Clinical trial NCT03311178: Dobutamine in the Treatment of Haemodynamic Insufficiency in the Immediate Postnatal Period
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Shock
Keywords: Shock
Preterm infant
Dobutamine
Lead sponsor: Fundacion para la Investigacion Biomedica del Hospital Universitario la Paz
Sponsor class: OTHER
Collaborators: name: Hospital Universitario La Paz
name: Brighton and Sussex University Hospitals NHS Trust
name: University of Luebeck
name: Servicio Vasco de Salud Osakidetza, Spain
name: University of Liverpool
name: Vest Children´s Hospital, Germany
name: Datteln University Witten-Herdecke
name: Iuliu Hatieganu University of Medicine and Pharmacy
name: Semmelweis University
name: University of Pecs
name: Gazi University
name: Tufts Medical Center
name: Hannover Medical School
name: Onorach Clinical Dundee, Scotland
name: Proveca Limited Daresbury, England
name: Institut National de la Santé Et de la Recherche Médicale, France
First posted: 2017-10-17
Enrollment: 15
Sex: ALL
Maximum age (years): 72
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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).


Eligibility criteria: 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.

Primary outcomes:
measure: Mortality, or intraventricular haemorrhage (IVH) grades 3 or 4, or cystic and non-cystic periventricular leukomalacia (PVL), or porencephalic cysts, ventriculomegaly, or cerebellar haemorrhage.
timeFrame: at 36 (+/-2 weeks) postmenstrual age
measure: Half-life of the neonatal formulation of dobutamine.
timeFrame: 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 outcomes:
measure: Arterial blood pressure
timeFrame: First 72 hours of life (data collection every 9 ±3 hrs)
measure: Capillary refill time
timeFrame: First 72 hours of life (data collection every 9 ±3 hrs)
measure: Urine output
timeFrame: First 72 hours of life (data collection every 9 ±3 hrs)
measure: Blood lactate concentration
timeFrame: First 72 hours of life (data collection every 9 ±3 hrs)
measure: Base excess
timeFrame: First 72 hours of life (data collection every 9 ±3 hrs)
measure: cerebral regional tissue oxygen saturation (rStO2)
timeFrame: First 72 hours of life (data collection every 6 ±1 hrs)
measure: Background pattern
timeFrame: First 72 hours of life (data collection every 6 ±1 hrs)
measure: Superior vena cava flow
timeFrame: First 72 hours of life (data collection every 9 ±3 hrs)
measure: Right cardiac output
timeFrame: First 72 hours of life (data collection every 9 ±3 hrs)
measure: Cerebral fractional oxygen extraction (FOE)
timeFrame: First 72 hours of life (data collection every 6 ±1 hrs)
measure: Interburst interval (IBI)
timeFrame: First 72 hours of life (data collection every 6 ±1 hrs)
measure: Discontinuity
timeFrame: First 72 hours of life (data collection every 6 ±1 hrs)
measure: Amplitude
timeFrame: Fist 72 hours of life (data collection every 6 ±1 hrs)
measure: Presence of abnormal transients
timeFrame: First 72 hours of life (data collection every 6 ±1 hrs)
measure: Synchrony
timeFrame: First 72 hours of life (data collection every 6 ±1 hrs)
measure: Mortality
timeFrame: From birth to 36 (+/-2 weeks) postmenstrual age
measure: Intraventricular haemorrhage 2-4
timeFrame: From birth to 36 (+/-2 weeks) postmenstrual age
measure: Survival free of severe brain injury
timeFrame: From birth to 36 (+/-2 weeks) postmenstrual age
measure: Hypotension
timeFrame: From birth to 36 (+/-2 weeks) postmenstrual age
measure: Hypertension
timeFrame: From birth to 36 (+/-2 weeks) postmenstrual age
measure: Necrotizing enterocolitis
timeFrame: From birth to 36 (+/-2 weeks) postmenstrual age
measure: Patent ductus (PDA)
timeFrame: From birth to 36 (+/-2 weeks) postmenstrual age
measure: Retinopathy of prematurity
timeFrame: at 36 (+/-2 weeks) postmenstrual age
measure: Chronic lung disease
timeFrame: at 36 (+/-2 weeks) postmenstrual age
measure: Oxygen-dependency at discharge
timeFrame: At discharge
measure: early infection
timeFrame: From birth to 72 hours after birth
measure: Nosocomial infection
timeFrame: From birth to 36 (+/-2 weeks) postmenstrual age
Other outcomes:
measure: Number of participants with adverse events
timeFrame: Daily during the first four days of life, at 36±2 weeks' gestation or discharge and at 38±2 weeks' gestation or discharge
Locations:
city: Madrid
country: Spain
facility: La Paz University Hospital, Department of Neonatology
Study officials:
affiliation: SERMAS La Paz University Hospital
name: Adelina Pellicer, MD PhD
role: STUDY_CHAIR
affiliation: Brighton and Sussex University Hospitals (BSUH)
name: Heike Rabe, MD PhD
role: STUDY_DIRECTOR
affiliation: Servicio Madrileño de Salud (SERMAS)
name: Fernando Cabañas, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
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. doi: 10.1136/fn.82.3.f188.
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. doi: 10.1136/fn.82.3.f182.
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;2007(1):CD005090. doi: 10.1002/14651858.CD005090.pub2.
citation: 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.