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    Summary
    EudraCT Number:2016-000222-19
    Sponsor's Protocol Code Number:H2020-PHC-18-2015-667224
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-07-30
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2016-000222-19
    A.3Full title of the trial
    Effect of ALlopurinol in addition to hypothermia for hypoxic-ischemic Brain Injury on Neurocognitive Outcome – a blinded randomized placebo-controlled parallel group multicenter trial for superiority (Phase III)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A European trial to evaluate the effect of Allopurinol administered very early after birth on brain injury in children with oxygen deficiency during birth
    A.3.2Name or abbreviated title of the trial where available
    ALBINO
    A.4.1Sponsor's protocol code numberH2020-PHC-18-2015-667224
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversity Hospital Tuebingen
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportEuropean Union
    B.4.2CountryEuropean Union
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCenter for Pediatric Clinical Studies
    B.5.2Functional name of contact pointClinical Trial Center
    B.5.3 Address:
    B.5.3.1Street AddressFrondsbergstr. 23
    B.5.3.2Town/ cityTuebingen
    B.5.3.3Post code72070
    B.5.3.4CountryGermany
    B.5.4Telephone number004970712981469
    B.5.5Fax number00497071294857
    B.5.6E-mailalbino@med.uni-tuebingen.de
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name ACEPURIN
    D.2.1.1.2Name of the Marketing Authorisation holderACE Pharmaceuticals
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/15/1493
    D.3 Description of the IMP
    D.3.1Product nameAllokid
    D.3.4Pharmaceutical form Powder for solution for injection
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAllopurinol sodium
    D.3.9.1CAS number 17795-21-0
    D.3.9.3Other descriptive nameALLOPURINOL SODIUM
    D.3.9.4EV Substance CodeSUB30291
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboPowder for solution for injection
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Perinatal Asphyxia, hypoxic-ischemic brain injury
    E.1.1.1Medical condition in easily understood language
    oxygen deficiency during birth
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10028923
    E.1.2Term Neonatal asphyxia
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10014633
    E.1.2Term Encephalopathy neonatal
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate whether in newborns with asphyxia and early clinical signs of hypoxic-ischemic encephalopathy, early postnatal allopurinol compared to placebo (mannitol) administered in addition to standard of care (including therapeutic hypothermia if indicated) reduces the incidence of death or severe neurodevelopmental impairment (as defined herein) at 24 months of age.
    E.2.2Secondary objectives of the trial
    To evaluate the effect of allopurinol in addition to hypothermia (if indicated) on:
    - components of the primary outcome variable
    - brain injury assessed by magnetic resonance imaging,
    - amplitude integrated electroencephalogram,
    - full scale electroencephalogram,
    - laboratory biomarkers and markers of peroxidation
    - heart function assessed by echocardiography
    To evaluate the safety of allopurinol in neonates treated with hypothermia.
    To study pharmacokinetics of allopurinol (verum) and mannitol (placebo) in neonates treated with hypothermia and not treated with hypothermia
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Near InfraRed Spectroscopy (NIRS)-monitored Cerebral Oxygen Saturation and Extraction (01/2016 V01.0/negative and positive predictive values at 12 h of life for outcome at 24 months. We hypothesize that early treatment of perinatally asphyxiated neonates with allopurinol (ALLO) have lower rScO2 values and higher cFTOE values as compared to placebo-treated asphyxiated neonates pointing to a better outcome at 24 months of age.
    E.3Principal inclusion criteria
    Term and near-term infants with a history of disturbed labour who meet at least one sign of perinatal asphyxia and early clinical signs of potentially evolving encephalopathy as defined herein:
    Perinatal asphyxia:
    At least 1 out of the following 4criteria must be met
    - Umbilical (or arterial or reliable venous) blood gas within 30 min after birth with pH<7.0
    - Umbilical (or arterial or reliable venous) blood gas within 30 min after birth with base deficit ≥16 mmol/l (i.e. a base excess ≤ -16mmol/l)
    - Need for ongoing cardiac massage at/beyond 5 min postnatally
    - Need for adrenalin administration during resuscitation or APGAR score ≤5 at 10min

