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 |
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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 |
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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 |
The primary objective is to answer some important questions required for the design of a larger (placebo-controlled) randomised trial, which will evaluate the effectiveness of a new neonatal formulation of Dobutamine to treat circulatory failure in the first 72 hours after birth in babies born too early. To help answer these questions, babies with circulatory failure will be observed based on a primary outcome of brain ultrasound and on secondary outcomes of other secondary diagnostic measures, with a view to determining the degree to which these diagnostic measures influence treatment decisions. The questions to answer are: • What inclusion criteria is best to use in the randomised trial from a selection of potential entry criteria that will be assessed in this trial? • What treatments are being used and what is their relationship with the entry criteria? • When and why do doctors decide to increase the dose, decrease the dose,or stop/re-start Dobutamine? • How stable are babi |
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E.2.2 | Secondary objectives of the trial |
One secondary objective is to evaluate the outcome of a list of biomarkers for circulatory failure (including the entry criteria) while a patient is being treated. Some of the biomarkers are commonly used in the Neonatal Intensive Care Units and others are more specialised optional biomarkers.
Another secondary objective is to evaluate pre-defined clinical outcomes at term equivalence and various major clinical neonatal diagnoses at 38 (± 4) weeks’ gestation.
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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 - Elimination half-life of a neonatal formulation of dobutamine in extremely premature neonates - 28 June 2013(Version 1). Primary objective: to estimate the elimination half-life, and consequently the time to steady-state of dobutamine in extremely premature neonates.
NeoCirc-001B - Population pharmacokinetic-pharmacodynamic (PK-PD) modelling for a neonatal formulation of dobutamine in extremely premature neonates - 28 June 2013(Version 1). Primary objective: to construct a population PK/PD model that will be validated using samples collected during a subsequent confirmatory trial. |
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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)
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E.4 | Principal exclusion criteria |
• 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.
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E.5 End points |
E.5.1 | Primary end point(s) |
A composite endpoint is defined as follows: treatment failure is when one of the following is true at or before gestational age 36 (+/-2 weeks), when 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. The primary assessment will be done centrally.
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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. |
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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). |
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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 |
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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 | Yes |
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 | No |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 15 |
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 | 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
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 1 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 1 |