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    Clinical Trial Results:
    Gadopiclenol Pharmacokinetics, Safety and Efficacy in Pediatric Patients < 2 Years of Age Undergoing Contrast-enhanced MRI

    Summary
    EudraCT number
    		 2021-003825-31
    Trial protocol
    		 HU   PL   BG  
    Global end of trial date
    30 Sep 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Apr 2025
    First version publication date
    16 Apr 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GDX-44-015
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05590884
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IND No.: : 123673
    Sponsors
    Sponsor organisation name
    Guerbet
    Sponsor organisation address
    15, rue des Vanesses, Villepinte, France, 93420
    Public contact
    Frantz Hebert, Global Head of Clinical Development, Guerbet, +33 680249334, frantz.hebert@guerbet.com
    Scientific contact
    Frantz Hebert, Global Head of Clinical Development, Guerbet, +33 680249334, frantz.hebert@guerbet.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001949-PIP01-16 EMEA-001949-PIP02-18
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    19 Dec 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Sep 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Sep 2024
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the pharmacokinetic profile of gadopiclenol in plasma following single intravenous injection of 0.05 mmol/kg body weight (BW) in pediatric population aged up to 23 months (inclusive) scheduled for a contrast-enhanced MRI examination of any body region including central nervous system (CNS).
    Protection of trial subjects
    This trial has been conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, that are consistent with Good Clinical Practice (GCP) according to International Conference on Harmonisation (ICH) guidelines and with the applicable regional/local regulations of the country in which the trial was conducted. The safety data were monitored during the whole study period. A Trial Safety Review Board (TSRB) was set up to ensure the participants’ safety, appraise the trial conduct and progress and make a decision on providing green light for next age group (when applicable).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Sep 2022
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 3 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 19
    Country: Number of subjects enrolled
    Hungary: 12
    Country: Number of subjects enrolled
    United States: 5
    Worldwide total number of subjects
    36
    EEA total number of subjects
    31
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    1
    Infants and toddlers (28 days-23 months)
    35
    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
    		 The inclusions started with the oldest patients (3 to 23 months). The aged-down staggered approach was discontinued to allow the inclusions of patients aged from birth to 27 days, simultaneously to inclusions of other 2 age groups (3-23 months group and 28- 89 days group). The inclusions in the 3 age groups were therefore completed in parallel.

    Pre-assignment
    Screening details
    		 A total of 41 patients were enrolled. Among them, five patients were screen failed. Therefore, 36 patients received an injection of gadopiclenol for MRI: 33 aged 3-23 months, 2 aged 28-89 days and 1 aged 0-27 days. One patient aged 3-23 months prematurely discontinued the study before the 1-day safety follow-up due to withdrawal of consent.

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group1: 3-23 months
    Arm description
    		 Patients aged 3-23 months who underwent a contrast-enhanced MRI examination of any body region including central nervous system (CNS cohort), vessels (Blood vessel cohort) and pool of others region (Body cohort)
    Arm type
    		 Experimental

    Investigational medicinal product name
    gadopiclenol
    Investigational medicinal product code
    P03277
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    gadopiclenol administered at a dose of 0.05 mmol/kg body weight (0.1 mL/kg body weight) in a single injection

    Arm title
    		 Group 2: 28-89 days
    Arm description
    		 Patients aged 28-89 days who underwent a contrast-enhanced MRI examination of any body region including central nervous system (CNS cohort), vessels (Blood vessel cohort) and pool of others region (Body cohort)
    Arm type
    		 Experimental

    Investigational medicinal product name
    gadopiclenol
    Investigational medicinal product code
    P03277
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    gadopiclenol administered at a dose of 0.05 mmol/kg body weight (0.1 mL/kg body weight) in a single injection

    Arm title
    		 Group 3: 0-27 days
    Arm description
    		 Patients aged 0-27 days who underwent a contrast-enhanced MRI examination of any body region including central nervous system (CNS cohort), vessels (Blood vessel cohort) and pool of others region (Body cohort)
    Arm type
    		 Experimental

