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    Summary
    EudraCT Number:2017-004596-31
    Sponsor's Protocol Code Number:NL62772
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-11-27
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2017-004596-31
    A.3Full title of the trial
    CeRebrUm and CardIac protection with Allopurinol in neonates with critical congenital heart disease requiring cardiac surgery with cardiopulmonary bypass
    Cerebrale en cardiale protectie met allopurinol bij neonaten met een ernstige aangeboren hartafwijking die een hartoperatie met behulp van hartlongmachine ondergaan
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The effect of allopurinol on the reduction of brain injury in neonates with severe congenital heart disease
    Het effect van allopurinol op het verminderen van hersenschade bij pasgeborenen met een ernstige aangeboren hartafwijking
    A.3.2Name or abbreviated title of the trial where available
    CRUCIAL
    CRUCIAL
    A.4.1Sponsor's protocol code numberNL62772
    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 SponsorUMC Utrecht
    B.1.3.4CountryNetherlands
    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 supportDutch Government
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationWilhelmina Children's Hospital
    B.5.2Functional name of contact pointClinical Trial Information Desk
    B.5.3 Address:
    B.5.3.1Street AddressLundlaan 6
    B.5.3.2Town/ cityUtrecht
    B.5.3.3Post code3508 AB
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31646919545
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAllokid
    D.3.4Pharmaceutical form Powder for solution for infusion
    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 infusion
    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
    Brain injury in neonates with critical congenital heart disease requiring cardiac surgery with cardiopulmonary bypass.
    E.1.1.1Medical condition in easily understood language
    Brain injury by insufficient oxygen and blood supply to the brain in neonates with critical congenital heart disease.
    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 LLT
    E.1.2Classification code 10010495
    E.1.2Term Congenital heart disease NOS
    E.1.2System Organ Class 100000004850
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10067967
    E.1.2Term Brain injury
    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 critical congenital heart disease, early postnatal (after birth) and perioperative (around cardiac surgery with cardiopulmonary bypass) allopurinol compared to placebo (mannitol) administration reduces relevant (moderate/severe) parenchymatous brain injury on postoperative MRI.
    E.2.2Secondary objectives of the trial
    To evaluate the effect of allopurinol on:
    - Brain injury severity score and volume of hypoxic-ischemic injury (MRI).
    - Brain function (amplitude integrated electroenchepalogram) and oxygenation (near-infrared spectroscopy).
    - Cardiac function (echocardiography).
    - Neurodevelopmental outcome (general movements, Bayley scales of infant development and executive functioning).
    - Quality of life.
    - Cost-effectiveness of allopurinol.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Pharmacokinetics of allopurinol. Pharmacokinetic evaluation of allopurinol will take place in a subpopulation of the first 24 patients, including allopurinol, oxypurinol, hypoxanthine, xanthine and uric acid levels postnatally and perioperatively.

    Inflammatory biomarkers. Blood samples will be taken postnatally and perioperatively in a subpopulation of 40 patients for analysis of inflammasome-mediated cytokines (as interleukines and TNF-alpha) and endothelial factors (as VEGF and others). Aim is to answer the question if allopurinol treatment affects inflammasome activation and neuroendothelial function early after birth and around cardiac surgery with cardiopulmonary bypass.

    Cardiac MRI. Cardiac MRI will be performed prenatally, postnatally and postoperatively in a subpopulation of 50 patients. Cardiac MRI is of great importance for a better understanding of cardiac function and physiology in relation to brain development and injury in neonates with duct-dependent congenital heart disease (heart-brain-axis).
    E.3Principal inclusion criteria
    Neonates with a prenatally (before birth) or postnatally (after birth) confirmed diagnosis of critical congenital heart disease requiring (anticipated) cardiac surgery with cardiopulmonary bypass (within the first 4 weeks of life).
    E.4Principal exclusion criteria
    - Inability to enroll the patient before the start of delivery in case of prenatal diagnosis, or 24 hours before surgery in case of postnatal diagnosis. - Gestational age below 36 weeks and/or birth weight less than 2000 gram.
    - Surgery not requiring cardiopulmonary bypass.
    - Patient considered “moribund”.
    - Decision for “comfort care only”.
    E.5 End points
    E.5.1Primary end point(s)
    Primary outcome is a composite endpoint of relevant (moderate/severe) parenchymatous brain injury on postoperative MRI or too instable for postoperative MRI or mortality
    E.5.1.1Timepoint(s) of evaluation of this end point
    Primary endpoint will be measured at postoperative MRI. The postoperative MRI takes place 5 to 10 days (and at least within 1 month) after cardiac surgery with cardiopulmonary bypass, which is usually within the neonatal period (first month of life).
    E.5.2Secondary end point(s)
    Secondary outcome measures are:
    - Brain injury severity score and volume of hypoxic-ischemic brain injury (pre- and postoperative MRI)
    - Brain function: background pattern and seizure activity (postnatal and perioperative amplitude integrated electroenchepalogram).
    - Brain oxygenation (postnatal and perioperative near-infrared spectroscopy).
    - Cardiac function (pre- and postoperative echocardiography).
    - Neurodevelopmental outcome (general movements at 3 months and Bayley scales of infant development and executive functioning testing at 24 months).
    - Quality of Life (TNO-TAPQOL at 24 months).
    - Cost-effectiveness of allopurinol (questionnaires during hospital stay, at 3 and 24 months).
    - Pharmacokinetics of allopurinol (substudy: postnatally, perioperatively).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Timepoints of each endpoint evaluation are mentioned in E.5.2. All endpoints will be expected within the neonatal period (first month of life) except neurodevelopmental outcome assessment and quality of life and cost-effectiveness questionnaires which takes place (also) at 3 and 24 months of age.
    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 No
    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
    Group sequential analysis with 1 interim (n=94) for prenatal diagnosis group
    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 concerned7
    E.8.5The trial involves multiple Member States No
    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
    The inclusion period is 2.5 years (including primary outcome assessment with postoperative brain MRI). The total duration of the trial is 4.5 years (including neurodevelopmental follow-up at 24 months of age).
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months54
    E.8.9.1In the Member State concerned days
    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: 236
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) Yes
    F.1.1.3.1Number of subjects for this age range: 236
    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 No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Neonates (first month of life) with critical congenital heart disease.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state236
    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 Decision2018-11-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-03-25
    P. End of Trial
    P.End of Trial StatusOngoing
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