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    Summary
    EudraCT Number:2016-000222-19
    Sponsor's Protocol Code Number:ALBINO
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2017-05-08
    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 ConcernedSpain - AEMPS
    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)
    Efecto del Alopurinol en pacientes con encefalopatía hipóxico-isquémica tratados con hipotermia – ALBINO – ensayo clínico multicéntrico, aleatorizado, ciego, controlado con placebo.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Effect of Allopurinol in addition to hypothermia for hypoxic-ischemic
    Brain Injury on Neurocognitive Outcome
    Efecto del Alopurinol en pacientes con encefalopatía hipóxico-isquémica tratados con hipotermia sobre el desarrollo neurológico
    A.3.2Name or abbreviated title of the trial where available
    ALBINO
    A.4.1Sponsor's protocol code numberALBINO
    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 Horizon 2020 framework program
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCentre for Pediatric Clinical Studies (CPCS)
    B.5.2Functional name of contact pointCentre for Pediatric Clinical Studi
    B.5.3 Address:
    B.5.3.1Street AddressFrondsbergstr. 23
    B.5.3.2Town/ cityTübingen
    B.5.3.3Post code72076
    B.5.3.4CountryGermany
    B.5.4Telephone number+49707129-86176
    B.5.5Fax number+49707129-4471
    B.5.6E-mailgabriele.oldershausen@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 No
    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 nameAllopurinol sodium
    D.3.2Product code Allopurinol
    D.3.4Pharmaceutical form Powder 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
    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/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 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
    hypoxic-ischemic brain injury
    daño cerebral hipóxico-isquémico
    E.1.1.1Medical condition in easily understood language
    hypoxic-ischemic encephalopathy
    encefalopatía hipóxico-isquémica
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate whether in newborns with severe perinatal metabolic
    acidosis or ongoing cardiopulmonary resuscitation at 5 min after birth
    and early clinical signs of potentially evolving 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.
    Evaluar si en los recién nacidos con acidosis metabólica perinatal grave o con
    necesidad de reanimación cardiopulmonar a los 5 min de vida y signos precoces
    de evolución potencial a encefalopatía hipóxico-isquémica, la administración
    temprana postnatal de alopurinol comparado con placebo
    (manitol) además del tratamiento estándar (incluyendo hipotermia terapéutica
    si indicada) disminuye la inicidencia de muerte o discapacidad neurológica
    grave (definido en el protocolo) a los 24 meses de vida.
    E.2.2Secondary objectives of the trial
    To evaluate the effect of allopurinol in addition to hypothermia (if
    indicated) on:
    - brain injury assessed by magnetic resonance imaging,
    - brain injury assessed by cerebral ultrasound,
    - amplitude integrated electroencephalogram,
    - full scale multichannel electroencephalogram,
    - laboratory biomarkers and markers of peroxidation
    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
    Evaluar el efecto del alopurinol además de la hipotermia (si indicada) en:
    Daño cerebral evaluado por resonancia magnética,
    Daño cerebral evaluado por ecografía cerebral,
    Electroencefalograma integrado por amplitud,
    Electroencefalograma multicanal,
    Biomarcadores y marcadores de peroxidación,
    Evaluar la seguridad del allopurinol en neonatos tratados con hipotermia y
    no tratados con hipotermia,
    Estudiar la farmacocinética del allopurinol y manitol (placebo) en neonates tratados con hipotermia y no tratados con hipotermia.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Term and near-term infants with a history of disturbed labour who meet at least one criterion of perinatal acidosis (or ongoing resuscitation) and at least two early clinical signs of potentially evolving encephalopathy as defined herein:

    Severe perinatal metabolic acidosis or ongoing cardiopulmonary resuscitation at 5 min after birth:

    At least 1 out of the following 5 criteria 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
    - Need for ongoing cardiac massage at/beyond 5 min postnatally
    - Need for adrenalin administration during resuscitation
    - 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)
    Los recién nacidos a término y casi a término con historia de parto complicado que cumplan al menos un criterio de acidosis perinatal (o necesidad de reanimación) y por lo menos dos signos clínicos tempranos de encefalopatía como se define aquí:

    Acidosis metabólica perinatal grave o reanimación a los 5 min del nacimiento:
    Debe cumplirse al menos uno de los 5 criterios siguientes:

    -Gasometría sangre cordón umbilical (o arterial o venosa) en los 30 min posteriores al nacimiento con un pH <7,0
    - Gasometría sangre cordón umbilical (o arterial o venosa) en los 30 min posteriores al nacimiento con déficit de base ≥ 16 mmol / L
    - Necesidad de masaje cardíaco a los de 5 min postnatal
    - Necesidad de administración de adrenalina durante la reanimación
    - APGAR ≤ 5 a las 10 min