    Investigational medicinal product name
    gadopiclenol
    Investigational medicinal product code
    P03277
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    gadopiclenol administered at a dose of 0.05 mmol/kg body weight (0.1 mL/kg body weight) in a single injection

    Number of subjects in period 1
    		Group1: 3-23 months Group 2: 28-89 days Group 3: 0-27 days
    Started
    33
    2
    1
    Completed
    33
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group1: 3-23 months
    Reporting group description
    		 Patients aged 3-23 months who underwent a contrast-enhanced MRI examination of any body region including central nervous system (CNS cohort), vessels (Blood vessel cohort) and pool of others region (Body cohort)

    Reporting group title
    Group 2: 28-89 days
    Reporting group description
    		 Patients aged 28-89 days who underwent a contrast-enhanced MRI examination of any body region including central nervous system (CNS cohort), vessels (Blood vessel cohort) and pool of others region (Body cohort)

    Reporting group title
    Group 3: 0-27 days
    Reporting group description
    		 Patients aged 0-27 days who underwent a contrast-enhanced MRI examination of any body region including central nervous system (CNS cohort), vessels (Blood vessel cohort) and pool of others region (Body cohort)

    Reporting group values
    		 Group1: 3-23 months Group 2: 28-89 days Group 3: 0-27 days Total
    Number of subjects
    		 33 2 1 36
    Age categorical
    Units: Subjects
        Newborns (0-27 days)
    		 0 0 1 1
        3-23 months
    		 33 0 0 33
        28-89 days
    		 0 2 0 2
    Age continuous
    Units: months
        arithmetic mean (standard deviation)
    		 13.11 ( 6.22 ) 1.94 ( 0.14 ) 0.8 ( 0 ) -
    Gender categorical
    Units: Subjects
        Female
    		 17 1 0 18
        Male
    		 16 1 1 18
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 9.40 ( 2.18 ) 5.10 ( 0.28 ) 4.50 ( ) -
    Subject analysis sets

    Subject analysis set title
    Pharmacokinetics Analyses
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients from the GDX-44-015 Per Protocol Set (PPS) population including all patients in the Safety Set without major deviations likely to impact the population PK model was used for the population PK analysis (35 patients). The reference population including 134 participants from studies GDX-44-003 (adult participants with normal renal function), GDX-44-005 (including adult participants with renal impairment [mild, moderate or severe]) and GDX-44-007 pediatric patients (2-17 years old) was used to set up gadopiclenol popPK model. Due to incomplete recruitment in study GDX-44-015, with only 2 patients aged 28-89 days and none aged less than 28 days who could be included in the popPK analysis, exposure in these groups was only obtained by simulation using the final model.

    Subject analysis sets values
    		 Pharmacokinetics Analyses
    Number of subjects
    35
    Age categorical
    Units: Subjects
        Newborns (0-27 days)
    1
        3-23 months
    32
        28-89 days
    2
    Age continuous
    Units: months
        arithmetic mean (standard deviation)
    12.1 ( 6.6 )
    Gender categorical
    Units: Subjects
        Female
    18
        Male
    17
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    9.16 ( 2.35 )

    End points

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    End points reporting groups
    Reporting group title
    Group1: 3-23 months
    Reporting group description
    		 Patients aged 3-23 months who underwent a contrast-enhanced MRI examination of any body region including central nervous system (CNS cohort), vessels (Blood vessel cohort) and pool of others region (Body cohort)

    Reporting group title
    Group 2: 28-89 days
    Reporting group description
    		 Patients aged 28-89 days who underwent a contrast-enhanced MRI examination of any body region including central nervous system (CNS cohort), vessels (Blood vessel cohort) and pool of others region (Body cohort)

    Reporting group title
    Group 3: 0-27 days
    Reporting group description
    		 Patients aged 0-27 days who underwent a contrast-enhanced MRI examination of any body region including central nervous system (CNS cohort), vessels (Blood vessel cohort) and pool of others region (Body cohort)

