| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Haemodynamic insufficiency
(Haemodynamic insufficiency after birth is commonly seen in babies born prematurely. The condition has a significant clinical impact. A final common pathway is seen but the consequences of functional impairment are diverse. During the neonatal period haemodynamic insufficiency can lead to loss of existing function and the loss of function that is yet to be developed.) |
Insuficiencia hemodinámica
(la insuficiencia hemodinámica después del nacimiento ocurre con mucha frecuencia en bebés nacidos prematuramente. La afección tiene un impacto clínico significativo. Las consecuencias funcionales son diversas . Durante el período neonatal la insuficiencia hemodinámica puede llevar a la pérdida de la función existente y a la pérdida de la función que aún no se ha desarrollado.) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Premature babies when their heart does not pump effectively after birth |
| Niños prematuros cuyo corazon no tienen la capacidad de bombear sangre de forma efectiva durante las primeras horas de vida |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10009196 |
| E.1.2 | Term | Circulatory failure neonatal |
| E.1.2 | System Organ Class | 10047065 - Vascular 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 |
• To demonstrate (short-term objective) that fluid bolus and dobutamine infusion as compared to fluid bolus and placebo infusion increases the proportion of neonates achieving and maintaining a clinically acceptable haemodynamic status with the dobutamine investigational infusion alone in the first 72 hours from birth.
• To demonstrate (medium-term objective) that fluid bolus and dobutamine infusion as compared to fluid bolus and placebo infusion increases the proportion of neonates alive without severe neurological complications at term-equivalence. |
- Objetivo a corto plazo: Demostrar que la solución en bolo y la
infusión de dobutamina en comparación con la solución en bolo y la
infusión de placebo aumentan la proporción de neonatos que
alcanzan y mantienen un estado hemodinámico clínicamente
aceptable en las primeras 72 horas desde el nacimiento.
- Objetivo a medio plazo: Demostrar que la solución en bolo y la
infusión de dobutamina en comparación con la solución en bolo y la
infusión de placebo aumenta la proporción de neonatos vivos y sin
complicaciones neurológicas graves al alcanzar la edad equivalente
al término. |
|
| E.2.2 | Secondary objectives of the trial |
• To assess (long term objective) the efficacy of dobutamine on long-term neurodevelopmental outcome.
• To evaluate (safety objective) the safety of dobutamine for the whole study population as well as for the three treatment groups separately.
• To assess which starting dose of dobutamine (2.5 μg/kg/min vs. 5 μg/kg/min) leads to better short-term outcomes.
• To assess the concentration/effect relationship of dobutamine and determine the individual covariates explaining the inter-individual pharmacokinetic/pharmacodynamics variability.
• To evaluate the effect of dobutamine therapy on infants with different genetic background for high vs. low genetic blood pressure estimates. |
-Evaluar la eficacia de la dobutamina en el neurodesarrollo a largo
plazo (objetivo a largo plazo).
- Evaluar la seguridad de la dobutamina en la población total de
estudio, así como en cada uno de los tres grupos de tratamiento por
separado (objetivo de seguridad).
- Evaluar qué dosis inicial de dobutamina (2.5 μg / kg / min vs. 5 μg /
kg / min) conduce a mejores resultados a corto plazo.
- Evaluar la relación concentración / efecto de la dobutamina y
determinar las covariables individuales que explican la variabilidad
farmacocinética / farmacodinámica interindividual.
- Evaluar el efecto del tratamiento con dobutamina en neonatos con
diferentes antecedentes genéticos para estimaciones de presión
arterial genéticas alta versus baja. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Advanced Biomarkers Sub-study: Study for the development of advanced biomarkers for diagnosis and treatment of circulatory failure
Version 1.0: 10 November 2017
Objectives:
To assess the ability of SVC flow determined by Echo-D to predict survival without severe neurological complications at term equivalent age (TEA).
To assess the ability of NIRS to predict survival without severe neurological complications at term equivalent age (TEA).
To assess the ability of aEEG/EEG to predict surviving without severe neurological complications at term equivalent age (TEA).
To assess the ability of the CBF autoregulation classifiers to predict surviving without severe neurological complications at term equivalent age (TEA).
