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    Summary
    EudraCT Number:2013-004655-21
    Sponsor's Protocol Code Number:KRN-001
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2014-04-25
    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 number2013-004655-21
    A.3Full title of the trial
    New Dosing Systems in Paediatrics.
    Application to the individualization of the dose of fentanyl in neonatal patients.
    Nuevos Sistemas de Dosificación en Pediatría.
    Aplicación a la individualización de la dosis de fentanilo en pacientes neonatos.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    New Dosing Systems in Paediatrics.
    Application to the individualization of the dose of fentanyl in neonatal patients.
    Nuevos Sistemas de Dosificación en Pediatría.
    Aplicación a la individualización de la dosis de fentanilo en pacientes neonatos.
    A.4.1Sponsor's protocol code numberKRN-001
    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 SponsorKern Pharma S.L.
    B.1.3.4CountrySpain
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMinisterio de Ciencia e Innovación
    B.4.2CountrySpain
    B.4.1Name of organisation providing supportKern Pharma S.L.
    B.4.2CountrySpain
    B.4.1Name of organisation providing supportDynaKin S.L.
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationDynaKin S.L.
    B.5.2Functional name of contact pointClinical Trial Information
    B.5.3 Address:
    B.5.3.1Street AddressParque Tecnológico de Bizkaia, Ed. 801-B, 1ª planta
    B.5.3.2Town/ cityDerio (Bizkaia)
    B.5.3.3Post code48160
    B.5.3.4CountrySpain
    B.5.4Telephone number+34944045504
    B.5.5Fax number+34946559463
    B.5.6E-mailnleal@dynakin.com
    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 Fentanest
    D.2.1.1.2Name of the Marketing Authorisation holderKern Pharma S.L.
    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.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    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 INNFentanyl Citrate
    D.3.9.1CAS number 990-73-8
    D.3.9.3Other descriptive nameFENTANYL CITRATE
    D.3.9.4EV Substance CodeSUB02129MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.05
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Analgesia, sedation.
    Analgesia, sedación.
    E.1.1.1Medical condition in easily understood language
    Analgesia, sedation.
    Analgesia, sedación.
    E.1.1.2Therapeutic area Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Anesthesia and Analgesia [E03]
    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
    -Study the pharmacokinetic behavior of fentanyl as an analgesic/sedative agent in neonates aged 0-27 days of postnatal age and >= 37 weeks of gestational age admitted to the Neonatal Intensive Care Unit (NICU), in order to confirm a predictive model developed for the drug in this population.
    -Analyze the role of those factors that may play an important role in the pharmacokinetic variability associated with fentanyl in the study population.
    - Analizar el comportamiento farmacocinético de fentanilo como agente analgésico/sedante en pacientes neonatos de 0-27 días de edad postnatal y edad gestacional >=37 semanas ingresados en la Unidad de Cuidados Intensivos Neonatales (UCIN), con el fin de confirmar un modelo predictivo desarrollado para el fármaco en esta población.
    - Analizar el papel de aquellos factores que puedan jugar un papel importante en la variabilidad cinética asociada a fentanilo en la población del estudio
    E.2.2Secondary objectives of the trial
    -Identify, between physiological parameters monitored in the NICU, an end-point or marker of efficacy that may be related to the degree of analgesia and sedation. This will be done through a study of correlations and the development of pharmacostatistical models (eg, pharmacokinetic-pharmacodynamic type, PK/PD) in order to optimize the dosage of fentanyl in this population.
    -Identificar entre los parámetros fisiológicos monitorizados en la UCIN, un end-point o marcador de eficacia que pueda estar relacionado con el grado de analgesia y sedación, a través un estudio de correlaciones y del desarrollo de modelos farmacoestadísticos (por ejemplo, de tipo farmacocinético-farmacodinámico, FC/FD) destinados a optimizar la dosificación de fentanilo en esta población.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Informed consent signed by parents or legal guardians. 2. Neonatal patients between 0 and 27 days of postnatal age and >= 37 weeks of gestational age admitted to the NICU of Cruces Universitary Hospital. 3. Treatment with iv fentanyl with analgesic or sedatives purposes, or with other indications by facultative prescription. 4. First stage of fentanyl treatment following the sedoanalgesia protocol of the NICU of the Cruces Universitary Hospital.
    1. Consentimiento informado firmado por los progenitores o tutores legales. 2. Pacientes neonatos de 0-27 días de edad postnatal y edad gestacional >= 37 semanas ingresados en la UCIN del Hospital Universitario Cruces. 3. Tratamiento con fentanilo iv con fines analgésicos, sedantes u otras indicaciones por prescripción facultativa. 4. Primer ciclo de tratamiento con fentanilo dentro del protocolo de sedoanalgesia de la UCIN del Hospital Universitario Cruces.