    Subject analysis set title
    Pharmacokinetics Analyses
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients from the GDX-44-015 Per Protocol Set (PPS) population including all patients in the Safety Set without major deviations likely to impact the population PK model was used for the population PK analysis (35 patients). The reference population including 134 participants from studies GDX-44-003 (adult participants with normal renal function), GDX-44-005 (including adult participants with renal impairment [mild, moderate or severe]) and GDX-44-007 pediatric patients (2-17 years old) was used to set up gadopiclenol popPK model. Due to incomplete recruitment in study GDX-44-015, with only 2 patients aged 28-89 days and none aged less than 28 days who could be included in the popPK analysis, exposure in these groups was only obtained by simulation using the final model.

    Primary: Area under the curve (AUCinf)

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    End point title
    		 Area under the curve (AUCinf) [1]
    End point description
    Exposure parameter by age group predicted from the final model in participants with normal renal function receiving gadopiclenol 0.05 mmol/kg
    End point type
    Primary
    End point timeframe
    Three blood samples per patient were collected post-injection of gadopiclenol for PK analysis, one within each window (10-60 min, 2-4 hours, 6-8 h). Each time window contained 4 time points for blood collection.
    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: The primary criteria was pharmacokinetics in plasma for pediatric patients aged up to 23 months (inclusive) assessed based on the following pharmacokinetic parameters determined from the population PK (popPK) model: simulated concentrations at 10, 20, and 30 minutes post injection (C10 min, C20 min, C30 min); Area Under the Curve (AUC); Elimination half-life; Total clearance (CL); Volume of distribution. Descriptive statistical analysis was performed for pharmacokinetic profile in plasma.
    End point values
    		 Group1: 3-23 months Group 2: 28-89 days Group 3: 0-27 days
    Number of subjects analysed
    33
    2
    0 [2]
    Units: h.mg/L
        geometric mean (geometric coefficient of variation)
    392.3 ( 27.6 )
    493.3 ( 9.9 )
    ( )
    Notes
    [2] - The patient aged 0-27 days was excluded from the Per Protocol Set due to a major deviation.
    No statistical analyses for this end point

    Primary: Terminal half-life (t1/2α)

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    End point title
    		 Terminal half-life (t1/2α) [3]
    End point description
    Exposure parameter by age group predicted from the final model in participants with normal renal function receiving gadopiclenol 0.05 mmol/kg
    End point type
    Primary
    End point timeframe
    Three blood samples per patient were collected post-injection of gadopiclenol for PK analysis, one within each window (10-60 min, 2-4 hours, 6-8 h). Each time window contained 4 time points for blood collection.
    Notes
    [3] - 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: The primary criteria was pharmacokinetics in plasma for pediatric patients aged up to 23 months (inclusive) assessed based on the following pharmacokinetic parameters determined from the population PK (popPK) model: simulated concentrations at 10, 20, and 30 minutes post injection (C10 min, C20 min, C30 min); Area Under the Curve (AUC); Elimination half-life; Total clearance (CL); Volume of distribution. Descriptive statistical analysis was performed for pharmacokinetic profile in plasma.
    End point values
    		 Group1: 3-23 months Group 2: 28-89 days Group 3: 0-27 days
    Number of subjects analysed
    33
    2
    0 [4]
    Units: h
        geometric mean (geometric coefficient of variation)
    0.3 ( 30.3 )
    0.3 ( 30.3 )
    ( )
    Notes
    [4] - The patient aged 0-27 days was excluded from the Per Protocol Set, due to a major deviation.
    No statistical analyses for this end point

    Primary: Terminal half-life (t1/2β)

