months old received a single oral dose of 0.1 milligrams per kg (mg/kg) ticagrelor.

Reporting group title

Ticagrelor 0.2 mg/kg: 6 to <12 months old

Reporting group description

Patients in the age group 6 to <12 months old received a single oral dose of 0.2 mg/kg ticagrelor.

Reporting group title

Ticagrelor 0.2 mg/kg: 12 to <24 months old

Reporting group description

Patients in the age group 12 to <24 months old received a single oral dose of 0.2 mg/kg ticagrelor.

Reporting group values	Ticagrelor 0.1 mg/kg: <6 months old	Ticagrelor 0.2 mg/kg: 6 to <12 months old	Ticagrelor 0.2 mg/kg: 12 to <24 months old	Total
Number of subjects	2	6	13	21
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	2	6	13	21
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	0	0	0	0
From 65-84 years	0	0	0	0
85 years and over	0	0	0	0
Age Continuous
Units: Months
arithmetic mean (standard deviation)	3.5 ± 0.71	9.0 ± 1.26	16.2 ± 3.00	-
Sex: Female, Male
Units: Subjects
Female	1	4	5	10
Male	1	2	8	11
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0
Asian	0	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0	0
Black or African American	0	6	8	14
White	2	0	5	7
More than one race	0	0	0	0
Unknown or Not Reported	0	0	0	0
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	0	0	0	0
Not Hispanic or Latino	2	6	13	21
Unknown or Not Reported	0	0	0	0

End points

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Reporting group title

Ticagrelor 0.1 mg/kg: <6 months old

Reporting group description

Patients in the age group <6 months old received a single oral dose of 0.1 milligrams per kg (mg/kg) ticagrelor.

Reporting group title

Ticagrelor 0.2 mg/kg: 6 to <12 months old

Reporting group description

Patients in the age group 6 to <12 months old received a single oral dose of 0.2 mg/kg ticagrelor.

Reporting group title

Ticagrelor 0.2 mg/kg: 12 to <24 months old

Reporting group description

Patients in the age group 12 to <24 months old received a single oral dose of 0.2 mg/kg ticagrelor.

Subject analysis set title

Ticagrelor 0.2 mg/kg: 6 to <24 months old

Subject analysis set type

Sub-group analysis

Subject analysis set description

Patients in the age group 6 to <24 months old received a single oral dose of 0.2 mg/kg ticagrelor.

Subject analysis set title

All Patients

Subject analysis set type

Full analysis

Subject analysis set description

Patients received single oral doses of 0.1 mg/kg ticagrelor (<6 months old) or 0.2 mg/kg ticagrelor (6 to <24 months old).

Primary: Ticagrelor Mean Observed Plasma Concentrations

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End point title

Ticagrelor Mean Observed Plasma Concentrations ^[1] ^[2]

End point description

Blood samples were taken up to 6 hours post-dose so that the number and volume of blood samples were compliant with European Ethical Considerations in a Paediatric Population 2008. The geometric mean observed plasma concentration of ticagrelor is presented for each timepoint of sampling after patients had received a single oral dose of ticagrelor. Data is presented for each of the 2 doses of ticagrelor as well as for all patients. The lower limit of quantification (LLOQ) of ticagrelor was 1.00 nanograms per millilitre (ng/mL). Data is presented for the PK analysis set which included all patients who received at least 1 dose of ticagrelor and provided at least 1 post-dose analysable plasma sample without any important protocol deviations or events that would exclude the patient. '(n=x,y,z)' indicates the number of patients analysed at each timepoint.

End point type

Primary

End point timeframe

Blood samples were collected on Day 1 at 1, 2, 4 and 6 hours post-dose.

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical comparisons were carried out for this study. All endpoints were evaluated using standard summary descriptive statistics.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data is presented for all patients in the baseline period, with data for patients in the arms 'Ticagrelor 0.2 mg/kg: 6 to <12 months old' and 'Ticagrelor 0.2 mg/kg: 12 to <24 months old' represented within the analysis set 'Ticagrelor 0.2 mg/kg: 6 to <24 months old'.