    Y

    Principales signos clínicos de encefalopatía:
    Deben cumplirse al menos 2 de los 4 criterios siguientes:
    - Alteración del nivel de consciencia (respuesta reducida o ausente a la estimulación o hiperexcitabilidad)
    - Hipotonía o hipertonía muscular severa,
    - Ausencia o respiración espontánea inefectiva (por ejemplo, “gasping”) con necesidad de soporte respiratorio a los 10 minutos de vida,
    - Reflejos primitivos anormales (ausencia de succión o reflejo nauseoso o reflejo corneal o de Moro) o movimientos anormales (por ejemplo, convulsiones)
    E.4Principal exclusion criteria
    - gestational age below 36 weeks
    - birth weight below 2500 g
    - postnatal age >30min at the end of screening phase
    - severe congenital malformation or syndrome requiring neonatal surgery or affecting longterm outcome
    - patient considered “moribund”
    - decision for “comfort care only” before study drug administration
    - parents declined study participation as response to measures of community engagement
    - parents haven’t had the chance to appraise the conduct of the ALBINO study at the study site and to refute that their child may receive study drug in the event of asphyxia/HIE
    - both parents are insufficiently fluent in the study site’s national language(s) 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 less than 18 years of age, in case of single parent/guardian this one less than 18 years of age
    Edad gestacional <36 semanas
    Peso al nacimiento < 2500 g.
    >30min de vida al final de la fase de screening
    Síndrome o malformación congénita grave que requiera cirugía neonatal o afecte a los resultados a largo plazo
    Paciente considerado “moribundo” / “no viable”
    Decisión únicamente de “cuidados de confort” antes de la administración del fármaco del estudio
    Rechazo de los padres a participar en el estudio.
    - los padres no han tenido la oportunidad de conocer el estudio ALBINO en el centro donde se realiza el estudio y rechazar que su hijo puede recibir el medicamento del estudio en caso de asfixia.
    - ambos padres no dominan suficientemente el idioma o los idiomas nacionales del estudio o no tienen la capacidad intelectual para comprender los procedimientos del estudio y dar su consentimiento según lo juzgue el personal que haya estado en contacto con la madre / padre antes del parto .
    - ambos padres / tutores menores de 18 años de edad, en el caso de familia monoparental menores de 18 años de edad
    E.5 End points
    E.5.1Primary end point(s)
    death or severe neurodevelopmental impairment versus
    survival without 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 a cognitive-composite-score or a language-composite-score on the Bayley Scales of Infant and Toddler Development (3rd edition) < 85 and/or cerebral
    palsy according to SCPE criteria [SCPE Dev Med Child Neurol 2000].
    Muerte o discapacidad neurológica severa versus supervivencia sin discapacidad neurológica severa a la edad de dos años.
    La discapacidad neurológica severa se define de la siguiente manera: retraso cognitivo o de lenguaje definido como una puntuación compuesta cognitiva o del lenguaje en la Escala de Bayley <85 y / o parálisis cerebral según los criterios SCPE [SCPE Dev Med Child Neurol 2000]
    E.5.1.1Timepoint(s) of evaluation of this end point
    at the age of two years
    a la edad de 2 años
    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).
    2) Incidence of CP
    3) 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.
    4) Motor-Composite-Score (Bayley III)
    5) Motor-Composite-Score dichotomised (Bayley III)
    The motor-composite-score will be dichotomised at the cut-off <85 versus ≥85
    6) Cognitive-Composite-Score (cognitive subscale, Bayley III)
    7) Cognitive-Composite-Score dichotomised (cognitive subscale, Bayley III)
    The cognitive-composite-score will be dichotomised at the cut-off <85 versus ≥85
    8) Language-Composite-Score (language subscale, Bayley III)
    9) Language-Composite-Score dichotomised (language subscale, Bayley III) The language-composite-score will be dichotomised at the cut-off <85 versus ≥85
    10) 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.
    1) Muerte o discapacidad neurológica
    El criterio de valoración primario se reconstituirá como criterio de valoración secundario compuesto dicotomizado (supervivencia sin discapacidad neurológica versus Muerte o puntuación compuesta del lenguaje o cognitiva <85 o parálisis cerebral presente).
    2) Incidencia de paralisis cerebral
    3) Puntuación del Sistema de Clasificación de la Función Motora Gruesa
    La puntuación para la cuantificación de los efectos de la parálisis cerebral está adaptada de Palisano y otros [Palisano Med Child Neurol 1997])
    4) Puntuación Compuesta Motora (Bayley III)
    5) Puntuación Compuesta Motora dicotomizada (Bayley III)
    La puntuación del motor compuesto se dicotomizará en el punto de corte <85 frente a 85
    6) Puntuación Compuesta Cognitiva (subescala cognitiva, Bayley III)
    7) Puntuación Compuesta Cognitiva dicotomizada (subescala cognitiva, Bayley III)
    La puntuación cognitivo-compuesto se dicotomizará en el corte <85 frente a ≥85
    8) Puntuación Compuesta del Lenguaje (subescala del lenguaje, Bayley III)
    9) Puntuación Compuesta del Lenguaje dicotomizada (subescala del lenguaje, Bayley III)
    La puntuación compuesta del lenguaje se dicotomizará en el punto de corte <85 frente a ≥85
    10) Componentes Únicos del objetivo primario - Gráfico Componentes individuales y combinaciones observadas del criterio de valoración primario (salud, muerte, CP, puntuación de compuesto de lenguaje <85, puntaje cognitivo-compuesto <85) se mostrarán estratificados gráficamente para los dos grupos de tratamiento
    E.5.2.1Timepoint(s) of evaluation of this end point
    at 24 months corrected age
    a los 24 meses de edad corregida
    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 No
    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 concerned15
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA15
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    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.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Yes
    F.1.1.2.1Number of subjects for this age range: 1
    F.1.1.3Newborns (0-27 days) No
    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 No
    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 No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state846
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 846
    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
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-07-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-07-12
    P. End of Trial
    P.End of Trial StatusOngoing
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