To measure cerebral blood flow (CBF) autoregulation and the effect of dobutamine on CBF autoregulation.
To validate the predictive capacity of two estimators of CBF autoregulation capacity (BiAR-COH and PDCMABP>>rStO2) to define disease progression and vulnerability to brain injury. |
Sub-estudio de biomarcadores avanzados: estudio para el desarrollo de biomarcadores avanzados para el diagnóstico y tratamiento del fallo circulatorio
OBJETIVOS:
Evaluar la capacidad del flujo de SVC determinado por echo-D para predecir la supervivencia sin complicaciones neurológicas severas a la edad equivalente a término del embarazo (TEA).
Evaluar la capacidad de la NIRS para predecir la supervivencia sin complicaciones neurológicas graves a término de edad equivalente del embarazo (TEA).
Evaluar la capacidad del aEEG/EEG para predecir la supervivencia sin complicaciones neurológicas severas a la edad equivalente a término del embarazo (TEA).
Evaluar la capacidad de los clasificadores de autoregulación de la FEBIC para predecir la supervivencia sin complicaciones neurológicas severas a la edad equivalente a término (TEA).
Medir la autoregulación del flujo sanguíneo cerebral (SVC) y el efecto de la dobutamina en la autorregulación del SVC flow.
Validar la capacidad predictiva de dos estimadores de la capacidad de autorregulación (BiAR-COH y PDCMABP > > rStO2) para definir la progresión de la enfermedad y la vulnerabilidad a las lesiones cerebrales. |
|
| E.3 | Principal inclusion criteria |
Infants are eligible to be included in the study only if they meet all of the following criteria:
• 24(+0) to 32(+6) weeks gestation
• Admitted in the neonatal intensive care unit
• Presence of haemodynamic insufficiency, defined as the presence of one or more of the following within first 72 hours after birth:
o MABP < GA-1 (two readings, 15min apart) OR
o Lactate > 4 mm/l OR
o SVC flow <51 ml/kg/min
• Provision of signed and dated informed consent form by patient’s parent/mother or legally designated representative; which can be given antenatally as described in section 5.4.
Three notes of caution are necessary with respect to inclusion of infants into this trial:
• The treating physician needs to be at “clinical” equipoise on providing the proposed trial of dobutamine-treatment or placebo to the infant; which can be justified as explained in section 2.1 above.
• To avoid over treatment, the treating physician needs to fully understand the determinant of the pathophysiology of circulatory impairment and use clinical judgment to decide treatment. For example during severe congenital anaemia a baby meeting the inclusion criteria will not be included and will instead get the required blood volume replacement first; and only afterwards could be considered for inclusion if still eligible.
• Deferred informed consent is plausible in this condition because it is in accord with Article 35 of the Regulation of the European Union on Clinical Trials (Regulations (EU) no536/2014), that states: Informed consent to participate in a clinical trial may be obtained, and information on the clinical trial may be given, after the decision to include the subject in the trial, provided that this decision is taken at the time of the first intervention on the subject, in accordance with the protocol for that clinical trial and that all the following conditions are fulfilled:
o Urgency of the situation, caused by a sudden life-threatening or other serious medical condition
o Scientific grounds to expect that participation of the subject in the trial will have the potential to produce a direct clinically relevant benefit for the subject resulting in a measurable health-related improvement or in the diagnosis of its condition
o It is not possible within the therapeutic window to supply all prior information to and obtain prior informed consent from his/her legally designated representative
o The investigator certifies that he or she is not aware of any objections to participate in the clinical trial previously expressed by the legally designated representative
o The clinical trial relates directly to the subject’s medical condition because of which it is not possible within the therapeutic window to obtain prior informed consent from the legally designated representative and to supply prior information, and the clinical trial is such a nature that it may be conducted exclusively in emergency situations
o The clinical trial poses a minimal risk to, and imposes a minimal burden on, the subject in comparison with the standard treatment of the condition.
Informed consent shall be sought to continue the participation of the subject in the clinical trial, and information on the clinical trial shall be given to the parent or the legally designated representative. |
Neonatos de edad gestacional comprendida entre las 24 semanas hasta menos de 33 semanas, con una edad postnatal menor a 72 horas.