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    End point title
    		 Terminal half-life (t1/2β) [5]
    End point description
    Exposure parameter by age group predicted from the final model in participants with normal renal function receiving gadopiclenol 0.05 mmol/kg
    End point type
    Primary
    End point timeframe
    Three blood samples per patient were collected post-injection of gadopiclenol for PK analysis, one within each window (10-60 min, 2-4 hours, 6-8 h). Each time window contained 4 time points for blood collection.
    Notes
    [5] - 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: The primary criteria was pharmacokinetics in plasma for pediatric patients aged up to 23 months (inclusive) assessed based on the following pharmacokinetic parameters determined from the population PK (popPK) model: simulated concentrations at 10, 20, and 30 minutes post injection (C10 min, C20 min, C30 min); Area Under the Curve (AUC); Elimination half-life; Total clearance (CL); Volume of distribution. Descriptive statistical analysis was performed for pharmacokinetic profile in plasma.
    End point values
    		 Group1: 3-23 months Group 2: 28-89 days Group 3: 0-27 days
    Number of subjects analysed
    33
    2
    0 [6]
    Units: h
        geometric mean (geometric coefficient of variation)
    1.5 ( 21.4 )
    2.1 ( 8.4 )
    ( )
    Notes
    [6] - The patient aged 0-27 days was excluded from the Per Protocol Set, due to a major deviation.
    No statistical analyses for this end point

    Primary: Gadopiclenol concentrations 10 min post-injection (C10 min)

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    End point title
    		 Gadopiclenol concentrations 10 min post-injection (C10 min) [7]
    End point description
    Exposure parameter by age group predicted from the final model in participants with normal renal function receiving gadopiclenol 0.05 mmol/kg
    End point type
    Primary
    End point timeframe
    Three blood samples per patient were collected post-injection of gadopiclenol for PK analysis, one within each window (10-60 min, 2-4 hours, 6-8 h). Each time window contained 4 time points for blood collection.
    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: The primary criteria was pharmacokinetics in plasma for pediatric patients aged up to 23 months (inclusive) assessed based on the following pharmacokinetic parameters determined from the population PK (popPK) model: simulated concentrations at 10, 20, and 30 minutes post injection (C10 min, C20 min, C30 min); Area Under the Curve (AUC); Elimination half-life; Total clearance (CL); Volume of distribution. Descriptive statistical analysis was performed for pharmacokinetic profile in plasma.
    End point values
    		 Group1: 3-23 months Group 2: 28-89 days Group 3: 0-27 days
    Number of subjects analysed
    33
    2
    0 [8]
    Units: mg/L
        geometric mean (geometric coefficient of variation)
    226.8 ( 15.8 )
    190.4 ( 16.2 )
    ( )
    Notes
    [8] - The patient aged 0-27 days was excluded from the Per Protocol Set, due to a major deviation.
    No statistical analyses for this end point

    Primary: Gadopiclenol concentration 20 min post-injection (C20 min)

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    End point title
    		 Gadopiclenol concentration 20 min post-injection (C20 min) [9]
    End point description
    Exposure parameter by age group predicted from the final model in participants with normal renal function receiving gadopiclenol 0.05 mmol/kg
    End point type
    Primary
    End point timeframe
    Three blood samples per patient were collected post-injection of gadopiclenol for PK analysis, one within each window (10-60 min, 2-4 hours, 6-8 h). Each time window contained 4 time points for blood collection.
    Notes
    [9] - 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: The primary criteria was pharmacokinetics in plasma for pediatric patients aged up to 23 months (inclusive) assessed based on the following pharmacokinetic parameters determined from the population PK (popPK) model: simulated concentrations at 10, 20, and 30 minutes post injection (C10 min, C20 min, C30 min); Area Under the Curve (AUC); Elimination half-life; Total clearance (CL); Volume of distribution. Descriptive statistical analysis was performed for pharmacokinetic profile in plasma.
    End point values
    		 Group1: 3-23 months Group 2: 28-89 days Group 3: 0-27 days
    Number of subjects analysed
    33
    2
    0 [10]
    Units: mg/L
        geometric mean (geometric coefficient of variation)
    161.5 ( 17.2 )
    149.8 ( 13.4 )
    ( )
    Notes
    [10] - The patient aged 0-27 days was excluded from the Per Protocol Set, due to a major deviation.
    No statistical analyses for this end point