End point values	Ticagrelor 0.1 mg/kg: <6 months old	Ticagrelor 0.2 mg/kg: 6 to <24 months old	All Patients
Number of subjects analysed	2 ^[3]	19	21
Units: ng/mL
geometric mean (geometric coefficient of variation)
1 hour post-dose (n=1,19,20)	99999999 ± 99999999	18.51 ± 154.70	18.59 ± 147.75
2 hours post-dose (n=2,19,21)	99999999 ± 99999999	21.82 ± 127.79	21.86 ± 118.47
4 hours post-dose (n=2,19,21)	99999999 ± 99999999	16.54 ± 61.78	16.12 ± 59.75
6 hours post-dose (n=2,18,20)	99999999 ± 99999999	10.39 ± 60.68	10.25 ± 58.23

Notes
[3] - '9999999' indicates the data was not calculated due to the sample size.

No statistical analyses for this end point

Primary: Ticagrelor Maximum Observed Plasma Concentrations (Cmax)

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End point title

Ticagrelor Maximum Observed Plasma Concentrations (Cmax) ^[4] ^[5]

End point description

Blood samples were taken up to 6 hours post-dose so that the number and volume of blood samples were compliant with European Ethical Considerations in a Paediatric Population 2008. The geometric mean Cmax for ticagrelor is presented for each of the 2 doses of ticagrelor and for all patients. Data is presented for the PK analysis set which included all patients who received at least 1 dose of ticagrelor and provided at least 1 post-dose analysable plasma sample without any important protocol deviations or events that would exclude the patient.

End point type

Primary

End point timeframe

Blood samples were collected on Day 1 at 1, 2, 4 and 6 hours post-dose.

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical comparisons were carried out for this study. All endpoints were evaluated using standard summary descriptive statistics.
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data is presented for all patients in the baseline period, with data for patients in the arms ‘Ticagrelor 0.2 mg/kg: 6 to <12 months old’ and ‘Ticagrelor 0.2 mg/kg: 12 to <24 months old’ represented within the analysis set ‘Ticagrelor 0.2 mg/kg: 6 to <24 months old’.

End point values	Ticagrelor 0.1 mg/kg: <6 months old	Ticagrelor 0.2 mg/kg: 6 to <24 months old	All Patients
Number of subjects analysed	2	19	21
Units: ng/mL
geometric mean (geometric coefficient of variation)	23.80 ± 23.78	34.44 ± 74.75	33.25 ± 71.67

No statistical analyses for this end point

Primary: Ticagrelor Area Under the Plasma Concentration-Time Curve from Zero to 6 Hours (AUC[0-6])

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End point title

Ticagrelor Area Under the Plasma Concentration-Time Curve from Zero to 6 Hours (AUC[0-6]) ^[6] ^[7]

End point description

Blood samples were taken up to 6 hours post-dose so that the number and volume of blood samples were compliant with European Ethical Considerations in a Paediatric Population 2008. The geometric mean AUC(0-6) for ticagrelor is presented for each of the 2 doses of ticagrelor and for all patients. Data is presented for the PK analysis set which included all patients who received at least 1 dose of ticagrelor and provided at least 1 post-dose analysable plasma sample without any important protocol deviations or events that would exclude the patient.

End point type

Primary

End point timeframe

Blood samples were collected on Day 1 at 1, 2, 4 and 6 hours post-dose.

Notes
[6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical comparisons were carried out for this study. All endpoints were evaluated using standard summary descriptive statistics.
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data is presented for all patients in the baseline period, with data for patients in the arms ‘Ticagrelor 0.2 mg/kg: 6 to <12 months old’ and ‘Ticagrelor 0.2 mg/kg: 12 to <24 months old’ represented within the analysis set ‘Ticagrelor 0.2 mg/kg: 6 to <24 months old’.

End point values	Ticagrelor 0.1 mg/kg: <6 months old	Ticagrelor 0.2 mg/kg: 6 to <24 months old	All Patients
Number of subjects analysed	2	19	21
Units: nghours/mL (ngh/mL)
geometric mean (geometric coefficient of variation)	87.22 ± 32.72	112.39 ± 52.21	109.71 ± 50.59

No statistical analyses for this end point

Secondary: Active Metabolite (AR-C124910XX) Mean Observed Plasma Concentrations

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End point title

Active Metabolite (AR-C124910XX) Mean Observed Plasma Concentrations ^[8]