Si el neonato cumple los criterios de tratamiento, será randomizado a un régimen de tratamiento ciego:
dosis inicial de dobutamina 1,
dosis inicial de dobutamina 2
placebo.
Criterios de Inclusión: Neonatos de 24(+0) a 32(+6) semanas de gestación ingresados en las Unidades Neonatales de Cuidados Intensivos que presentan uno o más de los siguientes criterios de fallo circulatorio medidos en las 72 horas posteriores al nacimiento:
• Presión Arterial media (MBP) < Edad gestacional GA-1 (dos lecturas espaciadas 15 minutos) o
• Lactato > 4 mmol/l o
• Flujo en VCS <51 ml/kg/min.
Se registrarán el deficit de base (BE) y el tiempo de llenado capilar (CRT). |
|
| E.4 | Principal exclusion criteria |
Patients will be excluded from the study if they meet any of the following criteria:
• Neonates considered non-viable, with a clinical decision not to provide life support
• Infants with severe congenital hydrops fetalis needing chest or peritoneal drainage before recruitment
• Infants already on commercial dobutamine treatment
• Infants with congenital malformations likely to affect cardiovascular adaptation (including: congenital diaphragmatic hernia, gastroschisis or congenital heart defects).
• Infants in whom a surgical treatment is planned within 72 hours of birth
• Infants carrying chromosomal anomalies
• Lack of parental signed informed consent |
Los pacientes se excluirán del estudio si cumplen alguno de los siguientes criterios:
Neonatos considerados no viables, con una decisión clínica de no proporcionar soporte vital
Neonatos con hidropesía fetal congénita grave que necesitan drenaje torácico o peritoneal antes del reclutamiento
- Pacientes en tratamiento con tratamiento con dobutamina comercial
- Neonatos con malformaciones congénitas que pueden afectar la adaptación cardiovascular (incluyendo: hernia diafragmática congénita, gastrosquisis o defectos cardíacos congénitos).
- Pacientes para los que se haya planificado una intervención quirúrgica dentro de las 72 horas posteriores al nacimiento
- Neonatos con anomalías cromosómicas
- Falta de consentimiento informado firmado por los padres |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Two co-primary efficacy endpoints will be investigated:
(1) Short term (pharmacodynamic) endpoint: proportion of neonates achieving and maintaining a clinically acceptable haemodynamic status [A] with the dobutamine investigational infusion alone in the first 72 hours from birth.
(2) Medium term (clinical) endpoint: Proportion of neonates surviving without severe neurological complications [B] at term equivalent age (TEA) [C].
[A] Acceptable haemodynamic status with investigational infusion is defined, for the purposes of this study, as the achievement and maintenance of dose success according to the study’s predefined PD effect assessment and dose adjusting (see sections 8.1.1.4 to 8.1.1.7) during the first 72 h from birth. The loss of such acceptable haemodynamics status occurs whenever there is a change in therapeutic strategy that involves cardiovascular treatment other than the investigational infusion alone due to exceeded safety parameters, treatment failure of the investigational infusion or the need for rescue treatment or death; any additional fluid bolus of normal saline or equivalent is considered as cardiovascular treatment.
[B] Severe neurological complications are defined based on worst cranial ultrasound (cUS) scan appearances at term-equivalent age from scans performed at screening, day 3, day 7, day 14, day 35 from birth and term-equivalent age. The cUS will be centrally reviewed and the investigators will be blinded for the medium term co-primary endpoint because they will not know which treatment the infant is receiving. Severity of cUS imaging is to be graded using a score published by the SafeBoosC trial (1, 4) to diagnose the infant with one of three predefined findings at each cUS scan: No brain injury, Mild/moderate brain injury or Severe brain injury.
[C] Time point for assessment of medium co-primary endpoint is at term-equivalent age (TEA) which is defined as 40 weeks GA age +/-2 weeks. |
Variables principales: El estudio ha sido diseñado utilizando dos variables co-principales de eficacia:
A corto plazo (variable farmacodinámica): proporción de neonatos que alcanzan y mantienen un estado hemodinámico clínicamente aceptable [A] únicamente con la infusión de dobutamina en las primeras 72 horas de vida desde el nacimiento.
