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    Clinical Trial Results:
    Phase I Trial of DNX-2401 for Diffuse Intrinsic Pontine Glioma newly diagnosed in pediatric patients.

    Summary
    EudraCT number
    2016-001577-33
    Trial protocol
    ES  
    Global end of trial date
    24 Jan 2022

    Results information
    Results version number
    v1(current)
    This version publication date
    22 May 2022
    First version publication date
    22 May 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D24-DIPG
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03178032
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Clínica Universidad de Navarra
    Sponsor organisation address
    Avda. Pío XII, 36, Pamplona, Spain, 31008
    Public contact
    UCEC, Clínica Universidad de Navarra, 34 9482554002725, ucicec@unav.es
    Scientific contact
    UCEC, Clínica Universidad de Navarra, 34 9482554002725, ucicec@unav.es
    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
    25 Jan 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Jan 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Jan 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the safety, tolerability and toxicity of DNX-2401 injected in the cerebellar peduncle in pediatric subjects with DIPG. The trial will look for hematologic and neurologic toxicity (NCI-CTCAE v 4.03).
    Protection of trial subjects
    The protection of the subjects will be in accordance with the standards of good clinical practice as well as the law of Data Protection Act
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Nov 2016
    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
    Spain: 12
    Worldwide total number of subjects
    12
    EEA total number of subjects
    12
    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)
    0
    Children (2-11 years)
    10
    Adolescents (12-17 years)
    1
    Adults (18-64 years)
    1
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Patients will be screened in the clinic by the investigators of the trial. Screening will take place within 28 days of selection and administration of DNX-2401. Screening will be preceded by a presentation of the complete information about the clinical study to the parents

    Pre-assignment
    Screening details
    -Recent clinical and radiological diagnosis of DIPG. - Physical Examination, including vital signs and weight - Neurological Examination and Functional Status assessment - Quality of Life instruments (PedsQLTM) - Clinical Laboratory Tests - Pregnancy testing - Serology - MRI

    Period 1
    Period 1 title
    Treatment (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Treatment
    Arm description
    DNX-2401 will be injected immediately after the biopsy. The injection will be intratumoral through the biopsy tract in the cerebellar peduncle.
    Arm type
    Experimental

    Investigational medicinal product name
    DNX-2401
    Investigational medicinal product code
    DNX-2401
    Other name
    DNX-2401
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intratumoral use
    Dosage and administration details
    Total dose will be D0=1x109, D1=1x1010 or D2=5x1010 viral particles (vp) suspended in 1 ml for all cases. Virus will be kept in an ≤ -80°C freezer, in the vial in which it was provided. Vial concentration is 2.0 x 1011 vp/mL. One dilution will be required to produce the total dose for the study of 5 x 1010 vp/mL in 1.0 mL as the dose to be delivered. However, it may be necessary to prepare enough DNX-2401 in order to fill the dead space in delivery equipment in order to ensure delivery of the complete dose. The Alcyone MEMS cannula to be used in the trial has a dead volume of 50uL, and the tubing has a dead volume of 500uL. That is why a total volume of 1.6mL will be load in the syringe. The virus will be diluted and prepared in the Pharmacy of the hospital and send to the Operating Room in a syringe, ready for injection. See below the procedure for each dose: D0, D1 and D2.

    Number of subjects in period 1
    Treatment
    Started
    12
    Completed
    3
    Not completed
    9
         progression
    9

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment
    Reporting group description
    DNX-2401 will be injected immediately after the biopsy. The injection will be intratumoral through the biopsy tract in the cerebellar peduncle.

    Reporting group values
    Treatment Total
    Number of subjects
    12 12
    Age categorical
    Units: Subjects
        Children (2-11 years)
    10 10
        Adolescents (12-17 years)
    1 1
        Adults (18-64 years)
    1 1
    Gender categorical
    Units: Subjects
        Female
    7 7
        Male
    5 5

    End points

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    End points reporting groups
    Reporting group title
    Treatment
    Reporting group description
    DNX-2401 will be injected immediately after the biopsy. The injection will be intratumoral through the biopsy tract in the cerebellar peduncle.