    E.4Principal exclusion criteria
    1. Sepsis. 2. Liver failure. 3. Renal replacement therapy. 4 Hypersensitivity to fentanyl or opioids in general. 5. Cranioencephalic trauma, increased of intracranial pressure and/or coma.
    1. Sepsis. 2. Fallo hepático. 3. Terapia sustitutiva renal . 4. Hipersensibilidad a fentanilo u opioides en general. 5. Traumatismo craneoencefálico, aumento de la presión intracraneal y/o coma.
    E.5 End points
    E.5.1Primary end point(s)
    Step 1: Determination of the basic population pharmacokinetic model.
    First, the basic population pharmacokinetic model (compartmental analyses) that best describes the temporal evolution of the plasma concentrations of fentanyl in the population is selected. The following parameters from the data of plasma concentration measured in this study will be estimated:
    - V1: Distribution volume of the drug in the central compartment of the body (Units: L)
    -CL: Systemic clearance: central compartment volume that is cleared of drug per time unit (units: L / h)
    -V2: Distribution volume of the drug in the peripheral compartment of rapid distribution (Units: L)
    -V3: Distribution volume of the drug in the peripheral compartment of slow distribution (Units: L)
    -CLd1-2: Disribution clearance or intercompartmental clearance between the central compartment and the peripheral compartment of rapid distribution (Units: L / h)
    -CLd1-3: Disribution clearance or intercompartmental clearance between the central compartment and the peripheral compartment of slow distribution (Units: L / h)

    Step 2: Selection of predictor variables.
    At this level, the relationship between pharmacokinetic parameters and possible predictors thereof will be evaluated. The influence of potential covariates on model parameters will be evaluated, including at least the following covariates:
    - Age
    - Weight
    - Height
    - Gender
    - Alkaline Phosphatase
    - ALT (Alanine transaminase)
    - AST (aspartate aminotransferase)
    - GGT (gamma-glutamyl transpeptidase)
    - Albumin
    - Bilirubin
    - Creatinine
    - Urea
    - Total Proteins
    - Prior and Concomitant Medication
    Etapa 1: Determinación del modelo farmacocinético poblacional básico.
    En primer lugar, se seleccionará el modelo farmacocinético poblacional básico (análisis compartimental) que mejor describa la evolución temporal de las concentraciones plasmáticas de fentanilo en la población. Se estimarán los siguientes parámetros a partir de los datos de concentraciones plasmáticas medidos en el presente estudio:
    - V1: Volumen de distribución del fármaco en el compartimento central del organismo (Unidades: L)
    -CL: Aclaramiento sistémico: volumen del compartimento central que es aclarado de fármaco por unidad de tiempo (Unidades: L/h)
    -V2: Volumen de distribución del fármaco en el compartimento periférico de distribución rápida (Unidades: L)
    -V3: Volumen de distribución del fármaco en el compartimento periférico de distribución lenta (Unidades: L)
    -CLd1-2: Aclaramiento de distribución o aclaramiento intercompartimental entre el compartimento central y el compartimento periférico de distribución rápida (Unidades: L/h)
    -CLd1-3 Aclaramiento de distribución o aclaramiento intercompartimental entre el compartimento central y el compartimento periférico de distribución lenta (Unidades: L/h)

    Etapa 2: Selección de las variables predictoras.
    A este nivel, se procederá a evaluar la relación entre los parámetros farmacocinéticos y las posibles variables predictoras de los mismos. Para ello, la influencia de potenciales covariables sobre los parámetros del modelo será evaluada, incluyendo como mínimo las siguientes covariables:
    - Edad
    - Peso
    - Altura
    - Género
    - Fosfatasa Alcalina
    - ALT (Alanina transaminasa)
    - AST (Aspartato aminotransferasa)
    - GGT (gamma-glutamil transpeptidasa)
    - Albúmina
    - Bilirrubina
    - Creatitnina
    - Urea
    - Proteínas totales
    - Medicación previa y concomitante
    E.5.1.1Timepoint(s) of evaluation of this end point
    -1 sample within 10 min before the initiation the treatment
    -1 sample after one loading dose (5 min), if applicable
    -1 sample within the first 24 hours of infusion
    -1 sample/day during the days 2-5 of infusion. If additional boluses are administered in this period, 1 additional daily sample (first 5 minutes) up to a total of 3 samples in this period
    -If the infusion lasts more than 5 days, between days 6-20 infusion, 1 sample every 72 h (up to 5 samples)
    -1 sample during the 10 minutes prior to end of the infusion, without exceeding the daily maximum of 2 samples
    -After completion of the infusion:
    *1 sample between 0 and 12 h
    *1 sample between 12 and 24 h
    *1 sample between 24 and 48 h
    *1 sample between 48 and 72 h (if continues instituzionalized in the NICU).
    -1 muestra en los 10 min anteriores a comenzar el tratamiento.
