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

Phase 1

Terminated

• Conditions: Shock
• Interventions: Drug: Dobutamine

• Registration Number: NCT03311178
• Lead Sponsor: Fundacion para la Investigacion Biomedica del Hospital Universitario la Paz

Brief Summary

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).

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2014-05-27
• Study Start: 2014-05-30
• Primary Completion: 2015-10-13
• Status Verified: 2017-10
• Study Completion: 2017-10-10
• Study First Submitted QC: 2017-10-10
• Last Update Submitted: 2017-10-10
• Study First Posted: 2017-10-17
• Last Update Posted: 2017-10-17

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 15

Inclusion Criteria

Not provided

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Dobutamine	Dobutamine	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).

Primary Outcome Measures

Name	Time	Method
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. The second sample will be taken at different study time points after the end of infusion (from 5 min to 6 hours).	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.
Mortality, 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	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.

Secondary Outcome Measures

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

Trial Locations

Locations (1)

La Paz University Hospital, Department of Neonatology; 🇪🇸 Madrid, Spain