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Clinical Trial Results:
A Prospective, Open-Label, Single-Arm, Multi-Center Study to Assess The Pharmacokinetics/Pharmacodynamics (PK/PD) AND Safety Of Different Cangrelor Doses In Neonatal Subjects At Risk Of Thrombosis.

Summary
EudraCT number	2016-000134-22
Trial protocol	Outside EU/EEA
Global end of trial date	30 Aug 2019

Results information
Results version number	v1(current)
This version publication date	10 Jun 2021
First version publication date	10 Jun 2021
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

MDCO-CAN-15-01

ISRCTN number

US NCT number

NCT02765633

WHO universal trial number (UTN)

Sponsor organisation name

Chiesi Farmaceutici S.p.A

Sponsor organisation address

Via Palermo 26/A, Parma, Italy,

Public contact

Clinical Trial Trasparency, Chiesi Farmaceutici S.p.A., clinicaltrials_info@chiesi.com

Scientific contact

Clinical Trial Trasparency, Chiesi Farmaceutici S.p.A., clinicaltrials_info@chiesi.com

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

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

15 Apr 2020

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

30 Aug 2019

Was the trial ended prematurely?

Main objective of the trial

- To assess the safety and PK / PD profile in this dose finding study of cangrelor in this neonatal population. - To determine the plasma concentrations of cangrelor and its primary metabolite, AR-C69712, during administration and after cessation of the infusion in neonates. - To determine the PD of cangrelor at various doses in neonates as assessed by light transmittance aggregometry (LTA) (primary)and microfluidic flow chamber (exploratory). - To assess recovery of platelet function in neonates by LTA after cessation of the infusion. - To determine the appropriate dose(s) to evaluate in future safety and efficacy trials in neonates. - To evaluate the safety of cangrelor in neonatal subjects by evaluating adverse events (AEs), serious adverse events (SAEs) and Adverse Events of special interest (AESIs).

Protection of trial subjects

An independent Data Monitoring Committee (DMC) was convened for this study for the purpose of reviewing safety data following completion of each initial cohort. A recommendation was to be provided by the DMC to the Sponsor to either continue the study without modification, to modify the study, or to discontinue the study following review of safety data from each cohort. The DMC was not charged with review of data from the Cohort 1 or Cohort 2 expansions. This study was conducted in compliance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E6 Good Clinical Practices (GCP) guidelines, the Declaration of Helsinki, and other local regulations as applicable. Written informed consent was obtained from all subjects’ parents, guardians, or legally authorized representatives as per IRB guidelines before any study-related procedures (including any protocol-specified pre-treatment procedures) were performed. However, standard-of-care laboratory tests obtained prior to informed consent could have been utilized for screening to assess subject eligibility for the study if obtained within 72 hours prior to signing the informed consent.

Background therapy

Cangrelor is an antiplatelet agent which is a non-thienopyridine adenosine triphosphate analogue. Cangrelor is an antagonist of the P2Y12 receptor that is given intravenously (IV) and is characterized by rapid, direct, potent, predictable, and reversible platelet inhibition with rapid offset of effect. Adenosine diphosphate (ADP) secreted from platelet-dense granules provides important autocrine and paracrine stimulation of platelet aggregation. Cangrelor effectively blocks ADP-induced platelet activation and aggregation as demonstrated in preclinical studies and clinical studies in the adult population.

Evidence for comparator

No comparator expected.

Actual start date of recruitment

03 Jan 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 20

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

A total of 22 subjects were enrolled consisting of 20 eligible subjects who were assigned to cohorts and 2 subjects that failed screening. The first cohort (1-1E) includes 13 subjects (only 8 subjects have received cangrelor 0.5 µg/kg/min); the second cohort (2-2E) includes 7 subjects and all of them receive cangrelor 0.25 µg/kg/min.

Screening details

During screening (Day -7 to Day -2), eligibility (inclusion/exclusion criteria) was assessed, medical history and concomitant medications were recorded, and the following assessments were performed: physical examination, clinical laboratory tests (complete blood count [CBC],chemistry panel), and an ultrasound examination of the head.

Number of subjects started

22 ^[1]

Number of subjects completed

Reason: Number of subjects

Physician decision: 1

Reason: Number of subjects

Protocol deviation: 2

Reason: Number of subjects

Consent withdrawn by subject: 2

Reason: Number of subjects

no central venous access post-surgery: 1

Reason: Number of subjects

subdural hemorrhage - hematoma: 1

Notes
[1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: According to the protocol, 22 subjects were screened for the study, but only 20 subjects were enrolled and 15 were treated as follow: COHORT 1-1E: 13 subjects enrolled and cohort-assigned, but only 8 subjects have received the treatment. COHORT 2-2E: 7 subjects enrolled and cohort-assigned, and all the 7 subjects have received the treatment.