    Primary: Gadopiclenol concentrations 30 min post-injection (C30 min)

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    End point title
    		 Gadopiclenol concentrations 30 min post-injection (C30 min) [11]
    End point description
    Exposure parameter by age group predicted from the final model in participants with normal renal function receiving gadopiclenol 0.05 mmol/kg
    End point type
    Primary
    End point timeframe
    Three blood samples per patient were collected post-injection of gadopiclenol for PK analysis, one within each window (10-60 min, 2-4 hours, 6-8 h). Each time window contained 4 time points for blood collection.
    Notes
    [11] - 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: The primary criteria was pharmacokinetics in plasma for pediatric patients aged up to 23 months (inclusive) assessed based on the following pharmacokinetic parameters determined from the population PK (popPK) model: simulated concentrations at 10, 20, and 30 minutes post injection (C10 min, C20 min, C30 min); Area Under the Curve (AUC); Elimination half-life; Total clearance (CL); Volume of distribution. Descriptive statistical analysis was performed for pharmacokinetic profile in plasma.
    End point values
    		 Group1: 3-23 months Group 2: 28-89 days Group 3: 0-27 days
    Number of subjects analysed
    33
    2
    0 [12]
    Units: mg/L
        geometric mean (geometric coefficient of variation)
    109.4 ( 22.4 )
    116.2 ( 13.3 )
    ( )
    Notes
    [12] - The patient aged 0-27 days was excluded from the Per Protocol Set, due to a major deviation.
    No statistical analyses for this end point

    Primary: Clearance

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    End point title
    		 Clearance [13]
    End point description
    Individual predicted final model parameters scaled by body weight
    End point type
    Primary
    End point timeframe
    Three blood samples per patient were collected post-injection of gadopiclenol for PK analysis, one within each window (10-60 min, 2-4 hours, 6-8 h). Each time window contained 4 time points for blood collection.
    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: The primary criteria was pharmacokinetics in plasma for pediatric patients aged up to 23 months (inclusive) assessed based on the following pharmacokinetic parameters determined from the population PK (popPK) model: simulated concentrations at 10, 20, and 30 minutes post injection (C10 min, C20 min, C30 min); Area Under the Curve (AUC); Elimination half-life; Total clearance (CL); Volume of distribution. Descriptive statistical analysis was performed for pharmacokinetic profile in plasma.
    End point values
    		 Group1: 3-23 months Group 2: 28-89 days Group 3: 0-27 days
    Number of subjects analysed
    33
    2
    0 [14]
    Units: L/h/kg
        arithmetic mean (standard deviation)
    0.128 ( 0.035 )
    0.097 ( 0.004 )
    ( )
    Notes
    [14] - The patient aged 0-27 days was excluded from the Per Protocol Set, due to a major deviation.
    No statistical analyses for this end point

    Primary: Central volume of distribution (V1)

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    End point title
    		 Central volume of distribution (V1) [15]
    End point description
    Individual predicted final model parameters scaled by body weight
    End point type
    Primary
    End point timeframe
    Three blood samples per patient were collected post-injection of gadopiclenol for PK analysis, one within each window (10-60 min, 2-4 hours, 6-8 h). Each time window contained 4 time points for blood collection.
    Notes
    [15] - 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: The primary criteria was pharmacokinetics in plasma for pediatric patients aged up to 23 months (inclusive) assessed based on the following pharmacokinetic parameters determined from the population PK (popPK) model: simulated concentrations at 10, 20, and 30 minutes post injection (C10 min, C20 min, C30 min); Area Under the Curve (AUC); Elimination half-life; Total clearance (CL); Volume of distribution. Descriptive statistical analysis was performed for pharmacokinetic profile in plasma.
    End point values
    		 Group1: 3-23 months Group 2: 28-89 days Group 3: 0-27 days
    Number of subjects analysed
    33
    2
    0 [16]
    Units: L/kg
        arithmetic mean (standard deviation)
    0.176 ( 0.033 )
    0.214 ( 0.03 )
    ( )
    Notes
    [16] - The patient aged 0-27 days was excluded from the Per Protocol Set, due to a major deviation.
    No statistical analyses for this end point

