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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

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    Trial identification
    Sponsor protocol code
    MDCO-CAN-15-01
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02765633
    WHO universal trial number (UTN)
    -
    Sponsors
    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
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 Apr 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Aug 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    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
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 20
    Worldwide total number of subjects
    20
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    20
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    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.

    Pre-assignment
    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.

    Pre-assignment period milestones
    Number of subjects started
    22 [1]
    Number of subjects completed
    15

    Pre-assignment subject non-completion reasons
    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
    Period 1 title
    1_Treatment and FU (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    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.

    Arm title
    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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    Baseline characteristics reporting groups
    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 sets

    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
    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 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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    End points reporting groups
    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
    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
    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 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.

    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
    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 as number of events.
    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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    Adverse events information
    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 used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    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%)
    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
    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
    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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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    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.

    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.
    None reported

    Online references

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