    Primary: Safety, tolerability and toxicity of DNX-2401

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    End point title
    Safety, tolerability and toxicity of DNX-2401 [1]
    End point description
    End point type
    Primary
    End point timeframe
    For each individual patient the timepoint of evaluation is from the DNX.2401 injection, to the last follow up visit
    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: Statistical considerations: Adverse events were described using frequencies. Kaplan-Meier methods were used to determine survival.
    End point values
    Treatment
    Number of subjects analysed
    12
    Units: number of adverse events
    12
    No statistical analyses for this end point

    Secondary: Survival

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    End point title
    Survival
    End point description
    End point type
    Secondary
    End point timeframe
    For each individual patient the timepoint of evaluation was from the DNX.2401 injection to the last follow up visit
    End point values
    Treatment
    Number of subjects analysed
    12
    Units: Months
    12
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Between study start and Last Visit of the last patient
    Adverse event reporting additional description
    None
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    D24-DIPG patients
    Reporting group description
    -

    Serious adverse events
    D24-DIPG patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 12 (25.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Nervous system disorders
    Hemiparesis (right)
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neurological decompensation
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Appendicitis
    Additional description: Sospecha de apendicitis y posterior descarte. El paciente mejoró trás su ingreso y se consideró cerrado el SAE sin relación con la medicación.
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    D24-DIPG patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 12 (100.00%)
    Vascular disorders
    Dizziness
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    8 / 12 (66.67%)
         occurrences all number
    10
    Irritability
         subjects affected / exposed
    3 / 12 (25.00%)
         occurrences all number
    3
    Pyrexia
         subjects affected / exposed
    6 / 12 (50.00%)
         occurrences all number
    9
    Seroma
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Fatigue
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Ataxia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Laryngospasm
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 12 (25.00%)
         occurrences all number
    3
    Respiratory distress
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Dyspnoea
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Psychiatric disorders
    Dysarthria
         subjects affected / exposed
    3 / 12 (25.00%)
         occurrences all number
    3
    Cushingoid facies
         subjects affected / exposed
    3 / 12 (25.00%)
         occurrences all number
    3
    Injury, poisoning and procedural complications
    Wound complication
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Incision site pain
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Nervous system disorders
    Worsening of previous instability
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Neurological decompensation
         subjects affected / exposed
    8 / 12 (66.67%)
         occurrences all number
    9
    Headache
         subjects affected / exposed
    9 / 12 (75.00%)
         occurrences all number
    12
    Instability
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Insomnia
         subjects affected / exposed
    4 / 12 (33.33%)
         occurrences all number
    6
    Somnolence
         subjects affected / exposed
    4 / 12 (33.33%)
         occurrences all number
    5
    Hydrocephalus
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Temporomandibular pain
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Paraesthesia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Hemiparesis
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Facial Dysesthesia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Olfactory nerve disorder
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    VIth nerve disorder
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Trigeminal nerve disorder
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Facial paralysis
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Hypoaesthesia
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Hyperreflexia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Lymphopenia
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Eye disorders
    Extraocular muscle paresis
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Nystagmus
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Diplopia
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Dry eye
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Gastrointestinal disorders
    Dysphagia
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Acid reflux (esophageal)
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Nausea with vomiting
         subjects affected / exposed
    9 / 12 (75.00%)
         occurrences all number
    12
    Nausea
         subjects affected / exposed
    5 / 12 (41.67%)
         occurrences all number
    9
    Abdominal pain
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    3
    Isolated acute Abdominal pain
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Stomatitis
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    2
    Constipation
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    4
    Skin and subcutaneous tissue disorders
    Dry skin face
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Alopecia
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Skin striae
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    2
    Polyuria
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Neck pain
         subjects affected / exposed
    4 / 12 (33.33%)
         occurrences all number
    4
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Pain in extremity
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Infections and infestations
    Bilateral otitis media
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Hyperphagia
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Jun 2017
    Changes in protocol and informed consent
    21 Dec 2017
    Protocol changes
    13 Jun 2018
    Importer/Manufacturing changes
    10 Dec 2018
    Protocol changes
    04 Jul 2019
    Protocol and Informed Consent changes due new team members and a principal investigator change
    03 Jun 2021
    Protocol changes

    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
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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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