Period 1 title

1_Treatment and FU (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Treatment - Cohort 1-1E

Arm description

Active treatment with cangrelor 0.5 µg/kg/min was administered as a single-dose continuous IV infusion for approximately 1 hour via a peripheral IV or central venous line.

Arm type

Experimental

Investigational medicinal product name

Cangrelor

Investigational medicinal product code

Other name

Kengreal®

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Cangrelor is a sterile lyophilized powder for reconstitution and dilution for administration. Diluted cangrelor was administered intravenously (IV) at 0.5 μg/kg/min, as a single-dose continuous infusion for approximately 1 hour via a peripheral IV or central venous line.

Treatment - Cohort 2-2E

Arm description

Active treatment with cangrelor 0.25 µg/kg/min was administered as a single-dose continuous IV infusion for approximately 1 hour via a peripheral IV or central venous line.

Arm type

Experimental

Investigational medicinal product name

Cangrelor

Investigational medicinal product code

Other name

Kengreal®

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Cangrelor is a sterile lyophilized powder for reconstitution and dilution for administration. Diluted cangrelor was administered intravenously (IV) at 0.25 μg/kg/min, as a single-dose continuous infusion for approximately 1 hour via a peripheral IV or central venous line.

Number of subjects in period 1 ^[2]	Treatment - Cohort 1-1E	Treatment - Cohort 2-2E
Started	8	7
Completed	8	7

Notes
[2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: According to the protocol, 22 subjects were screened for the study, but only 20 subjects were enrolled and 15 were treated as follow: COHORT 1-1E: 13 subjects enrolled and cohort-assigned, but only 8 subjects have received the treatment. COHORT 2-2E: 7 subjects enrolled and cohort-assigned, and all the 7 subjects have received the treatment.

Baseline characteristics

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Reporting group title

Treatment - Cohort 1-1E

Reporting group description

Active treatment with cangrelor 0.5 µg/kg/min was administered as a single-dose continuous IV infusion for approximately 1 hour via a peripheral IV or central venous line.

Reporting group title

Treatment - Cohort 2-2E

Reporting group description

Active treatment with cangrelor 0.25 µg/kg/min was administered as a single-dose continuous IV infusion for approximately 1 hour via a peripheral IV or central venous line.

Reporting group values	Treatment - Cohort 1-1E	Treatment - Cohort 2-2E	Total
Number of subjects	8	7	15
Age categorical
Units: Subjects
Newborns (0-28 days)	8	7	15
Age continuous
Units: days
arithmetic mean (standard deviation)	3.8 ( 2.87 )	4.7 ( 3.15 )	-
Gender categorical
Units: Subjects
Female	4	5	9
Male	4	2	6
Race characteristic
Units: Subjects
white	6	6	12
black/african american	2	1	3
Baseline weight
Units: Subjects
Baseline weight 2.60-3.00 Kg	3	6	9
Baseline weight 3.01-3.31 Kg	4	1	5
Baseline weight not recorded	1	0	1

Subject analysis set title

Treatment Cohort 1-1E - Safety

Subject analysis set type

Safety analysis

Subject analysis set description

Included all subjects who received any infusion length of study drug. Treatment classification was based on the actual cangrelor dosage received. This was the primary population for the safety analyses.

Subject analysis set title

Treatment Cohort 2-2E - Safety

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Treatment Cohort 1-1E - PK

Subject analysis set type

Sub-group analysis

Subject analysis set description

Sub-group analysis is referred to the PK population, that includes all subjects who had any valid samples measured for study drug concentrations. Treatment classification was based on the actual treatment received.

Subject analysis set title

Treatment Cohort 2-2E - PK

Subject analysis set type

Sub-group analysis

Subject analysis set description

Sub-group analysis is referred to the PK population,that includes all subjects who had any valid samples measured for study drug concentrations. Treatment classification was based on the actual treatment received.

