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    Summary
    EudraCT Number:2011-005696-17
    Sponsor's Protocol Code Number:1645-CI-058
    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:2013-03-21
    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 number2011-005696-17
    A.3Full title of the trial
    Multicenter, randomized, blinded clinical study comparing early use of total body moderate hypothermia plus topiramate or placebo in asphyxiated newborn infants evolving to moderate-to-severe hypoxic ischemic encephalopathy
    Ensayo clínico multicéntrico, aleatorizado, doble ciego y controlado por Placebo,
    comparando el uso de la hipotermia corporal total moderada precoz con Topiramato o con
    Placebo en recién nacidos asfixiados evolucionando a encefalopatía hipóxicoisquémica moderada a severa
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical trial of topiramate vs placebo for newborns with perinatal asficia body treated with hypothermia.
    Ensayo clínico con topiramato vs placebo para el recien nacidos con asfixia perinatal tratados con hipotermia corporal.
    A.4.1Sponsor's protocol code number1645-CI-058
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorInstituto de Investigacion Sanitaria La Fe
    B.1.3.4CountrySpain
    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 supportINSTITUTO DE INVESTIGACION SANITARIA LA FE
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationInstituto de Investigacion Sanitaria La Fe
    B.5.2Functional name of contact pointUREC
    B.5.3 Address:
    B.5.3.1Street AddressBulevar S/N
    B.5.3.2Town/ cityValencia
    B.5.3.3Post code46026
    B.5.3.4CountrySpain
    B.5.4Telephone number3496124 66 11
    B.5.5Fax number3496124 66 20
    B.5.6E-mailinvestigacion_clinica@iislafe.es
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleComparator
    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 Topiramato ratiopharm 200
    D.2.1.1.2Name of the Marketing Authorisation holderRatiopharm
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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 nameTopiramate
    D.3.4Pharmaceutical form Spot-on suspension
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPNasogastric use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTopiramate
    D.3.9.1CAS number 97240-79-4
    D.3.9.3Other descriptive nameTOPIRAMATE
    D.3.9.4EV Substance CodeSUB11190MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/kg milligram(s)/kilogram
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number5
    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 placeboNasal/oromucosal solution
    D.8.4Route of administration of the placeboNasogastric use (Noncurrent)
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Asphyxiated newborn infants evolving to moderate-to-severe hypoxic ischemic encephalopathy
    Recién nacidos con asfixia evolución de moderada a severa encefalopatía hipóxico-isquémica
    E.1.1.1Medical condition in easily understood language
    Asphyxiated newborn infants evolving to moderate to severe hypoxic ischemic encephalopathy
    Recién nacidos con asfixia evolución de moderada a severa encefalopatía hipóxico-isquémica
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    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 the effectiveness of Topiramate administered immediately after birth, on the reduction of HIE-associated seizures and consequently, the neurodevelopmental outcome in newly born infants with birth asphyxia evolving to hypoxic ischemic encephalopathy
    E.2.2Secondary objectives of the trial
    To evaluate the effectiveness of Topiramate in the long term neurodevelopmental outcome at 24 months of age.
    ? To enhance our knowledge about pharmacokinetics and pharmacodynamics of TPM in newborn infants treated with mild whole body hypothermia.
    ? To compare the need for additional anticonvulsivant drugs during the acute period with those patients randomized to TPM Arm.
    ? To compare the abnormal brain ultrasounds and MRI findings at 7 days and 6 months (sub-study) after birth with those patients treated with TPM.
    ? To evaluate the histological brain lesions in deceased patients.
    To evaluate possible reductions in the need for anticonvulsive therapy after discharge.
    ? To compare the effects of TPM on biomarkers of neuronal damage and oxidative stress.
    ? To evaluate the tolerance/toxicity of TPM in the newborn period
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Signed informed consent by parents or legal guardians.
    ? Term near term gestation (?36weeks)
    ? Birth weight ? 2000g
    ? Significant moderate to severe Hypoxic Ischemic Encephalopathy, estimated with the modified Sarnat classification (see Annex 2)
    ? Evident signs of asphyxia during labor: meconium and/or alteration of fetal heart rate.
    ? Inborn in referral center or arrival to referral center within the acceptable timeframe for initiating hypothermia (6 hours after birth).
