Dobutamine in the Treatment of Haemodynamic Insufficiency in the Immediate Postnatal Period

Study Overview
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Brief Summary
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Haemodynamic insufficiency after birth is seen commonly in babies born prematurely and is associated with adverse outcomes. In current clinical practice, a combination of blood pressure and clinical signs is used to guide therapy. However, blood pressure is a poor surrogate of systemic and organ (brain) blood flow distribution during transitional circulation. This state is characterised by increased peripheral vascular resistance and increased afterload causing myocardial depression and impaired blood flow distribution in spite of 'normal' blood pressure. Echocardiography-Doppler (Echo-D) measurement of superior vena cava (SVC) flow has been proposed as a more clinically relevant marker of circulatory impairment shortly after birth than systemic hypotension. When there is low SVC flow, several small-scale clinical trials have suggested dobutamine as the optimal therapeutic option. However the associations between SVC flow and short- and long- term outcomes are not strong enough to allow SVC flow alone to be the basis for the inclusion of patients into a confirmatory trial to demonstrate the efficacy and safety of dobutamine. NeoCirc-001 - The primary objective is to answer some important questions required for the design of a subsequent placebo-controlled trial (NeoCirc-003), 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. Observational data will be collected from this population with a view to determining the degree to which diagnostic measures influence treatment decisions. The primary outcome is death or worst cranial ultrasound (CUS) appearance at or before 36 weeks' gestation. NeoCirc-001A - The primary objective is to estimate the elimination half-life, and consequently the time to steady-state of dobutamine in extremely premature neonates. NeoCirc-001B - The primary objective is to construct a population pharmacokinetic pharmacodynamic model that will be validated using samples collected during the confirmatory trial (NeoCirc-003).

Official Title
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An International Multicentre Open-label Comparative Therapeutic Exploratory Trial to Investigate the Role of a New Neonatal Formulation of Dobutamine in the Treatment of Haemodynamic Insufficiency in the Immediate Postnatal Period

Conditions
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Shock

Intervention / Treatment
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* Drug: Dobutamine


Participation Criteria
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Eligibility Criteria
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Inclusion criteria for NeoCirc-001, 001A and 001B - Target population for informed consent: neonates 24 to 32+6 weeks´ gestation, postnatal age <72 hours; Infants eligible for circulatory failure pathway: parental informed consent obtained; The infants will be assessed, as per routine clinical practice, for clinical signs indicating infants at risk of poor perfusion, and will be recruited if they develop 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) capillary refill time (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) Exclusion Criteria: NeoCirc-001, 001A and 001B - 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.

Ages Eligible for Study
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Maximum Age: 72 Hours