Subject analysis sets values	Treatment Cohort 1-1E - Safety	Treatment Cohort 2-2E - Safety	Treatment Cohort 1-1E - PK	Treatment Cohort 2-2E - PK
Number of subjects	8	7	8	7
Age categorical
Units: Subjects
Newborns (0-28 days)	8	7	8	7
Age continuous
Units: days
arithmetic mean (standard deviation)	3.8 ( 2.87 )	4.7 ( 3.15 )	3.8 ( 2.87 )	4.7 ( 3.15 )
Gender categorical
Units: Subjects
Female	4	5	4	5
Male	4	2	4	2
Race characteristic
Units: Subjects
white	6	6	6	6
black/african american	2	1	2	1
Baseline weight
Units: Subjects
Baseline weight 2.60-3.00 Kg	3	6	3	6
Baseline weight 3.01-3.31 Kg	4	1	4	1
Baseline weight not recorded	1	0	1	0

End points

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Reporting group title

Treatment - Cohort 1-1E

Reporting group description

Active treatment with cangrelor 0.5 µg/kg/min was administered as a single-dose continuous IV infusion for approximately 1 hour via a peripheral IV or central venous line.

Reporting group title

Treatment - Cohort 2-2E

Reporting group description

Active treatment with cangrelor 0.25 µg/kg/min was administered as a single-dose continuous IV infusion for approximately 1 hour via a peripheral IV or central venous line.

Subject analysis set title

Treatment Cohort 1-1E - Safety

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Treatment Cohort 2-2E - Safety

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Treatment Cohort 1-1E - PK

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Treatment Cohort 2-2E - PK

Subject analysis set type

Sub-group analysis

Subject analysis set description

Sub-group analysis is referred to the PK population,that includes all subjects who had any valid samples measured for study drug concentrations. Treatment classification was based on the actual treatment received.

Primary: 1_Proportion of subjects who achieved ≥90% inhibition of maximal and final platelet aggregation

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End point title

1_Proportion of subjects who achieved ≥90% inhibition of maximal and final platelet aggregation ^[1]

End point description

Proportion of subjects in each cohort who achieved ≥90% inhibition of maximal and final platelet aggregation as measured by LTA using 5 μM and 20 μM ADP in platelet ‑ rich plasma. % Inhibition is defined, only for timepoints during and after infusion, as (the pre-infusion value - the value during or after infusion)/the pre-infusion value) * 100. Data are presented as % of subjects who achieved ≥90% inhibition of maximal and final platelet aggregation, with their 95% confidence intervals (CIs).

End point type

Primary

End point timeframe

Inhibition of aggregation was measured by LTA at baseline, at 15 min before completing the cangrelor infusion, and at 60 min after completing the cangrelor infusion.

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 statistical analysis is planned for this end point.

End point values	Treatment Cohort 1-1E - Safety	Treatment Cohort 2-2E - Safety
Number of subjects analysed	8 ^[2]	7 ^[3]
Units: percentage of subjects
number (confidence interval 95%)
A≥90% inhibition of final aggregation using 5μM	100 (29.2 to 100)	100 (29.2 to 100)
B≥90% inhibition of maximal aggregation using 5μM	80 (28.4 to 99.5)	60 (14.7 to 94.7)
C≥90% inhibition of maximal aggregation using 20μM	50 (11.8 to 88.2)	28.6 (3.7 to 71.0)
D≥90% inhibition of final aggregation using 20μM	50 (11.8 to 88.2)	80 (28.4 to 99.5)

Notes
[2] - Patients reached target/patients evaluable: A:3/3(100%) B:4/5(80%) C:3/6(50%) D:3/6(50%)
[3] - Patients reached target/patients evaluable: A:3/3(100%) B:3/5(60%) C:2/7(28.6%) D:4/5(80%)

No statistical analyses for this end point

Primary: 1_Percent inhibition of platelet aggregation by LTA during the infusion-mean values

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End point title

1_Percent inhibition of platelet aggregation by LTA during the infusion-mean values ^[4]

End point description

Inhibition of platelet aggregation was measured by LTA at baseline (15 to 60 minutes before the start of the cangrelor infusion), at 15 minutes before completing the cangrelor infusion, and at 60 minutes after completing the cangrelor infusion. The percent inhibition of platelet aggregation 45 minutes into the cangrelor infusion was measured by LTA using 5 μM and 20 μM ADP in platelet-rich plasma. Data are presented as % inhibition of maximal and final platelet aggregation reporting mean and relevant standard deviation.

End point type

Primary

End point timeframe

Inhibition of aggregation was measured by LTA at baseline, at 15 min before completing the cangrelor infusion, and at 60 min after completing the cangrelor infusion.

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 statistical analysis is planned for this end point.

