Dobutamine in the Treatment of Haemodynamic Insufficiency in the Immediate Postnatal Period (NeoCirc-001)

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

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).

Study Overview

• Status: Terminated
• Conditions: Shock
• Intervention / Treatment: Drug: Dobutamine

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Spain
  • Madrid, Spain, 28046
    • La Paz University Hospital, Department of Neonatology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 1 year (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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).	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).

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Collaborators and Investigators

• Sponsor: Fundacion para la Investigacion Biomedica del Hospital Universitario la Paz
• Collaborators: University of Pecs; Institut National de la Santé Et de la Recherche Médicale, France; Hannover Medical School; Gazi University; Tufts Medical Center; University of Luebeck; Iuliu Hatieganu University of Medicine and Pharmacy; Brighton and Sussex University Hospitals NHS Trust; University of Liverpool; Semmelweis University; Hospital Universitario La Paz; Servicio Vasco de Salud Osakidetza, Spain; Vest Children´s Hospital, Germany; Datteln University Witten-Herdecke; Onorach Clinical Dundee, Scotland; Proveca Limited Daresbury, England
• Investigators: Study Chair: Adelina Pellicer, MD PhD, SERMAS La Paz University Hospital; Study Director: Heike Rabe, MD PhD, Brighton and Sussex University Hospitals (BSUH); Principal Investigator: Fernando Cabañas, MD PhD, Servicio Madrileño de Salud (SERMAS)

Publications and helpful links

General Publications

• 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. doi: 10.1136/fn.82.3.f188.
• 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. doi: 10.1136/fn.82.3.f182.
• 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;2007(1):CD005090. doi: 10.1002/14651858.CD005090.pub2.
• 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. doi: 10.1038/sj.jp.7211774.

Study record dates

Study Major Dates

• Study Start (Actual): May 30, 2014
• Primary Completion (Actual): October 13, 2015
• Study Completion (Actual): October 10, 2017

Study Registration Dates

• First Submitted: May 27, 2014
• First Submitted That Met QC Criteria: October 10, 2017
• First Posted (Actual): October 17, 2017

Study Record Updates

• Last Update Posted (Actual): October 17, 2017
• Last Update Submitted That Met QC Criteria: October 10, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: Shock; Dobutamine; Preterm infant
• Additional Relevant MeSH Terms: Pathologic Processes; Shock; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Protective Agents; Adrenergic Agonists; Cardiotonic Agents; Adrenergic beta-Agonists; Sympathomimetics; Adrenergic beta-1 Receptor Agonists; Dobutamine
• Other Study ID Numbers: Neocirculation 001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided