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

Shock Clinical Trial

— NeoCirc-001  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03311178
• Other study ID #: Neocirculation 001
• Status: Terminated
• Phase: Phase 1/Phase 2
• First received: May 27, 2014
• Last updated: October 10, 2017
• Start date: May 30, 2014
• Est. completion date: October 10, 2017

Study information

• Verified date: October 2017
• Source: Fundacion para la Investigacion Biomedica del Hospital Universitario la Paz
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 15
• Est. completion date: October 10, 2017
• Est. primary completion date: October 13, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 72 Hours

Eligibility

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.

Related Conditions & MeSH terms

• Shock

Intervention

Drug:
• 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).

Locations

Country	Name	City	State
Spain	La Paz University Hospital, Department of Neonatology	Madrid

Sponsors (17)

Lead Sponsor

Collaborator

Fundacion para la Investigacion Biomedica del Hospital Universitario la Paz

Brighton and Sussex University Hospitals NHS Trust, Datteln University Witten-Herdecke, Gazi University, Hannover Medical School, Hospital Universitario La Paz, Institut National de la Santé Et de la Recherche Médicale, France, Iuliu Hatieganu University of Medicine and Pharmacy, Onorach Clinical Dundee, Scotland, Proveca Limited Daresbury, England, Semmelweis University, Servicio Vasco de Salud Osakidetza, Spain, Tufts Medical Center, University of Liverpool, University of Luebeck, University of Pecs, Vest Children´s Hospital, Germany

Country where clinical trial is conducted

Spain, 

References & Publications (4)

Dempsey EM, Barrington KJ. Treating hypotension in the preterm infant: when and with what: a critical and systematic review. J Perinatol. 2007 Aug;27(8):469-78. Review. — View Citation

Kluckow M, Evans N. Low superior vena cava flow and intraventricular haemorrhage in preterm infants. Arch Dis Child Fetal Neonatal Ed. 2000 May;82(3):F188-94. — View Citation

Kluckow M, Evans N. Superior vena cava flow in newborn infants: a novel marker of systemic blood flow. Arch Dis Child Fetal Neonatal Ed. 2000 May;82(3):F182-7. — View Citation

Osborn DA, Paradisis M, Evans N. The effect of inotropes on morbidity and mortality in preterm infants with low systemic or organ blood flow. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD005090. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Number of participants with adverse events	Number of Participants with Adverse Events as a Measure of Safety and Tolerability	Daily during the first four days of life, at 36±2 weeks' gestation or discharge and at 38±2 weeks' gestation or discharge
Primary	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
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	Background pattern	Background pattern measured by means of Amplitude-integrated electroencephalography (aEEG/EEG)	First 72 hours of life (data collection every 6 ±1 hrs)
Secondary	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)
Secondary	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)
Secondary	Cerebral fractional oxygen extraction (FOE)	FOE= [peripheral oxygen saturation (SaO2)-rStO2] /SaO2	First 72 hours of life (data collection every 6 ±1 hrs)
Secondary	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)
Secondary	Discontinuity	Discontinuity measured by means of Amplitude-integrated electroencephalography (aEEG/EEG)	First 72 hours of life (data collection every 6 ±1 hrs)
Secondary	Amplitude	The amplitude measured by means of aEEG/EEG	Fist 72 hours of life (data collection every 6 ±1 hrs)
Secondary	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)
Secondary	Synchrony	The synchrony measured by means of aEEG/EEG	First 72 hours of life (data collection every 6 ±1 hrs)
Secondary	Mortality		From birth to 36 (+/-2 weeks) postmenstrual age
Secondary	Intraventricular haemorrhage 2-4		From birth to 36 (+/-2 weeks) postmenstrual age
Secondary	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
Secondary	Hypotension		From birth to 36 (+/-2 weeks) postmenstrual age
Secondary	Hypertension		From birth to 36 (+/-2 weeks) postmenstrual age
Secondary	Necrotizing enterocolitis		From birth to 36 (+/-2 weeks) postmenstrual age
Secondary	Patent ductus (PDA)		From birth to 36 (+/-2 weeks) postmenstrual age
Secondary	Retinopathy of prematurity		at 36 (+/-2 weeks) postmenstrual age
Secondary	Chronic lung disease		at 36 (+/-2 weeks) postmenstrual age
Secondary	Oxygen-dependency at discharge		At discharge
Secondary	early infection		From birth to 72 hours after birth
Secondary	Nosocomial infection		From birth to 36 (+/-2 weeks) postmenstrual age