    -1 muestra tras una dosis de carga (5 min), si procede.
    -1 muestra en las primeras 24 h de infusión
    -1 muestra/día durante los días 2-5 de infusión. Si se administran bolos adicionales durante este periodo, se extraeré 1 muestra extra al día (5 primeros min), hasta un total de 3 en todo el periodo
    -Si el tratamiento se prolonga más de 5 días, entre los días 6-20 de infusión 1 muestra cada 72 h (máximo 5 muestras)
    -1 muestra en los 10 minutos anteriores a detener la infusión, sin que se supere el máximo de 2 muestras diarias
    -Tras finalizar la infusión:
    *1 muestra entre las 0 y 12 h.
    *1 muestra entre 12 y 24 h.
    *1 muestra entre 24 y 48 h.
    *1 muestra entre 48 y 72 h (únicamente si sigue ingresado en la UCIN).
    E.5.2Secondary end point(s)
    Pharmacodynamic analysis
    The model that commonly best fits the effects of opioid drugs corresponds with a sigmoid model of maximum effect (Emax). However, the pharmacological effects of opioids generally show a delay with respect to the plasma concentration, being necessary to introduce what is known as the effect compartment model.
    The parameters that include this type of model are summarized below:
    -Ke0: Equilibrium constant between the plasma compartment and the effect compartment or biophase (units: h-1)
    -t1/2Ke0: Equilibrium half-life between the plasma compartment and the effect compartment or biophase (units: h)
    - CE50: Plasma concentration that produces 50% of the maximum effect (Units: ng / mL)
    - Emax: Maximum effect for that particular drug (%)
    -?: Hill constant or slope of the sigmoidal curve

    At least, the following variables as potential markers of clinical effect (effective and / or toxic) will be scanned:
    - Heart rate
    - Scheduled Respiratory rate
    - Spontaneous Respiratory rate
    - Peak pressure
    - Positive end-expiratory pressure (PEEP)
    - Saturation transcutaneous
    - Brain Saturation (cerebral oximetry)
    - Clinical Pain Scale
    Análisis Farmacodinámico
    El modelo que mejor ajusta normalmente los efectos de los fármacos opiáceos se corresponde con un modelo sigmoide de efecto máximo (Emax). Sin embargo, los efectos farmacológicos de los opiáceos muestran por lo general un retraso con respecto a las concentraciones plasmáticas, siendo necesario introducir lo que se conoce como modelo del compartimento del efecto.
    Los parámetros que comprenden este tipo de modelos se resumen a continuación:
    - Ke0: Constante de equilibrio entre el compartimento plasmático y la biofase o compartimento del efecto (Unidades: h-1)
    - t1/2Ke0: Semivida de equilibrio entre el compartimento plasmático y la biofase o compartimento del efecto (Unidades: h)
    - CE50: Concentración plasmática que produce el 50% del efecto máximo (Unidades: ng/mL)
    - Emax: Efecto máximo para ese fármaco concreto (%)
    - ?: Constante de Hill o pendiente de la curva sigmoidea

    Se explorarán al menos las siguientes variables como posibles marcadores clínicos de efecto (eficaz y/o tóxico).
    - Frecuencia cardíaca
    - Frecuencia respiratoria programada
    - Frecuencia respiratoria espontánea
    - Pico de presión
    - Presión positiva espiratoria final (PEEP)
    - Saturación transcutánea
    - Saturación cerebral (oximetría cerebral)
    - Escala clínica de dolor
    E.5.2.1Timepoint(s) of evaluation of this end point
    During the study
    A lo largo del estudio
    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 No
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised Information not present in EudraCT
    E.8.1.2Open Information not present in EudraCT
    E.8.1.3Single blind Information not present in EudraCT
    E.8.1.4Double blind Information not present in EudraCT
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Information not present in EudraCT
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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 No
    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 study will finish when it is considered that the number of subjects needed to achieve the objectives have been involved, and it will be determined by interim analyses. This will allow to recruit the minimum number of necessary individuals due to the type of study population.
    El estudio finalizará cuando se considere que han participado los voluntarios necesarios para alcanzar los objetivos del mismo, y esto se ira determinando mediante análisis intermedios. Esto permitirá reclutar el mínimo número de individuos necesarios debido al tipo de población del estudio.
    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 months30
    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: 60
    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: 60
    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
    Their clinical condition and their age, do not allow them to understand the nature, objectives and possible consequences of their participation in the study and therefore they are not able to sign the consent at the time.
    Su situación clínica y su edad, no les permiten entender la naturaleza, objetivos y posibles consecuencias de su participación en el estudio y, por tanto, no están en condiciones de firmar el consentimiento en ese momento.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state60
    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
    Ninguno
    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 Decision2014-06-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-05-27
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2017-06-28
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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
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