End point description

Blood samples were taken up to 6 hours post-dose so that the number and volume of blood samples were compliant with European Ethical Considerations in a Paediatric Population 2008. The geometric mean observed plasma concentration of AR-C124910XX is presented for each timepoint of sampling after patients had received a single oral dose of ticagrelor. Data is presented for each of the 2 doses of ticagrelor as well as for all patients. The LLOQ of AR-C124910XX was 2.50 ng/mL. Data is presented for the PK analysis set which included all patients who received at least 1 dose of ticagrelor and provided at least 1 post-dose analysable plasma sample without any important protocol deviations or events that would exclude the patient. '(n=x,y,z)' indicates the number of patients analysed at each timepoint.

End point type

Secondary

End point timeframe

Blood samples were collected on Day 1 at 1, 2, 4 and 6 hours post-dose.

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data is presented for all patients in the baseline period, with data for patients in the arms ‘Ticagrelor 0.2 mg/kg: 6 to <12 months old’ and ‘Ticagrelor 0.2 mg/kg: 12 to <24 months old’ represented within the analysis set ‘Ticagrelor 0.2 mg/kg: 6 to <24 months old’.

End point values	Ticagrelor 0.1 mg/kg: <6 months old	Ticagrelor 0.2 mg/kg: 6 to <24 months old	All Patients
Number of subjects analysed	2 ^[9]	19	21
Units: ng/mL
geometric mean (geometric coefficient of variation)
1 hour post-dose (n=1,19, 20)	99999999 ± 99999999	4.65 ± 88.79	4.70 ± 85.91
2 hours post-dose (n=2,19,21)	99999999 ± 99999999	7.40 ± 81.31	7.35 ± 76.39
4 hours post-dose (n=2,19,21)	99999999 ± 99999999	7.33 ± 53.57	7.16 ± 52.08
6 hours post-dose (n=2,18,20)	99999999 ± 99999999	5.89 ± 49.02	5.77 ± 47.77

Notes
[9] - '99999999' indicates the data was not calculated due to the sample size.

No statistical analyses for this end point

Secondary: Active Metabolite (AR-C124910XX) Cmax

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End point title

Active Metabolite (AR-C124910XX) Cmax ^[10]

End point description

Blood samples were taken up to 6 hours post-dose so that the number and volume of blood samples were compliant with European Ethical Considerations in a Paediatric Population 2008. The geometric mean Cmax for AR-C124910XX is presented for each of the 2 doses of ticagrelor and for all patients. Data is presented for the PK analysis set which included all patients who received at least 1 dose of ticagrelor and provided at least 1 post-dose analysable plasma sample without any important protocol deviations or events that would exclude the patient.

End point type

Secondary

End point timeframe

Blood samples were collected on Day 1 at 1, 2, 4 and 6 hours post-dose.

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data is presented for all patients in the baseline period, with data for patients in the arms ‘Ticagrelor 0.2 mg/kg: 6 to <12 months old’ and ‘Ticagrelor 0.2 mg/kg: 12 to <24 months old’ represented within the analysis set ‘Ticagrelor 0.2 mg/kg: 6 to <24 months old’.

End point values	Ticagrelor 0.1 mg/kg: <6 months old	Ticagrelor 0.2 mg/kg: 6 to <24 months old	All Patients
Number of subjects analysed	2	19	21
Units: ng/mL
geometric mean (geometric coefficient of variation)	6.89 ± 22.55	9.17 ± 61.25	8.93 ± 58.76

No statistical analyses for this end point

Secondary: Active Metabolite (AR-C124910XX) AUC(0-6)

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End point title

Active Metabolite (AR-C124910XX) AUC(0-6) ^[11]

End point description

Blood samples were taken up to 6 hours post-dose so that the number and volume of blood samples were compliant with European Ethical Considerations in a Paediatric Population 2008. The geometric mean AUC(0-6) for AR-C124910XX is presented for each of the 2 doses of ticagrelor and for all patients. Data is presented for the PK analysis set which included all patients who received at least 1 dose of ticagrelor and provided at least 1 post-dose analysable plasma sample without any important protocol deviations or events that would exclude the patient.

End point type

Secondary

End point timeframe

Blood samples were collected on Day 1 at 1, 2, 4 and 6 hours post-dose.