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dobutamine<br>Infants who meet the definition of poor perfusion state will be treated at the discretion of the responsible physician following the standard local policies. The interventions will be dobutamine from a new neonatal formulation developed for NeoCirc and/or other treatments (including any other cardiovascular drug or volume replacement with normal saline). | Drug: Dobutamine<br>* Infants who meet the definition of poor perfusion state will be treated at the discretion of the responsible physician following the standard local policies. The interventions will be dobutamine from a new neonatal formulation developed for NeoCirc and/or other treatments (including any other cardiovascular drug or volume replacement with normal saline).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality, or intraventricular haemorrhage (IVH) grades 3 or 4, or cystic and non-cystic periventricular leukomalacia (PVL), or porencephalic cysts, ventriculomegaly, or cerebellar haemorrhage. | 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)- Neonate dies, or Intraventricular haemorrhage (IVH) grades 3 or 4, or cystic and non-cystic periventricular leukomalacia (PVL), or porencephalic cysts, ventriculomegaly, or cerebellar haemorrhage. | at 36 (+/-2 weeks) postmenstrual age | 
| Half-life of the neonatal formulation of dobutamine. | NeoCirc-001A: Half-life of the neonatal formulation of dobutamine. The first sample will be drawn after the end of the infusion, at the time when dobutamine ceases reaching the systemic circulation of the neonate, defined as time end (te). To calculate the end of infusion (te) the dead space used in each unit will be taken into account (see below). The second sample will be taken at different study time points after the end of infusion: 5 min after te 15 min after te 45 min after te 2 hours after te 6 hours after te Two infants will be allocated to each time point. Sampling times will be assigned randomly to the patients. | The first sample will be drawn after the end of the infusion, at the time when dobutamine ceases. The second sample will be taken at different study time points after the end of infusion (from 5 min to 6 hours). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Arterial blood pressure | Short-term outcomes of biomarkers for circulatory assessment while a patient is receiving cardiovascular support | First 72 hours of life (data collection every 9 ±3 hrs) | 
| Capillary refill time | Short-term outcomes of biomarkers for circulatory assessment while a patient is receiving cardiovascular support | First 72 hours of life (data collection every 9 ±3 hrs) | 
| Urine output | Short-term outcomes of biomarkers for circulatory assessment while a patient is receiving cardiovascular support | First 72 hours of life (data collection every 9 ±3 hrs) | 
| Blood lactate concentration | Short-term outcomes of biomarkers for circulatory assessment while a patient is receiving cardiovascular support | First 72 hours of life (data collection every 9 ±3 hrs) | 
| Base excess | Short-term outcomes of biomarkers for circulatory assessment while a patient is receiving cardiovascular support | First 72 hours of life (data collection every 9 ±3 hrs) | 
| cerebral regional tissue oxygen saturation (rStO2) | Cerebral regional tissue oxygen saturation (rStO2) measured by means of near-infrared spectroscopy | First 72 hours of life (data collection every 6 ±1 hrs) | 
| Background pattern | Background pattern measured by means of Amplitude-integrated electroencephalography (aEEG/EEG) | First 72 hours of life (data collection every 6 ±1 hrs) | 
| Superior vena cava flow | Short-term outcomes of biomarkers for circulatory assessment while a patient is receiving cardiovascular support | First 72 hours of life (data collection every 9 ±3 hrs) | 
| Right cardiac output | Short-term outcomes of biomarkers for circulatory assessment while a patient is receiving cardiovascular support | First 72 hours of life (data collection every 9 ±3 hrs) | 
| Cerebral fractional oxygen extraction (FOE) | FOE= [peripheral oxygen saturation (SaO2)-rStO2] /SaO2 | First 72 hours of life (data collection every 6 ±1 hrs) | 
| Interburst interval (IBI) | Interburst interval (IBI) measured by means of Amplitude-integrated electroencephalography (aEEG/EEG) | First 72 hours of life (data collection every 6 ±1 hrs) | 
| Discontinuity | Discontinuity measured by means of Amplitude-integrated electroencephalography (aEEG/EEG) | First 72 hours of life (data collection every 6 ±1 hrs) | 
| Amplitude | The amplitude measured by means of aEEG/EEG | Fist 72 hours of life (data collection every 6 ±1 hrs) | 
| Presence of abnormal transients | The presence of abnormal transients measured by means of aEEG/EEG | First 72 hours of life (data collection every 6 ±1 hrs) | 
| Synchrony | The synchrony measured by means of aEEG/EEG | First 72 hours of life (data collection every 6 ±1 hrs) | 
| Mortality |  | From birth to 36 (+/-2 weeks) postmenstrual age | 
| Intraventricular haemorrhage 2-4 |  | From birth to 36 (+/-2 weeks) postmenstrual age | 
| Survival free of severe brain injury | Survival free of severe brain injury measured by means of cranial ultrasound studies | From birth to 36 (+/-2 weeks) postmenstrual age | 
| Hypotension |  | From birth to 36 (+/-2 weeks) postmenstrual age | 
| Hypertension |  | From birth to 36 (+/-2 weeks) postmenstrual age | 
| Necrotizing enterocolitis |  | From birth to 36 (+/-2 weeks) postmenstrual age | 
| Patent ductus (PDA) |  | From birth to 36 (+/-2 weeks) postmenstrual age | 
| Retinopathy of prematurity |  | at 36 (+/-2 weeks) postmenstrual age | 
| Chronic lung disease |  | at 36 (+/-2 weeks) postmenstrual age | 
| Oxygen-dependency at discharge |  | At discharge | 
| early infection |  | From birth to 72 hours after birth | 
| Nosocomial infection |  | From birth to 36 (+/-2 weeks) postmenstrual age | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Shock, Preterm infant, Dobutamine