E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
babies with evidence of haemodynamic insufficiency within 72 hours after birth |
bebés con evidencia de insuficiencia hemodinámica en las 72 horas siguientes al nacimiento |
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E.1.1.1 | Medical condition in easily understood language |
babies within 72 hours after birth with circulatory failure causing insufficient blood to reach important organs |
bebés en las 72 horas posteriores al nacimiento que presentan fallo circulatorio que provoque riego sanguineo insuficiente a organos importantes |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
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 |
NeoCirc-001 - The primary objective is to answer some important questions required for the design of a forthcoming placebo-controlled trial, which will evaluate the effectiveness of a new neonatal formulation of dobutamine to treat haemodynamic insufficiency in the first 72 hours after birth in babies born at less than 33 weeks gestation (see issues requiring consideration below).This population will be observed with a view to determining which diagnostic measures lead to treatment decisions. The primary outcome is death or worst cranial ultrasound (CUS) appearances at or before 36 weeks gestation and will be observed in all cases. |
El objetivo principal es responder a una serie de cuestiones importantes para el diseño de un estudio subsecuente controlado con placebo (NeoCirc-003), que evaluará la eficacia de una nueva formulación neonatal de dobutamina para tratar la insuficiencia hemodinámica durante las primeras 72 h de vida en recién nacidos de menos de 33 semanas de gestación (ver cuestiones más abajo). Se observarán y recogerán prospectivamente los datos de interés en esta población con el objeto de determinar en qué medida los diferentes procedimientos diagnósticos llevan a la toma de decisiones terapéuticas. La variable de resultado principal es la muerte o el diagnostico más grave de lesión cerebral por ultrasonografía (CUS) a las 36 semanas de edad postconcepcional o antes. |
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E.2.2 | Secondary objectives of the trial |
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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 |
NeoCirc-001A - The primary objective is to estimate the half-life of a neonatal formulation of dobutamine in extremely premature neonates. NeoCirc-001B - The primary objective is to construct a population PK/PD model that will be validated using samples collected during the confirmatory trial (NeoCirc-003). |
NeoCirc-001A – El principal objetivo es estimar la vida media de eliminación de la dobutamina y, consecuentemente, el tiempo en alcanzar el equilibrio estacionario en la población de neonatos extremadamente prematuros. NeoCirc-001B – El objetivo principal es construir un modelo poblacional cinético-dinámico de la dobutamina que será validado mediante muestras que se obtendrán en el estudio confirmatorio (NeoCirc-003). |
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E.3 | Principal inclusion criteria |
-neonates 24 to 32+6 weeks´ gestation, -postnatal age <72 hours; -parental informed consent; -clinical signs indicating infants at risk of poor perfusion (i.e. evidence of haemodynamic insufficiency) defined as: -either two or more of: (i) Mean blood pressure (MBP) < gestational age (GA)-1 mmHg (invasive/non-invasive, two readings 15 min apart); (ii) SVC flow < 51 ml/kg/min; (iii) CRT > 4 sec; (iv) Lactate > 4 mmol/l (v) Base excess <-9 mmol/l
-or: MBP < GA -5 mmHg (invasive/non-invasive, two readings 15 min apart) |
neonatos de 24 a 32+6 semanas de gestación; edad postnatal <72 horas; consentimiento informado; signos clínicos indicativos de estado de perfusión deficitaria, definido como: bien dos o más de: (i) Presión arterial media (MBP) < edad gestacional (GA)-1 mmHg (invasiva/no invasiva, dos lecturas espaciadas 15 min); (ii) flujo en VCS< 51 ml/kg/min; (iii) CRT > 4 seg; (iv) Lactato > 4 mmol/l (v) Déficit de bases <-9 mmol/l
o: MBP < GA -5 mmHg (invasiva/no invasiva, dos lecturas espaciadas 15 min) |
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E.4 | Principal exclusion criteria |
NeoCirc-001 - -non-viability; -congenital hydrops or malformations likely to affect cardiovascular adaptation; -surgery planned within 72 hours of birth; -chromosomal anomalies; -informed consent form (ICF) not signed. |