End point values	Treatment Cohort 1-1E - Safety	Treatment Cohort 2-2E - Safety
Number of subjects analysed	8 ^[5]	7 ^[6]
Units: percentage
arithmetic mean (standard deviation)
A inhibition of final aggregation using 5 μM	99 ( 1.75 )	100 ( 0 )
B inhibition of maximal aggregation using 5 μM	93.7 ( 6.45 )	88.2 ( 13.49 )
C inhibition of final aggregation using 20 μM	89 ( 12.5 )	94.1 ( 8.68 )
D inhibition of maximal aggregation using 20 μM	89 ( 11.42 )	76.3 ( 16.89 )

Notes
[5] - number of patients evaluated: A:3 B:5 C:6 D:6
[6] - number of patients evaluated: A:3 B:5 C:5 D:7

No statistical analyses for this end point

Primary: 1_Percent inhibition of platelet aggregation by LTA during the infusion-median values

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End point title

1_Percent inhibition of platelet aggregation by LTA during the infusion-median values ^[7]

End point description

Inhibition of platelet aggregation was measured by LTA at baseline (15 to 60 minutes before the start of the cangrelor infusion), at 15 minutes before completing the cangrelor infusion, and at 60 minutes after completing the cangrelor infusion. The percent inhibition of platelet aggregation 45 minutes into the cangrelor infusion was measured by LTA using 5 μM and 20 μM ADP in platelet-rich plasma. Data are presented as inhibition of maximal and final platelet aggregation reporting median (min and max).

End point type

Primary

End point timeframe

Inhibition of aggregation was measured by LTA at baseline, at 15 min before completing the cangrelor infusion, and at 60 min after completing the cangrelor infusion.

Notes
[7] - 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 statistical analysis is planned for this end point.

End point values	Treatment Cohort 1-1E - Safety	Treatment Cohort 2-2E - Safety
Number of subjects analysed	8 ^[8]	7 ^[9]
Units: percentage
median (full range (min-max))
A inhibition of final aggregation using 5 μM	100 (97 to 100)	100 (100 to 100)
B inhibition of maximal aggregation using 5 μM	92.9 (84.8 to 100)	96 (68.1 to 100)
C inhibition of final aggregation using 20 μM	91.7 (73.1 to 100)	97.3 (79.2 to 100)
Dinhibition of maximal aggregation using 20 μM	91.2 (69 to 100)	69.6 (53.2 to 98.3)

Notes
[8] - number of patients evaluated: A:3 B:5 C:6 D:6
[9] - number of patients evaluated: A:3 B:5 C:5 D:7

No statistical analyses for this end point

Primary: 2_Percent recovery of platelet function by LTA assay after the infusion

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End point title

2_Percent recovery of platelet function by LTA assay after the infusion ^[10]

End point description

Recovery of platelet function in neonates was defined, only for timepoints after infusion, as 100 - percent inhibition. The recovery of platelet was measured by LTA using 5 μM and 20 μM ADP in platelet-rich plasma. Data are presented as % of subjects who achieved ≥ 90% recovery of maximal and final platelet aggregation.

End point type

Primary

End point timeframe

Percent recovery of platelet function was measured by LTA assay 1 hour after completion of the cangrelor infusion.

Notes
[10] - 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 statistical analyses for this end point.

End point values	Treatment Cohort 1-1E - Safety	Treatment Cohort 2-2E - Safety
Number of subjects analysed	8 ^[11]	7 ^[12]
Units: percentage of subjects
number (not applicable)
A≥90% recovery of final aggregation using 5μM	33.3	66.7
B≥90% recovery of maximal aggregation using 5μM	40.0	60
C≥90% recovery of final aggregation using 20 μM	66.7	60
D ≥90% recovery of maximal aggregation using 20μM	66.7	71.4

Notes
[11] - Patients reached target/patients evaluable: A:1/3(33.3%) B:2/5(40%) C:4/6(66.7%) D:4/6(66.7%)
[12] - Patients reached target/patients evaluable: A:2/3(66.7%) B:3/5(60%) C:3/5(60%) D:5/7(71.4%)

No statistical analyses for this end point

Primary: 2_Percent recovery of platelet function by LTA assay after the infusion-mean values

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End point title

2_Percent recovery of platelet function by LTA assay after the infusion-mean values ^[13]

End point description

Recovery of platelet was measured by LTA (1 hour after completion of the cangrelor infusion). The percent inhibition of platelet aggregation 1 hour after cangrelor infusion was measured by LTA using 5 μM and 20 μM ADP in platelet-rich plasma. Data are presented as ≥ 90% inhibition of maximal and final platelet aggregation (mean and relevant standard deviation).