    ? The patient must meet at least, one criteria of A and one of B:
    A. Existence of perinatal data compatible with peripartum hypoxic ischemia:
    - Non-reassuring fetal status during fetal monitoring
    - Pathological scalp pH (<7.2)
    - Hypoxic-ischemic sentinel signs (cord prolapse, placenta abruptio, uterine rupture, severe fetal hemorrhage); dystocia during delivery.
    B. Objective status of perinatal affectation:
    - Apgar score ? 5 at 5 minutes after birth
    - Need of resuscitation with positive pressure ventilation (with mask or E.T.) at 10 minutes from birth.
    pH ? 7 estimated at worse gasometry during the first 60 minutes (cordon, arterial, venous or capilar blood)
    - Base Deficit (BE) ? 16 mmol/L estimated at worse gasometry during the first 60 minutes (cordon, arterial, venous or capilar blood)
    E.4Principal exclusion criteria
    ? Gestational age <36weeks? gestation
    ? Birth weight < 2000g
    ? Any pathology requiring surgery prior to discharge
    ? Major congenital malformations
    ? Imminent death
    ? Chromosomopathies
    ? Rejection to participate or to sign inform consent
    ? Erroneous or impossibility for randomization
    ? Incapability of initiating active or passive hypothermia (rectal temperature ? 34ºC) within the 6 hours timeframe
    ? Use of another investigational agent
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome is a reduction in a 50% of HIE-associated seizure activity (clinical and/or electrical) in number, frequency, intensity and/or duration, during the acute phase of hypoxic ischemic encephalopathy (first 7 days after birth, aprox) in those patients randomized to Topiramate group.
    Primary Outcome:
    Seizures will be measured by continuous registration of amplitude integrated EEG (aEEG): subjects will be continuously monitored starting immediately after birth and ceasing at discharge.
    An experienced neonatologist per shift will evaluate the readings and decide if additional medication is needed. A specially trained neonatologist and/or pediatric neurologist will review daily aEEG registers and evaluate brain activity, number, duration and intensity of seizures, if present.
    E.5.1.1Timepoint(s) of evaluation of this end point
    From birth until hospital discharge.
    Desde el nacimiento hasta el alta hospitalaria
    E.5.2Secondary end point(s)
    o Improved neurodevelopmental outcome at 24 months of age (22-26 limits) using the Bayley III scale.
    Secondary Outcomes:
    o Need for additional anticonvulsivants during the acute period. They will be evaluated before discharge by reviewing the patient?s medical records.
    o Topiramate pharmacokinetic and pharmacodynamic behavior in newborn infants treated with mild whole body hypothermia.
    o Neuronal damage measured by MRI and US imaging at 7 days (MRI includes Spectroscopy) and 6 months (MRI without Spectroscopy) after birth.
    o Histological brain lesions in deceased patients, measured by histology and histochemistry of the Central Nervous System.
    o Measurement of Oxidative Stress biomarkers in plasma at birth, 24h, 48h and 72h since first study treatment administration. They will be measured to evaluate relationship with the study intervention.
    o Measurement of CNS damage biomarkers in urine at birth, 12h, 24h, 48h, 72h and 96h since first study treatment administration. They will be measured to evaluate relationship with the study intervention.
    o Evaluation of brain electrical activity by conventional multichannel EEG.
    o Neurological status during the acute phase (hospitalization) and after discharge.
    o Evaluation of clinical laboratory parameters (to be evaluated and corrected by the neonatologist in charge or on call.
    o Reduction of seizures during re-warming.
    o Survival.
    E.5.2.1Timepoint(s) of evaluation of this end point
    -At 24 months of age as measured by Bayley III scale
    -A los 24 meses de edad, según lo medido por la escala Bayley III
    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 No
    E.6.5Efficacy No
    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 concerned13
    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 end of trial will be the date of the last visit of the last participant to the Follow Up Clinic.
    The End of Study Visit Form will include:Assessment of endpoints/outcome measures
    será la fecha de la última visita del último participante de la Clínica de Seguimiento.
    El final de la clase Visita de estudio se incluyen: Evaluación de los criterios de valoración / medidas de resultado
    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 months0
    E.8.9.1In the Member State concerned days0
    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: 152
    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: 152
    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 state152
    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)
    Assessment of endpoints/outcome measures.
    Evaluación de los criterios de valoración / medidas de resultado
    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 Decision2013-06-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-03-12
    P. End of Trial
    P.End of Trial StatusOngoing
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