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data is presented for all patients in the baseline period, with data for patients in the arms ‘Ticagrelor 0.2 mg/kg: 6 to <12 months old’ and ‘Ticagrelor 0.2 mg/kg: 12 to <24 months old’ represented within the analysis set ‘Ticagrelor 0.2 mg/kg: 6 to <24 months old’.

End point values	Ticagrelor 0.1 mg/kg: <6 months old	Ticagrelor 0.2 mg/kg: 6 to <24 months old	All Patients
Number of subjects analysed	2	19	21
Units: ng*h/mL
geometric mean (geometric coefficient of variation)	29.76 ± 22.84	34.97 ± 58.67	34.44 ± 55.80

No statistical analyses for this end point

Secondary: Observer Assessment of Acceptability and Palatability of Ticagrelor

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End point title

Observer Assessment of Acceptability and Palatability of Ticagrelor

End point description

An observer's assessment of the patient's behaviour was performed directly as the patient was administered the single dose of ticagrelor on Day 1. The patient's willingness to swallow was recorded as one of the following: swallowed without a problem, some resistance but did swallow, spat out some/all of medication, vomited up the medication. The patient's negative response to palatability was assessed and the following outcomes were recorded: turned head to reject intake of the medication, twisted face or mouth in an expression of displeasure or other negative response. Data is presented for the safety analysis set which included all patients who received at least 1 single dose of ticagrelor, and for whom any post-dose data was available.

End point type

Secondary

End point timeframe

Day 1 (directly after treatment administration)

End point values	Ticagrelor 0.1 mg/kg: <6 months old	Ticagrelor 0.2 mg/kg: 6 to <12 months old	Ticagrelor 0.2 mg/kg: 12 to <24 months old
Number of subjects analysed	2	6	13
Units: Participants
Swallowed without problem	2	5	10
Some resistance but did swallow	0	0	3
Spat out some/all	0	1	0
Vomited up medication	0	0	0
Turned head to reject intake	0	1	3
Twisted face/mouth in displeasure	0	1	0
Other negative response	0	0	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

On-treatment adverse events (AEs) were collected from Day 1 up to Day 8 (approximately 1 week).

Adverse event reporting additional description

AEs are presented for the safety analysis set which included all patients who received at least 1 single dose of ticagrelor, and for whom any post-dose data was available.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.1

Reporting group title

Ticagrelor 0.1 mg/kg: <6 months old

Reporting group description

Patients in the age group <6 months old received a single oral dose of 0.1 mg/kg ticagrelor.

Reporting group title

Ticagrelor 0.2 mg/kg: 12 to <24 months old

Reporting group description

Patients in the age group 12 to <24 months old received a single oral dose of 0.2 mg/kg ticagrelor.

Reporting group title

Ticagrelor 0.2 mg/kg: 6 to <12 months old

Reporting group description

Patients in the age group 6 to <12 months old received a single oral dose of 0.2 mg/kg ticagrelor.

Serious adverse events	Ticagrelor 0.1 mg/kg: <6 months old	Ticagrelor 0.2 mg/kg: 12 to <24 months old	Ticagrelor 0.2 mg/kg: 6 to <12 months old
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 2 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events	0	0	0
Infections and infestations
Bronchiolitis
subjects affected / exposed	0 / 2 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Ticagrelor 0.1 mg/kg: <6 months old	Ticagrelor 0.2 mg/kg: 12 to <24 months old	Ticagrelor 0.2 mg/kg: 6 to <12 months old
Total subjects affected by non serious adverse events
subjects affected / exposed	0 / 2 (0.00%)	3 / 13 (23.08%)	3 / 6 (50.00%)
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 2 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)
occurrences all number	0	1	0
Injury
subjects affected / exposed	0 / 2 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)
occurrences all number	0	1	0
Vascular disorders
Pallor
subjects affected / exposed	0 / 2 (0.00%)	1 / 13 (7.69%)	1 / 6 (16.67%)
occurrences all number	0	1	1
Blood and lymphatic system disorders
Sickle cell anaemia with crisis
subjects affected / exposed	0 / 2 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)
occurrences all number	0	1	0
Splenomegaly
subjects affected / exposed	0 / 2 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)
occurrences all number	0	1	0
Respiratory, thoracic and mediastinal disorders
Nasal congestion
subjects affected / exposed	0 / 2 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)
occurrences all number	0	1	0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	0 / 2 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)
occurrences all number	0	1	0
Infections and infestations
Gastroenteritis
subjects affected / exposed	0 / 2 (0.00%)	1 / 13 (7.69%)	0 / 6 (0.00%)
occurrences all number	0	1	0
Viral upper respiratory tract infection
subjects affected / exposed	0 / 2 (0.00%)	0 / 13 (0.00%)	2 / 6 (33.33%)
occurrences all number	0	0	2