End point type

Primary

End point timeframe

Percent recovery of platelet function was measured by LTA assay 1 hour after completion of the cangrelor infusion.

Notes
[13] - 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 statistical analysis is planned for this end point.

End point values	Treatment Cohort 1-1E - Safety	Treatment Cohort 2-2E - Safety
Number of subjects analysed	8 ^[14]	7 ^[15]
Units: percentage
arithmetic mean (standard deviation)
A≥90% recovery of final aggregation using 5 μM	77 ( 11.51 )	66.2 ( 57.31 )
B≥90% recovery of maximal aggregation using 5 μM	86.9 ( 12.42 )	68.5 ( 44.28 )
C ≥90% recovery of final aggregation using 20 μM	82.6 ( 32.62 )	64.6 ( 48.69 )
D≥90% recovery of maximal aggregation using 20μM	84.5 ( 30.02 )	82.5 ( 32.07 )

Notes
[14] - number of patients evaluated: A:3 B:5 C:6 D:6
[15] - number of patients evaluated: A:3 B:5 C:5 D:7

No statistical analyses for this end point

Primary: 3_Summary of PK parameters by dose (Cmax)

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End point title

3_Summary of PK parameters by dose (Cmax) ^[16]

End point description

PK parameter was measured by Cmax (ng/mL) after 60-minute IV infusion with a cangrelor dose of 0.50 µg/kg/min and 0.25 µg/kg/min. Cmax was mesaured for cangrelor and AR-C69712XX (Cangrelor metabolite). The maximum measured cangrelor plasma concentrations were observed at the first sampling time point at 45 minutes post-start of infusion. Data was expressed with mean and standard deviation.

End point type

Primary

End point timeframe

Following the 60-minute IV infusion with a cangrelor dose of 0.50 µg/kg/min and 0.25 µg/kg/min, the maximum measured cangrelor plasma concentrations were observed at the first sampling time point at 45 minutes post-start of infusion.

Notes
[16] - 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 statistical analysis is planned for this end point.

End point values	Treatment Cohort 1-1E - PK	Treatment Cohort 2-2E - PK
Number of subjects analysed	8 ^[17]	7 ^[18]
Units: ng/mL
arithmetic mean (standard deviation)
Cangrelor	59.5 ( 15.1 )	18.9 ( 7.43 )
AR-C69712XX	18.6 ( 5.29 )	9.6 ( 3.44 )

Notes
[17] - PK population
[18] - PK population

No statistical analyses for this end point

Primary: 3_Summary of PK parameters by dose (Tmax)

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End point title

3_Summary of PK parameters by dose (Tmax) ^[19]

End point description

PK parameter was measured by Tmax (min) for cangrelor and AR-C69712XX (Cangrelor metabolite). Cangrelor was administrated at the following dose: 0.50 µg/kg/min and 0.25 µg/kg/min. Tmax for cangrelor was occurred at the first sampling time near to the end of infusion. Tmax for AR-C69712XX occurred at the end of IV infusion duration of 1 hour or at the first sampling time post end of infusion. Data was expressed with median (minimum-maximum).

End point type

Primary

End point timeframe

Tmax for cangrelor was occurred at the first sampling time near to the end of infusion. Tmax for AR-C69712XX occurred at the end of IV infusion duration of 1 hour or at the first sampling time post end of infusion.

Notes
[19] - 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 statistical analysis is planned for this end point.

End point values	Treatment Cohort 1-1E - PK	Treatment Cohort 2-2E - PK
Number of subjects analysed	8 ^[20]	7 ^[21]
Units: minutes
median (full range (min-max))
Cangrelor	45 (30 to 55)	45 (30 to 55)
AR-C69712XX	70 (45 to 90)	65 (55 to 70)

Notes
[20] - PK population
[21] - PK population

No statistical analyses for this end point

Primary: 3_Summary of PK parameters by dose (AUC 0-t)

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End point title

3_Summary of PK parameters by dose (AUC 0-t) ^[22]

End point description

PK parameter was measured by AUC 0-t from the start of dosing (zero) until the time of the last measurable concentration (AUC0-t) values. AUC 0-t was mesaured for cangrelor and AR-C69712XX (Cangrelor metabolite). The subjects received the following dose of cangrelor: 0.50 µg/kg/min and 0.25 µg/kg/min. Data was expressed with mean and standard deviation.

End point type

Primary

End point timeframe

Area under the plasma concentration time curve was mesaured from the start of dosing (zero) until the time of the last measurable concentration (AUC0-t) values.

