E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
patent ductus arteriosus |
ductus arterioso persistente |
|
E.1.1.1 | Medical condition in easily understood language |
patent ductus arteriosus |
ductus arterioso persistente |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10034130 |
E.1.2 | Term | Patent ductus arteriosus |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Reduce the incidence of NEC or AIP in preterm infants receiving treatment for closure of PDA with EchoG continuous IV infusion Iv EchoG IV. bolus of IB |
Disminuir la incidencia de ECN o PIA en los recién nacidos prematuros que reciben tratamiento para el cierre del DA con IB en perfusión iv continua y EchoG vs bolos iv y EchoG. |
|
E.2.2 | Secondary objectives of the trial |
Identify genetic polymorphisms in patients refractory to medical treatment of PDA and those most vulnerable to develop ECN or AIP. Exploratory Objectives: To evaluate the incidence of neonatal morbidity and mortality associated with each way of treatment |
Identificar polimorfismos genéticos en los pacientes refractarios a tratamiento médico del DA y en aquellos más vulnerables a presentar ECN o PIA. Objetivos exploratorios: Evaluar la incidencia de morbilidad y mortalidad neonatal asociada a cada una de las formas de tratamiento
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Preterm infants less than 33 weeks gestational age 2. PDA ≥ 1.5 mm and medical decision to start drug treatment 3. Signed informed consent by the legal representative |
1. Recién nacidos prematuros con menos de 33 semanas de edad gestacional 2. DA ≥ 1,5 mm con decisión de iniciar tratamiento farmacológico 3. Consentimiento informado firmado por el representante legal
|
|
E.4 | Principal exclusion criteria |
1. Consent Denied 2. Presence of severe birth defects 3. Congenital Heart Disease 4. Contraindication for administration of IB: • oligoanuria (diuresis <1 cc / kg / h) • recent severe intraventricular bleeding (IVH grade III or extensive periventricular hemorrhagic infarction) • Serum creatinine> 1.5 mg / dl or clinical suspicion of intestinal ischemia. |
1. Consentimiento denegado 2. Presencia de alteraciones congénitas graves 3. Cardiopatías congénitas 4. Contraindicación para la administración de IB: • Oligoanuria (diuresis < 1cc/kg/h), • Sangrado intraventricular reciente grave (HIV grado III o infarto hemorrágico periventricular extenso), • Creatinina sérica > 1,5 mg/dl o sospecha clínica de isquemia intestinal.
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
Incidence of NEC or API, defined as the presence of intestinal pneumatosis, pneumoperitoneum, or air in portal vein |
Incidencia de ECN o PIA, definida como la presencia de neumatosis intestinal, neumoperitoneo, o aire en vena porta |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Time of discharge of Neonatology Department or at completed 40 weeks post-menstrual age (whichever comes first) |
Al alta del servicio de Neonatología o al haber cumplido 40 semanas de edad postmenstrual (lo que ocurra primero) |
|
E.5.2 | Secondary end point(s) |
• Perinatal endpoints: o Mother's age o gestational age o maternal medication (antibiotics, anticonvulsants, antihypertensives, drugs of abuse, heparin, tocolytic, etc) o Birthweight o Sex o weight (<P10) o prenatal corticosteroids (full cycle) o 5 minutes Apgar o amniorrhexis> 18 hours o Advanced Resuscitation at birth o SNAPPE II o clinical chorioamnionitis o histologically confirmed Chorioamnionitis o cord pH o Multiple Pregnancy o Need surfactant Age of onset or treatment • echocardiographic endpoints: o Prior to treatment: ductus size color Doppler supraesternal in a sagittal cut. Relationship AI / Ao (left atrium / aorta) in a long axis parasternal M-mode diastolic velocity in the left pulmonary branch with a sagittal parasternal. ratio E / A (wave left ventricular filling) with an apical 4-chamber window. scFv (superior vena cava flow) measuring the size from a half left parasternal and speed from a subcostal window. postductal diastolic velocity in aorta from supraesternal court. • cardiorespiratory endpoints: o Prior to each dose: Heart Rate Blood Pressure Respiratory rate ventilation mode PMVA (mean airway pressure) FiO2 SatO2 capillary pCO2 arterial pCO2 venous pCO2 EB (Excess bases) Lactic acid diuresis 24 hours before treatment Capillary refill Gradient center-peripheral Tª cardiovascular support prior to treatment (blood volume expanders in previous 24 hours, prior to each dose inotropic score of treatment = (dopamine x 1) + (dobutamine x 1) + (adrenaline x 10) or need for hydrocortisone. • Efficacy endpoints: o treatment failure, defined as the presence of ≥ 1.5 mm DA 24-48 hours after finishing a maximum of 6 doses of ibuprofen (2 full cycles). o number of doses administered ibuprofen. o closing rate after a treatment cycle o closing rate after two cycles of treatment. o time required until closing. o need for surgical ligation. o reopening rate: defined as the presence of ductal color Doppler flow after confirming previous close echocardiographic. • Genetic enpoints: o Study of genetic polymorphisms associated to therapeutic failure or risk of necrotizing enterocolitis or isolated intestinal perforation. o Study of genetic polymorphisms associated with the metabolism and elimination of ibuprofen and its relationship with the occurrence of adverse events. o Security Variables: o mortality before discharge from the