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    Clinical Trial Results:
    NOR-GRASPALL 2016: SINGLE-ARM PHARMACOKINETIC/PHARMACODYNAMIC AND SAFETY STUDY OF ERYASPASE (GRASPA®) FOR PATIENTS WITH HYPERSENSITIVITY TO PEG-ASPARAGINASE, DIAGNOSED WITH PH(-) ACUTE LYMPHOBLASTIC LEUKEMIA

    Summary
    EudraCT number
    		 2016-004451-70
    Trial protocol
    		 DK   NO   FI   SE   EE   LT  
    Global end of trial date
    22 Nov 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Mar 2022
    First version publication date
    13 Mar 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NOR-GRASPALL-2016
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03267030
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Aarhus University Hospital
    Sponsor organisation address
    Palle Juul-Jensens Boulevard 99, Aarhus N, Denmark, 8200
    Public contact
    Birgitte Klug Albertsen, Department of Paediatrics and Adolescent Medicine, Aarhus University Hospital, 0045 20224643, biralber@rm.dk
    Scientific contact
    Birgitte Klug Albertsen, Department of Paediatrics and Adolescent Medicine, Aarhus University Hospital, 0045 20224643, biralber@rm.dk
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Feb 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Nov 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Nov 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Main objectives of this study are to evaluate the pharmakinetic and pharmacodynamic profile of eryaspase administered to patients who experience a PEG-asparaginase hypersensitivity event during treatment with the multi-agent NOPHO ALL 2008 or ALLTogether chemotherapy for the treatment of children and adult patients with ALL
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements related to safety of trial subjects were also followed during the conduct of the trial. Written informed consent was obtained from all participants, for children both parents or legal guardians signed the informed consent. Children aged 15 to 17 years were allowed to give written informed consent for themselves, in close collaboration with their parents or legal guardians. Data was registered, saved and managed using REDCap (Research Electronic Data Capture), hosted at the Department of Clinical Medicine, Aarhus University. REDCap is a secure, web-based software platform designed to support data capture for research studies.
    Background therapy
    		 All patients received backbone therapy according to the NOPHO ALL2008 protocol or the ALLTogether Pilot protocol.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Jan 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Norway: 5
    Country: Number of subjects enrolled
    Sweden: 15
    Country: Number of subjects enrolled
    Denmark: 10
    Country: Number of subjects enrolled
    Estonia: 3
    Country: Number of subjects enrolled
    Finland: 8
    Country: Number of subjects enrolled
    Lithuania: 14
    Worldwide total number of subjects
    55
    EEA total number of subjects
    55
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    2
    Children (2-11 years)
    40
    Adolescents (12-17 years)
    11
    Adults (18-64 years)
    2
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study participants were recruited on the site when a participant developed clinical allergy or if inactivation of asparaginase enzyme activity was identified using therapeutic drug monitoring.

    Pre-assignment
    Screening details
    		 Medical assessment and therapeutic drug monitoring

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Intervention
    Arm description
    		 Single-arm study. All patients with hypersensitivity to PEG-asparaginase recieved 1–7 doses of eryaspase (150 IU/kg) with two-week or six-week intervals. The number of doses depended on number of PEG-asparaginase doses administered before inclusion and the number of dose sheduled in the backbone treatment protocol (NOPHO ALL2008 protocol 8 doses with 2- and 6-weeks intervals for all patients. ALLTogether Pilot protocol 1-4 doses scheduled with 2-weeks interval stratified by ALL risk group)
    Arm type
    		 Experimental

    Investigational medicinal product name
    GRASPA
    Investigational medicinal product code
    Other name
    Eryaspase
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    All patients with hypersensitivity to PEG-asparaginase recieved 1–7 doses of eryaspase (150 IU/kg) with two-week or six-week intervals. The number of doses depended on number of PEG-asparaginase doses administered before inclusion and the number of dose sheduled in the backbone treatment protocol (NOPHO ALL2008 protocol 8 doses with 2- and 6-weeks intervals for all patients. ALLTogether Pilot protocol 1–4 doses scheduled with 2-weeks interval stratified by ALL risk group)

    Number of subjects in period 1
    		Intervention
    Started
    55
    Completed
    50
    Not completed
    5
         Adverse event, serious fatal
    1
         Consent withdrawn by subject
    1
         Adverse event, non-fatal
    2
         Protocol deviation
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 Total study population

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 55 55
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 2 2
        Children (2-11 years)
    		 43 43
        Adolescents (12-17 years)
    		 8 8
        Adults (18-64 years)
    		 2 2
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 6.1 (3.5 to 10.6) -
    Gender categorical
    Units: Subjects
        Female
    		 17 17
        Male
    		 38 38

    End points

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    End points reporting groups
    Reporting group title
    Intervention
    Reporting group description
    		 Single-arm study. All patients with hypersensitivity to PEG-asparaginase recieved 1–7 doses of eryaspase (150 IU/kg) with two-week or six-week intervals. The number of doses depended on number of PEG-asparaginase doses administered before inclusion and the number of dose sheduled in the backbone treatment protocol (NOPHO ALL2008 protocol 8 doses with 2- and 6-weeks intervals for all patients. ALLTogether Pilot protocol 1-4 doses scheduled with 2-weeks interval stratified by ALL risk group)

    Primary: Primary Pharmacokinetic Parameters

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    End point title
    		 Primary Pharmacokinetic Parameters [1]
    End point description
    The primary endpoint was patients with ASNase activity >100 U/L at 14 days following the first infusion (nadir). The primary Evaluable Patients Population was used for the analysis of the primary and key secondary endpoints, defined as all patients recruited into the study who provided data on ASNase level on Day 14 (±2 days) following the first administration of eryaspase.
    End point type
    Primary
    End point timeframe
    6 months
    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 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 have been performed for the end points due to few included patients and only one study group. The manuscript (containing some statistics information) will be uploaded as soon as it is published.
    End point values
    		 Intervention
    Number of subjects analysed
    53 [2]
    Units: 53
    49
    Notes
    [2] - Two patients were not included in the primary evaluable patients population due to missing sampling
    No statistical analyses for this end point

    Secondary: Secondary Pharmacokinetic Parameters

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    End point title
    		 Secondary Pharmacokinetic Parameters
    End point description
    Patients with ASNase activity >100 U/L at 14 days following the fourth infusion of the 2-week dosing intervals. The Evaluable Patients Population for this outcome was defined as all patients recruited into the study who provided data on ASNase level on Day 14 (±2 days) following the fourth administration of eryaspase of 2-week dosing intervals.
    End point type
    Secondary
    End point timeframe
    1 months
    End point values
    		 Intervention
    Number of subjects analysed
    9
    Units: subjects
    6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    1 month
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    5.0
    Reporting groups
    Reporting group title
    Total study population
    Reporting group description
    		 -

    Serious adverse events
    		 Total study population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 55 (10.91%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    1
    Nervous system disorders
    Leukoencephalopathy
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Haemophagocytic lymphohistiocytosis
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    Hypersensitivity
         subjects affected / exposed
    2 / 55 (3.64%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Device related infection
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Total study population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 55 (32.73%)
    General disorders and administration site conditions
    pyrexia
         subjects affected / exposed
    5 / 55 (9.09%)
         occurrences all number
    9
    Hyperthermia
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Immune system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Hypersensitivity
         subjects affected / exposed
    3 / 55 (5.45%)
         occurrences all number
    4
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Stomatitis
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Hepatobiliary disorders
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Infections and infestations
    Device related infection
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Herpes zoster
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Pneumonia
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1
    Infection
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    Few patients included in the subgroups due to different number of doses and different intervals.
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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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