NEO-CIRC

Dobutamine for NEOnatal CIRCulatory failure defined by novel biomarkers

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 Obiettivo del progetto (Objective)

'Dobutamine and adrenaline are widely used as second line therapy for systemic hypotension in infants. Dopamine is currently the most widely used first line drug. In neonates, sustained hypotension may, and impaired organ perfusion will, cause brain injury and poor neurodevelopmental outcomes. All three catecholamines are currently used off-label and have different modes of action which may result in potentially harmful haemodynamic effects. No reliable safety or efficacy data exists for the use of these drugs in neonates or newborns. Furthermore, no uniform criteria exist to define hypotension and there is little evidence to support current intervention strategies, which vary widely. Recently, superior vena cava (SVC) flow has been proposed as a more reliable indicator of circulatory failure than low blood pressure and preliminary results suggest Dobutamine is the optimum therapeutic in such cases. NEO-CIRC proposes 1) a randomised placebo controlled trial to provide safety and efficacy data for Dobutamine as a first line inotrope for all gestational ages 2) to perform pre-clinical; pharmacokinetic; pharmacodynamic; metabolomic and pharmacogenomic studies 3) to develop improved biomarkers of hypotension 4) to develop and adapt a formulation of Dobutamine suitable for newborns with the aim to apply for a Paediatric Use Marketing Authorisation. The NEO-CIRC consortium includes international experts in neonatal medicine, pharmacology, pharmacogenomics, drug formulation and pre-clinical neonatal models and an experienced group of experienced multicentre clinical trials NICU’s. Outcomes anticipated include improved biomarkers of organ perfusion; a new consensus definition of neonatal circulatory failure and answers to key clinical practice uncertainties, including variability of response to Dobutamine in common pathophysiologies seen in newborn infants impact on longer term developmental outcomes so important to the patients, families and wider society.'

Introduzione (Teaser)

Neonatal circulatory failure in the first two days after birth impairs blood flow, resulting in brain injury and decreased neurodevelopment. A European consortium is addressing the efficacy and safety of the drug dobutamine in treating infants.

Descrizione progetto (Article)

Dobutamine is used to treat infants with abnormally low blood pressure (hypotension) after birth. Preliminary data indicates that dobutamine treatment is beneficial. However, the current formulation is not certified for safe use in infants and it is being used off-label.

The EU-funded http://www.neocirculation.eu (NEO-CIRC) (Dobutamine for neonatal circulatory failure defined by novel biomarkers) project will conduct clinical trials to determine the safety and efficacy of age-appropriate formulation of dobutamine for infants. Other areas of focus include potential genetic polymorphisms that may influence drug response in infants and determining a standardised definition for circulatory failure in infants.

Project members revised their paediatric investigation plan and obtained approval for a series of three clinical trials. These studies will test dobutamine efficacy in preterm neonates using a new age-appropriate neonatal drug formulation.

During the second project phase, significant progress was achieved towards launching the clinical trials. NEO-CIRC finalised experimental studies on animal models to determine dobutamine pharmacokinetics (PK) and pharmacodynamics (PD). Analysis of PK/PD in tissue and blood samples is ongoing. Requisite manuals and standard operating protocols were also finalised.

Project findings were published in several peer-reviewed journals, and communicated in nine oral conference presentations and one poster presentation. Moreover, one publication is currently under review and another two are being prepared.

Staff training as well as preparatory work for clinical trial, sample and data management, regulatory framework and pilot batch of trial medicines has been completed. The pilot batch of medicines has already been distributed to two clinical study sites.

Overall, the NEO-CIRC trials will provide important information on the kinetics, dynamics and safety of administering dobutamine in infants as treatment for hypotension. Importantly, the adapted drug formulation for infants, alongside the improved consensus definition of neonatal circulatory failure, will improve the clinical outcome of affected babies.