    Primary: Inter-compartment clearance (Q)

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    End point title
    		 Inter-compartment clearance (Q) [17]
    End point description
    Individual predicted final model parameters scaled by body weight
    End point type
    Primary
    End point timeframe
    Three blood samples per patient were collected post-injection of gadopiclenol for PK analysis, one within each window (10-60 min, 2-4 hours, 6-8 h). Each time window contained 4 time points for blood collection.
    Notes
    [17] - 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: The primary criteria was pharmacokinetics in plasma for pediatric patients aged up to 23 months (inclusive) assessed based on the following pharmacokinetic parameters determined from the population PK (popPK) model: simulated concentrations at 10, 20, and 30 minutes post injection (C10 min, C20 min, C30 min); Area Under the Curve (AUC); Elimination half-life; Total clearance (CL); Volume of distribution. Descriptive statistical analysis was performed for pharmacokinetic profile in plasma.
    End point values
    		 Group1: 3-23 months Group 2: 28-89 days Group 3: 0-27 days
    Number of subjects analysed
    33
    2
    0 [18]
    Units: L/h/kg
        arithmetic mean (standard deviation)
    0.099 ( 0.025 )
    0.123 ( 0.029 )
    ( )
    Notes
    [18] - The patient aged 0-27 days was excluded from the Per Protocol Set, due to a major deviation.
    No statistical analyses for this end point

    Primary: Peripheral volume of distribution (V2)

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    End point title
    		 Peripheral volume of distribution (V2) [19]
    End point description
    Individual predicted final model parameters scaled by body weight
    End point type
    Primary
    End point timeframe
    Three blood samples per patient were collected post-injection of gadopiclenol for PK analysis, one within each window (10-60 min, 2-4 hours, 6-8 h). Each time window contained 4 time points for blood collection.
    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: The primary criteria was pharmacokinetics in plasma for pediatric patients aged up to 23 months (inclusive) assessed based on the following pharmacokinetic parameters determined from the population PK (popPK) model: simulated concentrations at 10, 20, and 30 minutes post injection (C10 min, C20 min, C30 min); Area Under the Curve (AUC); Elimination half-life; Total clearance (CL); Volume of distribution. Descriptive statistical analysis was performed for pharmacokinetic profile in plasma.
    End point values
    		 Group1: 3-23 months Group 2: 28-89 days Group 3: 0-27 days
    Number of subjects analysed
    33
    2
    0 [20]
    Units: L/kg
        arithmetic mean (standard deviation)
    0.066 ( 0.014 )
    0.066 ( 0.003 )
    ( )
    Notes
    [20] - The patient aged 0-27 days was excluded from the Per Protocol Set, due to a major deviation
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AE) occurring from the beginning of patient’s participation in the trial (Informed Consent Form signature) until the end of the participation (up to 3 months following gadopiclenol administration.
    Adverse event reporting additional description
    Physical examination at visits; Vital signs at 3 times points; Safety laboratory variables centrally analyzed; Estimated glomerular filtration rate (eGFR) centrally calculated; Tolerance at the injection site at 3 time points; Clinical examination for active detection of Nephrogenic Systemic Fibrosis (NSF) at 3-month follow-up safety visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    Safety Set
    Reporting group description
    		 All patients who received at least one administration of IMP. This set was used for evaluation of safety, exposure to IMP, description of demographic data and baseline characteristics.