More information

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Were there any global substantial amendments to the protocol? Yes

05 Jan 2018

- The synopsis (Investigational product, dosage and mode of administration) and sections of the protocol relating to the rationale for study design, doses, and control groups, and interim analysis were changed to declare that any dose adjustments would require a protocol amendment and regulatory approval. The prediction level of reduction in platelet reactivity unit text was amended. These updates reflected the Medicines and Healthcare products Regulatory Agency request.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

For the endpoint 'Ticagrelor Mean Plasma Concentrations', '9999999' indicates the data was not calculable for the sample size.

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Clinical trials

Clinical Trial Results:
A Multi-centre, Phase I, Open-label, Single-dose Study to Investigate Pharmacokinetics (PK) of Ticagrelor in Infants and Toddlers, Aged 0 to less than 24 Months, with Sickle Cell Disease (HESTIA4)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Ticagrelor Mean Observed Plasma Concentrations

Primary: Ticagrelor Mean Observed Plasma Concentrations

Primary: Ticagrelor Maximum Observed Plasma Concentrations (Cmax)

Primary: Ticagrelor Maximum Observed Plasma Concentrations (Cmax)

Primary: Ticagrelor Area Under the Plasma Concentration-Time Curve from Zero to 6 Hours (AUC[0-6])

Primary: Ticagrelor Area Under the Plasma Concentration-Time Curve from Zero to 6 Hours (AUC[0-6])

Secondary: Active Metabolite (AR-C124910XX) Mean Observed Plasma Concentrations

Secondary: Active Metabolite (AR-C124910XX) Mean Observed Plasma Concentrations

Secondary: Active Metabolite (AR-C124910XX) Cmax

Secondary: Active Metabolite (AR-C124910XX) Cmax

Secondary: Active Metabolite (AR-C124910XX) AUC(0-6)

Secondary: Active Metabolite (AR-C124910XX) AUC(0-6)

Secondary: Observer Assessment of Acceptability and Palatability of Ticagrelor

Secondary: Observer Assessment of Acceptability and Palatability of Ticagrelor

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: A Multi-centre, Phase I, Open-label, Single-dose Study to Investigate Pharmacokinetics (PK) of Ticagrelor in Infants and Toddlers, Aged 0 to less than 24 Months, with Sickle Cell Disease (HESTIA4)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Ticagrelor Mean Observed Plasma Concentrations

Primary: Ticagrelor Mean Observed Plasma Concentrations

Primary: Ticagrelor Maximum Observed Plasma Concentrations (Cmax)

Primary: Ticagrelor Maximum Observed Plasma Concentrations (Cmax)

Primary: Ticagrelor Area Under the Plasma Concentration-Time Curve from Zero to 6 Hours (AUC[0-6])

Primary: Ticagrelor Area Under the Plasma Concentration-Time Curve from Zero to 6 Hours (AUC[0-6])

Secondary: Active Metabolite (AR-C124910XX) Mean Observed Plasma Concentrations

Secondary: Active Metabolite (AR-C124910XX) Mean Observed Plasma Concentrations

Secondary: Active Metabolite (AR-C124910XX) Cmax

Secondary: Active Metabolite (AR-C124910XX) Cmax

Secondary: Active Metabolite (AR-C124910XX) AUC(0-6)

Secondary: Active Metabolite (AR-C124910XX) AUC(0-6)

Secondary: Observer Assessment of Acceptability and Palatability of Ticagrelor

Secondary: Observer Assessment of Acceptability and Palatability of Ticagrelor

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Multi-centre, Phase I, Open-label, Single-dose Study to Investigate Pharmacokinetics (PK) of Ticagrelor in Infants and Toddlers, Aged 0 to less than 24 Months, with Sickle Cell Disease (HESTIA4)