    AND

    Early clinical signs of potentially evolving encephalopathy:
    At least 2 out of the following 4 criteria must be met:
    - Altered state of consciousness (reduced or absent response to stimulation or hyperexcitability)
    - Severe muscular hypotonia or hypertonia,
    - Absent or insufficient spontaneous respiration (e.g., gasping only) with need for respiratory support at 10 min postnatally,
    - Abnormal primitive reflexes (absent suck or gag or corneal or Moro reflex) or abnormal movements (e.g., potential clinical correlates of seizure activity)
    E.4Principal exclusion criteria
    - gestational age below 36 weeks
    - birth weight below 2500 g
    - postnatal age >30min at the end of the screening phase
    - severe congenital malformation or syndrome requiring neonatal
    surgery or affecting long-term outcome
    - patient considered “moribund” or decision for “comfort care only”
    before study drug administration
    - parents declined study participation as response to community
    engagment
    - both parents are insufficiently fluent in the study site’s national language or English or do not have the intellectual capacity to understand the study procedures and to give consent as judged by the personel who had been in contact with the mother/father before delivery.
    - both parents/guardians underaged, in case of single parent/guardian this one underaged
    E.5 End points
    E.5.1Primary end point(s)
    Death or severe neurodevelopmental impairment at the age of two years (where severe neurodevelopmental impairment is defined as any of the following: cognitive or language delay defined as mental developmental index (MDI) cognitive or language score on the Bayley Scales of Infant Development (3rd edition) < 85 and/or cerebral palsy according to SCPE criteria [SCPE Dev Med Child Neurol 2000].
    E.5.1.1Timepoint(s) of evaluation of this end point
    at the age of two years
    E.5.2Secondary end point(s)
    1) Death or neurodevelopmental impairment (NDI)
    The primary endpoint will be reconstituted as dichotomised composite secondary endpoint (survival without NDI versus Death or language-composite-score < 85 or cognitive-composite-score <85 or cerebral palsy present). This will be analyzed by Cochrane-Mantel-Haenzel- X²-Test.
    2) Incidence of death
    Incidence of death will be analyzed by Cochrane-Mantel-Haenzel- X²-Test.
    3) Incidence of CP
    Incidence of CP will be analyzed by Cochrane-Mantel-Haenzel- X²-Test.
    4) GMFCS-score
    GMFCS-Score for quantification of the effects of cerebral palsy and other motor impairments (adapted from Palisano et al. [Palisano Med Child Neurol 1997]) using the ALBINO-GMFCS-score sheet (separate document not part of this protocol) will be analysed. GMFCS-score consists of six categories. Analysis will be done by using Wilcoxon-Mann-Whitney test.
    5) Motor-Composite-Score (Bayley III)
    The nummerical data of the motor-composite-score will be analysed using Wilcoxon-Mann-Whitney test. The use of this test accounts for the fact that data will be cut due to lack sensitivity below 50 points.
    6) Motor-Composite-Score dichotomised (Bayley III)
    The motor-composite-score will be dichotomised at the cut-off <85 versus ≥85 and analysed by Cochrane-Mantel-Haenzel- X²-Test.
    7) Cognitive-Composite-Score (cognitive subscale, Bayley III)
    The nummerical data of the cognitive-composite-score will be analysed using Wilcoxon-Mann-Whitney test. The use of this test accounts for the fact that data will be cut due to lack sensitivity below 50 points.
    8) Cognitive-Composite-Score dichotomised (cognitive subscale, Bayley III)
    The cognitive-composite-score will be dichotomised at the cut-off <85 versus ≥85 and analysed by Cochrane-Mantel-Haenzel- X²-Test.
    9) Language-Composite-Score (language subscale, Bayley III)
    The raw nummerical data of the language-composite-score will be analysed using Wilcoxon-Mann-Whitney test. The use of this test accounts for the fact that data will be cut due to lack sensitivity below 50 points.
    10) Language-Composite-Score dichotomised (language subscale, Bayley III)
    The language-composite-score will be dichotomised at the cut-off <85 versus ≥85 and analysed by Cochrane-Mantel-Haenzel- X²-Test.
    11) Single Components of primary endpoint - Graph
    Single components and observed combinations of the primary endpoint (healthy, death, CP, language-composite-score <85, cognitive-composite-score <85) will be displayed graphically stratified for the two treatment groups.

    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary endpoints will be analysed at 24 months corrected age between the two treatment groups.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    multicenter trial
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned40
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA80
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Switzerland
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    the inclusion window will be 30 months, follow-up patients will be up till 24 months of age. Taking the last included patient into account, that means the duration of the trial will be 54months (4.5years) in total.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months6
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 846
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Yes
    F.1.1.2.1Number of subjects for this age range: 100
    F.1.1.3Newborns (0-27 days) Yes
    F.1.1.3.1Number of subjects for this age range: 746
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation Yes
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    newborn infants
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state280
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 806
    F.4.2.2In the whole clinical trial 846
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation Hypothermie-Netzwerk
    G.4.3.4Network Country Germany
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-09-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-12-18
    P. End of Trial
    P.End of Trial StatusOngoing
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