neonatal unit o Days of income o Chronic Lung Disease (CLD), defined as the need for supplemental oxygen at 36 weeks post-menstrual age. o pulmonary hemorrhage diagnosed in the presence of fresh blood or discharge tinged with blood drawn from the endotracheal tube, associated with respiratory and radiological diagnosis deterioration or autopsy. o secondary pulmonary hypertension, in case the patient had an estimated ecocariografía ≥ 60% of systemic pressure after treatment with ibuprofen associated with respiratory impairment pulmonary pressure started. Time to reach or exclusive enteral nutrition. o gastrointestinal bleeding, if the presence of fresh blood in gastric aspiration remains collected by nasogastric tube during treatment with ibuprofen or bloody fluid. o oligoanuria defined as diuresis <1 cc / kg / h. Diagnosis of structural damage or central nervous system by USC at the age of the term. o drugs that the patient has received before and during treatment with ibuprofen |
• Variables perinatales: o Edad de la madre o Edad gestacional o Medicación materna (antibióticos, anticonvulsivantes, antihipertensivos, drogas de abuso, heparina, tocolíticos, etc) o Peso al nacer o Sexo o Peso (<P10) o Corticoides prenatales (ciclo completo) o Apgar 5 minutos o Amniorrexis > 18 horas o Reanimación avanzada al nacer o SNAPPE II o Corioamnionitis clínica o Corioamnionitis confirmada histológicamente o pH del cordón o Embarazo múltiple o Necesidad de surfactante o Edad de inicio de tratamiento • Variables ecocardiográficas: o Previo al tratamiento: Tamaño de ductus con Doppler color en un corte supraesternal sagital. Relación AI/Ao (aurícula izquierda/aorta) en un corte paraesternal eje largo en modo M. Velocidad diastólica en la rama pulmonar izquierda con un corte paraesternal sagital. Relación E/A (onda de llenado ventricular izquierdo) con una ventana apical 4 cámaras. FVCS (flujo en vena cava superior) midiendo el tamaño desde una ventana paraesternal izquierda media y la velocidad desde una ventana subcostal. Velocidad diastólica en aorta postductal desde un corte supraesternal. • Variables cardiorrespiratorias: o Previo a cada una de las dosis: Frecuencia cardiaca Presión arterial Frecuencia respiratoria Modalidad de asistencia respiratoria PMVA (presión media en vía aérea) FiO2 SatO2 pCO2 capilar pCO2 arterial pCO2 venosa EB (Exceso de bases) Ácido láctico Diuresis 24 horas previas al tratamiento Relleno capilar Gradiente de Tª central-periférico Soporte cardiovascular previo al tratamiento (expansores de volemia en 24 horas previas, el score inotrópico previo a cada dosis de tratamiento = (dopamina x 1) + (dobutamina x 1) + (adrenalina x 10) o necesidad de hidrocortisona. • Variables de evaluación de Eficacia: o Fracaso terapéutico, definido como la presencia de DA ≥ 1,5 mm 24-48 horas después de finalizar hasta un máximo de 6 dosis de ibuprofeno (2 ciclos completos). o Número de dosis de ibuprofeno administrados. o Tasa de cierre tras un ciclo de tratamiento o Tasa de cierre tras dos ciclos de tratamiento. o Tiempo necesario hasta el cierre. o Necesidad de ligadura quirúrgica. o Tasa de reapertura: definido como la presencia de flujo ductal por Doppler color tras haber confirmado cierre previo ecocardiográfico. • Variables Genéticas: o Estudio de polimorfismos genéticos asociados a fracaso terapéutico o riesgo de enterocolitis necrotizante o perforación intestinal aislada. o Estudio de polimorfismos genéticos asociados al metabolismo y eliminación del ibuprofeno y su relación con la aparición de acontecimientos adversos. o Variables de Seguridad: o Mortalidad antes del alta de la unidad de neonatología o Días de ingreso o Enfermedad Pulmonar Crónica (EPC), definida como la necesidad de oxígeno suplementario a las 36 semanas de edad postmenstrual. o Hemorragia pulmonar, diagnosticada ante la presencia de sangre fresca o secreción teñida de sangre extraída del tubo endotraqueal, asociado a deterioro respiratorio y radiológico o diagnóstico en autopsia. o Hipertensión pulmonar secundaria, en caso de que el paciente presentara una presión pulmonar estimada por ecocariografía ≥ 60% de la presión sistémica, una vez iniciado el tratamiento con ibuprofeno asociado a deterioro respiratorio. o Tiempo en alcanzar la nutrición enteral exclusiva. o Sangrado gastrointestinal, en caso de presencia de líquido sanguinolento o sangre fresca en los restos gástricos recogidos por aspiración de la sonda nasogástrica durante el tratamiento con ibuprofeno. o Oligoanuria, definida como diuresis < 1 cc/kg/h. o Diagnóstico de lesión estructural del sistema nervioso central por USC a la edad del término. o Fármacos que el paciente ha recibido antes y durante el tratamiento con ibuprofeno.
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Time of discharge of Neonatology Department or at completed 40 weeks post-menstrual age (whichever comes first) |
Al alta del servicio de Neonatología o al haber cumplido 40 semanas de edad postmenstrual (lo que ocurra primero) |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Echo guided slow intravenous bolus of ibuprofen |
|
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial 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
|
last programmed visit of last enrolled subject |
última visita programada del último paciente incluido en el estudio |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 30 |
E.8.9.1 | In the Member State concerned days | |