Notes
[22] - 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 statistical analysis is planned for this end point.

End point values	Treatment Cohort 1-1E - PK	Treatment Cohort 2-2E - PK
Number of subjects analysed	8 ^[23]	7 ^[24]
Units: min*ng/mL
arithmetic mean (standard deviation)
Cangrelor	1985 ( 643 )	519 ( 161 )
AR-C69712XX	3400 ( 2110 )	1540 ( 650 )

Notes
[23] - PK population
[24] - PK population

No statistical analyses for this end point

Primary: 4_Summary of TEAEs (number of subject %)

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End point title

4_Summary of TEAEs (number of subject %) ^[25]

End point description

TEAEs were recorded from the time of the start of the cangrelor infusion until 48 ±6 hours post-treatment. TEAE includes any TEAE, Treatment emergent AESI and Treatment emergent SAE. Data were expressed with percent of number of subjects.

End point type

Primary

End point timeframe

TEAEs were recorded from the time of the start of the cangrelor infusion until 48 ±6 hours post-treatment.

Notes
[25] - 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 statistical analysis is planned for this end point.

End point values	Treatment Cohort 1-1E - Safety	Treatment Cohort 2-2E - Safety
Number of subjects analysed	8 ^[26]	7 ^[27]
Units: percentage of subjects
number (not applicable)
Any TEAE	100	85.7
Treatment-Emergent AESI	12.5	14.3
Treatment-Emergent SAE	12.5	14.3

Notes
[26] - safety population
[27] - safety population

No statistical analyses for this end point

Primary: 4_Summary of TEAEs (event)

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End point title

4_Summary of TEAEs (event) ^[28]

End point description

End point type

Primary

End point timeframe

TEAEs were recorded from the time of the start of the cangrelor infusion until 48 ±6 hours post-treatment.

Notes
[28] - 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 statistical analysis is planned for this end point.

End point values	Treatment Cohort 1-1E - Safety	Treatment Cohort 2-2E - Safety
Number of subjects analysed	8 ^[29]	7 ^[30]
Units: event
Any TEAE	24	27
Treatment-Emergent AESI	2	1
Treatment-Emergent SAE	2	1

Notes
[29] - safety population
[30] - safety population

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

AEs recorded from the time of the start of cangrelor infusion until 48 ±6 hours post-treatment.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.0

Reporting group title

Treatment- Cohort 1-1E

Reporting group description

8 subjects treated with 0.5 µg/kg/min of cangrelor.

Reporting group title

Treatment- Cohort 2-2E

Reporting group description

7 subjects treated with 0.25 µg/kg/min of cangrelor.

Serious adverse events	Treatment- Cohort 1-1E	Treatment- Cohort 2-2E
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 8 (12.50%)	1 / 7 (14.29%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0
Cardiac disorders
Supraventricular tachycardia
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 8 (12.50%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pneumothorax
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 8 (0.00%)	1 / 7 (14.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory failure
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 8 (12.50%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Treatment- Cohort 1-1E	Treatment- Cohort 2-2E
Total subjects affected by non serious adverse events
subjects affected / exposed	8 / 8 (100.00%)	6 / 7 (85.71%)
Investigations
Blood magnesium
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 8 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	1
C-reactive protein increased
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 8 (12.50%)	0 / 7 (0.00%)
occurrences all number	1	0
Calcium ionised decreased
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 8 (12.50%)	0 / 7 (0.00%)
occurrences all number	1	0
Haematocrit decreased
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 8 (12.50%)	0 / 7 (0.00%)
occurrences all number	1	0
Haemoglobin decreased
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 8 (12.50%)	0 / 7 (0.00%)
occurrences all number	1	0
Oxygen saturation decreased
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 8 (12.50%)	0 / 7 (0.00%)
occurrences all number	1	0
Prothrombin time prolonged
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 8 (12.50%)	0 / 7 (0.00%)
occurrences all number	1	0
Urine output decreased
alternative assessment type: Non-systematic
subjects affected / exposed	4 / 8 (50.00%)	0 / 7 (0.00%)
occurrences all number	4	0
Haemoglobin
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 8 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	1
Vascular disorders
Capillary leak syndrome
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 8 (12.50%)	0 / 7 (0.00%)
occurrences all number	1	0
Deep vein thrombosis
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 8 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	1
Haemorrhage
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 8 (12.50%)	0 / 7 (0.00%)
occurrences all number	1	0
Hypotension
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 8 (12.50%)	2 / 7 (28.57%)
occurrences all number	1	2
Peripheral artery thrombosis
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 8 (12.50%)	0 / 7 (0.00%)
occurrences all number	1	0
Thrombosis
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 8 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	1
Cardiac disorders
Atrial tachycardia
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 8 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	1
Low cardiac output syndrome
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 8 (12.50%)	0 / 7 (0.00%)
occurrences all number	1	0
Supraventricular tachycardia
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 8 (12.50%)	0 / 7 (0.00%)
occurrences all number	1	0
Blood and lymphatic system disorders
Thrombocytopenia
subjects affected / exposed	2 / 8 (25.00%)	0 / 7 (0.00%)
occurrences all number	2	0
General disorders and administration site conditions
Oedema
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 8 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	1
Pain
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 8 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	1
Psychiatric disorders
Agitation
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 8 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	1
Renal and urinary disorders
Hydronephrosis
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 8 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	1
Metabolism and nutrition disorders
Fluid overload
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 8 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	1
Hyperglycaemia
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 8 (0.00%)	3 / 7 (42.86%)
occurrences all number	0	3
Hyperkalaemia
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 8 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	1
Hypervolaemia
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 8 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	1
Hypocalcaemia
alternative assessment type: Non-systematic
subjects affected / exposed	3 / 8 (37.50%)	3 / 7 (42.86%)
occurrences all number	3	3
Hypokalaemia
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 8 (12.50%)	2 / 7 (28.57%)
occurrences all number	1	2
Hypomagnesaemia
alternative assessment type: Non-systematic
subjects affected / exposed	1 / 8 (12.50%)	1 / 7 (14.29%)
occurrences all number	1	1
Hyponatraemia
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 8 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	1
Hypovolaemia
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 8 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	1
Metabolic acidosis
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 8 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	1