A medio plazo (variable clínica): proporción de neonatos que sobreviven sin complicación neurológica grave [B] a la edad equivalente al término del embarazo (TEA) [C].
[A] Se define, para este estudio, como estado hemodinámico aceptable (con el medicamento en investigación) a alcanzar y mantener el éxito terapéutico de la dosis administrada y sus ajustes de acuerdo con la evaluación predefinida del efecto farmacodinámico durante las primeras 72 h desde el nacimiento.
La pérdida de tal estado hemodinámico aceptable ocurre siempre que hay un cambio en la estrategia terapéutica que implica un tratamiento cardiovascular distinto de la infusión única del medicamento en investigación debido a alteraciones en los parámetros de seguridad, el fracaso del tratamiento o la necesidad de tratamiento de rescate o muerte; cualquier solución en bolo adicional se considera como tratamiento cardiovascular. [B] Las complicaciones neurológicas severas se definen según el diagnóstico más grave de lesión cerebral por ultrasonografía (CUS) a la edad equivalente al término de las exploraciones realizadas en el screening, el día 3, el día 7, el día 14, el día 35 desde el nacimiento y la edad equivalente al término. La CUS se revisará centralmente y los investigadores serán ciegos en relación a esta variable co-primaria a mediano plazo porque no sabrán qué tratamiento está recibiendo el neonato. La gravedad de las imágenes de la CUS se debe calificar utilizando una puntuación publicada por el ensayo SafeBoosC para diagnosticar al niño con uno de los tres hallazgos predefinidos en cada exploración CUS: sin lesión cerebral, lesión cerebral leve / moderada o lesión cerebral grave. [C] La evaluación de la variable co-primaria a medio plazo se realiza en el momento en el que el neonato alcanza la edad equivalente al término del embarazo (TEA) que se define como 40 semanas GA +/- 2 semanas. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
(1) Short term: The first 72 hours from birth
(2) Medium term: Term equivalent age (TEA) |
(1) Corto Plazo: Primeras 72 horas desde el nacimiento
(2) Medio Plazo: Edad equivalente al término del embarazo (semana 40+/-2semanas) (TEA) |
|
| E.5.2 | Secondary end point(s) |
• Proportion of patients that arrive at 24 months corrected gestational age without neurodevelopmental disability.
• Absolute and relative frequencies of AEs and SAEs, to be recorded and compared between groups.
-Optimal Starting Dose: Defined as the starting dose that provides the
minimum number of dose steps until the efficient dose.
- Population pharmacokinetics and PK/PD modelling based on sparse
blood sampling yielding the following endpoints: Lack of bias of the
model on the Visual Predictive Checks and Goodness of fit plots,
Residual standard Errors > 50 % on the estimated PK/PD parameters.
-Response of infants to dobutamine therapy with high (> percentile
75), intermediate (percentile 25-75) and low (< percentile 25) genetic
blood pressure estimates. |
-Proporción de pacientes que llegan a los 24 meses de edad gestacional corregida sin discapacidad del desarrollo neurológico.
-Frecuencias absolutas y relativas de Acontecimientos Adversos y Acontecimientos Adversos Graves, registradas y comparadas entre los tres grupos.
- Dosis de inicio óptima: definida como la dosis inicial que proporciona el número mínimo de escaladas hasta la dosis eficiente.
- Farmacocinética poblacional y modelado PK / PD basado en muestreo de sangre para determinar las siguientes variables: falta de sesgo del modelo en los controles predictivos visuales y gráficos de bondad de ajuste, errores estándar residuales> 50% en los parámetros PK / PD estimados.
- Estimaciones genéticas de la respuesta de los neonatos con tensión arterial alta (> percentil 75), intermedia (percentil 25-75) y baja (<percentil 25).al tratamiento con dobutamina. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Long term objective: 24 months |
| Objetivos a largo plazo: 24 meses |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| 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
| Yes |
| 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 | 40 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 38 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial 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 the study is defined as completion of the last visit or procedure shown in the SoA in the trial globally. |
|
| 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 | 36 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 36 |
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