    Serious adverse events
    		 Safety Set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 36 (22.22%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Surgical and medical procedures
    Tumour excision
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Cerebral cyst
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Microcytic anaemia
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Gastroenteritis norovirus
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia parainfluenzae viral
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Product issues
    Device malfunction
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Feeding disorder
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Safety Set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 36 (41.67%)
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences all number
    1
    Serum ferritin increased
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences all number
    1
    White blood cell count increased
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences all number
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences all number
    1
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences all number
    1
    Eye disorders
    Astigmatism
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences all number
    1
    Myopia
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences all number
    1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    5 / 36 (13.89%)
         occurrences all number
    5
    Diarrhoea
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Choking
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences all number
    1
    Cough
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences all number
    1
    Nasal congestion
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences all number
    1
    Rhinorrhoea
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences all number
    1
    Rash
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences all number
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences all number
    1
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences all number
    1
    Hand-foot-and-mouth disease
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences all number
    1
    Paronychia
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences all number
    1
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences all number
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences all number
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Jul 2022
    The main changes in this amendment were implemented to allow local testing of creatinine (Cr) and estimated Glomerular Filtration Rate (eGFR) calculation based on bedside Schwartz equation to check the non-inclusion criterion 3. The rational for this change was to shorten turnaround time to obtain eGFR to check patient’s eligibility when central laboratory results might not be available at the time of the planned inclusion MRI. Other changes implemented in the amendment were linked to the information regarding completed clinical trials updated in the Investigator’s Brochure (IB) version N°11 dated 22 April 2022 and typo corrections.
    24 Jun 2023
    The following changes were implemented: • Discontinuation of the aged-down staggered approach to allow the inclusions in Group 3 (patients aged from birth to 27 days), • Inclusion criteria# 2 updated to clarify that it is not mandatory for patients to have previous imaging examinations, • Exceptional circumstances related to COVID-19 restrictions removed, due to the end of COVID-19 pandemic. This version has not been applicable and was not distributed to sites. The changes were implemented in the following version v4.0.
    09 Oct 2023
    The protocol V4 includes both amendments 2 described above and Amendment 3. The amendment 3 allows the collection of PK samples from the same line used for the IMP injection, considering that the saline flush after IMP injection will eliminate all remnants of IMP from the line, or alternatively the use of a capillary specimen (for example heel-pricks or finger pricks), in the event of any difficulties to place and/or maintain the peripheral intravenous line into a vein.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    17 Jul 2024
    Following consultation with FDA and EMA and their favorable opinion for reducing the sample size initially considered, an early termination of the study was decided on 17 July 2024. The total number of patients enrollment was reduced to at least 33 patients less than 2 years old and the requirement for a minimum number of enrolled patients less than 28 days old (FDA) or less than 3 months (EMA) was removed. This early termination was not due to any safety or tolerability concern or event with the use of Gadopiclenol. Pharmacokinetic samples collected from the 33 first patients included in the study in the 3-23 months age group were used for a preliminary check of the adequacy of the pre-existing population PK model developed with serum creatinine as covariate, based on PK data obtained in adults, renal impaired subjects and children aged 2 years and older. This preliminary evaluation confirmed that the data for the 33 patients could be included in the existing popPK model and were sufficient to achieve the study objectives. Based on the above rationale and as per the concurrence by the FDA and EMA, the expected exposure parameters for the younger age groups will be predicted by simulation, since the preliminary evaluation performed on the data collected from the first 33 patients demonstrated that the following conditions are met: 1. There is no concern to combine pediatric and pre-existing data in a single population PK model, 2. The maturation of the renal function in children from age groups 2 and 3 is appropriately incorporated in the model, 3. Reducing the sample size will not compromise the achievement of the primary objective. From 17 July 2024, no further patient was screened and received an injection of gadopiclenol while all ongoing patients were followed for 3 months post gadopiclenol administration as per protocol.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to incomplete recruitment in study GDX-44-015, with only 2 patients aged 28-89 days and none aged less than 28 days who could be included in the popPK analysis, exposure in these groups was only obtained by simulation using the final model.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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