-no viabilidad; -hidrops congénito o malformación que con probablilidad alta afecte al estado cardiovascular; -cirugía planeada dentro de primeras 72 h; -anomalías cromosómicas; -consentimiento informado (ICF) no firmado. |
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E.5 End points |
E.5.1 | Primary end point(s) |
A composite endpoint is defined as follows: a neonate is called a failure as soon as one of the following is true at or before gestational age 36 (+/-2 weeks), where all surviving patients will have a cranial ultrasound (CUS)- 1. Neonate dies, or 2. Intraventricular haemorrhage (IVH) grades 3 or 4, or 3. cystic and non-cystic periventricular leukomalacia (PVL), or 4. porencephalic cysts, ventriculomegaly, or cerebellar haemorrhage. |
Resultado compuesto definido como: fracaso terapeútico si cualquiera de los siguientes es cierto a las 36 (+/-2 semanas) o antes, momento en el que todos los supervivientes tendrán una evaluación de CUS- 1. Neonato fallece, o 2. Hemorragia intraventricular (IVH) grados 3 o 4, o 3. leucomalacia periventricular (PVL) quística o no quística, o 4. quiste porencefálico, ventriculomegalia, o hemorragia cerebelosa. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
A first CUS scan will be done as soon as possible at enrolment, preferably within the first 6 hours, but always before treatment is started. Subsequent scans will be done between 48 to 72 hours of treatment, at postnatal day 7 (±1), day 14 (±1), day 35 (±1) and at 36 (± 2) week?s gestation. |
Un primer scan CUS será realizado lo antes posible durante el reclutamiento, preferiblemente en las 6 primeras horas, pero siempre ante de comenzar el tratamiento. Scaners subsecuentes se realizarán a las 48 y 72 h del tratamiento, y a los dias postnacimiento: 7 (±1), 14 (±1), 35(±1) y al cumplirse la semana 36 (± 2) de gestación |
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E.5.2 | Secondary end point(s) |
-Clinical parameters The clinical condition of all the participants will be monitored using regular assessments (at 5 to 7 -hourly intervals) of: Haemodynamic parameters (blood pressure, heart rate, pulse oximetry) CRT Urine output Plasma lactate concentration and base excess -Lactate, base excess and urine output will be assessed at the next clinically indicated opportunity to avoid unjustified burdens on the babies to mandate non-clinically indicated procedures. Assessments at clinically indicated times override the 6 hourly intervals described above.
-Optional research parameters available in a selection of centres These parameters will be measured in selected centres at enrolment and at regular intervals while the infant is on cardiovascular support: Echo-D derived SVC flow and RVO (every 6-to-12 h). NIRS (continuous monitoring). aEEG (continuous monitoring). |
Evolución a corto plazo de los biomarcadores de insuficiencia circulatoria mientras el paciente recibe tratamiento cardiovascular: presión arterial, CRT, diuresis, lactato, déficit de bases, flujo en VCS y gasto ventricular derecho (RVO), NIRS y electroencefalografía integrada de amplitud (aEEG). Diagnósticos clínicos a la edad del término: muerte; diagnóstico combinado de IVH grado 2-4 y muerte; y diagnósticos clínicos principales a las 38 (± 4) semanas postconcepcionales (supervivencia sin lesión cerebral grave, mortalidad global, diagnósticos por CUS, hipotensión, hipertensión, enterocolitis necrotizante, ductus arterioso persistente, retinopatía de la prematuridad, enfermedad pulmonar crónica (dependencia de oxígeno a las 36 semanas) e infección nosocomial. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Clinical and research parameters will be measured while the infants are receiving cardiovascular support |
Los parametros clinicos será medidos mientras los niños reciban apoyo cardiovascular. |
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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 | No |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | No |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 9 |
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 |
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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
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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 | 14 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 14 |