More information

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Were there any global substantial amendments to the protocol? Yes

16 Apr 2016

Amendment #1 - The main changes from original version to Version 1 are: - Made the microfluidic flow chamber measurements an exploratory endpoint; - Inclusion criterion #2 modified to more specifically identify populations at high risk of a thrombotic event; - Exclusion criterion #5 changed to exclude subjects with weight ˂2.5 kg.

27 May 2016

Amendment #2 - The main changes from Version 1 to Version 2 are: - LTA to be performed using 5 μM and 20 μM ADP in platelet rich plasma to provide as complete information as possible on the PD profile of cangrelor in this population; - AEs and bleeding events to be graded using the 5-point scale recommended by the CTCAE (changed from grading AEs and bleeding events as mild, moderate, or severe for more accurate grading of the severity of AEs.

05 May 2017

Amendment # 3 - The main changes from Version 2 to Version 3 are: - The study was to include a minimum of 20 neonatal subjects; - The references to the volume of blood to be collected for PK and PD assessments was removed, and maximum mL/kg specified. The volumes of blood collected would be based on weight. - Added that any abnormal clinical laboratory test result obtained after treatment with cangrelor and/or during the follow up period which met the definition of AE or SAE. To provide guidelines to assist with determination of laboratory abnormalities as AEs and SAEs and to ensure they were properly recorded and repored. - Medication errors associated with AEs or SAEs to be reported as protocol deviations.

20 Jun 2017

Amendment #4 - The main changes from Version 3 to Version 4 are: - Added that the baseline ultrasound of the head could be performed up until 2 hours prior to surgery.To define the initial head ultrasound as baseline ultrasound and clarify the time frame in which the baseline ultrasound was performed.

22 Jan 2018

Amendment #5 - The main changes from Version 4 to Version 5 are: - Exclusion criterion #8 modified to “chest and/or mediastinal tube total fluid volume output of >3 mL/kg/hr at the time cangrelor is to be administered”. To clarify that the exclusionary volume of 3mL/kg/hr applied to the total output from both chest and mediastinal tubes, inclusive of all types of fluid output (e.g., clear, serosanguinous fluid,grossly bloody); - Exclusion criterion #9 modified to “subjects with evidence of sever hepatic or renal impairmen". To clarify that subjects with hepatic and renal impairment rather than failure were excluded per protocol criteria; - Safety endpoint(s) were revised to specify “clinically relevant” bleeding and to include bleeding in the urinary tract. To provide clarification regarding bleeding asAESI; add reference to urinary tract as bleeding is also assessed via urinalysis post-infusion.

25 Sep 2018

Amendment #6 - The main changes from Version 5 to Version 6 are: - Added expansion Cohort 1 and Cohort 2 To specify the expansion of the number of subjects in Cohort 1 and Cohort 2 and to obtain complete data from at least 5 subjects in each cohort; - Changed the PK and PD sample collection schedule for the expansion Cohorts 1 and 2 compared with the original PK and PD time points used for the first 5 subjects in Cohorts 1 and 2; - Addition of “diagnosed intravascular thrombosis” and “a confirmed decrease in either hemoglobin or hematocrit of >20% from the most proximate value measured at a protocol-required time point” to the list of AESIs to comply with the request of the DMC to include intravascular thrombosis as an AESI.

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.

None reported

http://www.ncbi.nlm.nih.gov/pubmed/33078501

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Clinical trials

Clinical Trial Results:
A Prospective, Open-Label, Single-Arm, Multi-Center Study to Assess The Pharmacokinetics/Pharmacodynamics (PK/PD) AND Safety Of Different Cangrelor Doses In Neonatal Subjects At Risk Of Thrombosis.

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Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: 1_Proportion of subjects who achieved ≥90% inhibition of maximal and final platelet aggregation

Primary: 1_Proportion of subjects who achieved ≥90% inhibition of maximal and final platelet aggregation

Primary: 1_Percent inhibition of platelet aggregation by LTA during the infusion-mean values

Primary: 1_Percent inhibition of platelet aggregation by LTA during the infusion-mean values

Primary: 1_Percent inhibition of platelet aggregation by LTA during the infusion-median values

Primary: 1_Percent inhibition of platelet aggregation by LTA during the infusion-median values

Primary: 2_Percent recovery of platelet function by LTA assay after the infusion

Primary: 2_Percent recovery of platelet function by LTA assay after the infusion

Primary: 2_Percent recovery of platelet function by LTA assay after the infusion-mean values

Primary: 2_Percent recovery of platelet function by LTA assay after the infusion-mean values

Primary: 3_Summary of PK parameters by dose (Cmax)

Primary: 3_Summary of PK parameters by dose (Cmax)

Primary: 3_Summary of PK parameters by dose (Tmax)

Primary: 3_Summary of PK parameters by dose (Tmax)

Primary: 3_Summary of PK parameters by dose (AUC 0-t)

Primary: 3_Summary of PK parameters by dose (AUC 0-t)

Primary: 4_Summary of TEAEs (number of subject %)

Primary: 4_Summary of TEAEs (number of subject %)

Primary: 4_Summary of TEAEs (event)

Primary: 4_Summary of TEAEs (event)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

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Clinical trials

Clinical Trial Results: A Prospective, Open-Label, Single-Arm, Multi-Center Study to Assess The Pharmacokinetics/Pharmacodynamics (PK/PD) AND Safety Of Different Cangrelor Doses In Neonatal Subjects At Risk Of Thrombosis.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: 1_Proportion of subjects who achieved ≥90% inhibition of maximal and final platelet aggregation

Primary: 1_Proportion of subjects who achieved ≥90% inhibition of maximal and final platelet aggregation

Primary: 1_Percent inhibition of platelet aggregation by LTA during the infusion-mean values

Primary: 1_Percent inhibition of platelet aggregation by LTA during the infusion-mean values

Primary: 1_Percent inhibition of platelet aggregation by LTA during the infusion-median values

Primary: 1_Percent inhibition of platelet aggregation by LTA during the infusion-median values

Primary: 2_Percent recovery of platelet function by LTA assay after the infusion

Primary: 2_Percent recovery of platelet function by LTA assay after the infusion

Primary: 2_Percent recovery of platelet function by LTA assay after the infusion-mean values

Primary: 2_Percent recovery of platelet function by LTA assay after the infusion-mean values

Primary: 3_Summary of PK parameters by dose (Cmax)

Primary: 3_Summary of PK parameters by dose (Cmax)

Primary: 3_Summary of PK parameters by dose (Tmax)

Primary: 3_Summary of PK parameters by dose (Tmax)

Primary: 3_Summary of PK parameters by dose (AUC 0-t)

Primary: 3_Summary of PK parameters by dose (AUC 0-t)

Primary: 4_Summary of TEAEs (number of subject %)

Primary: 4_Summary of TEAEs (number of subject %)

Primary: 4_Summary of TEAEs (event)

Primary: 4_Summary of TEAEs (event)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
A Prospective, Open-Label, Single-Arm, Multi-Center Study to Assess The Pharmacokinetics/Pharmacodynamics (PK/PD) AND Safety Of Different Cangrelor Doses In Neonatal Subjects At Risk Of Thrombosis.