Final Report Summary - NEO-CIRC (Dobutamine for NEOnatal CIRCulatory failure defined by novel biomarkers)
Executive Summary:
Dobutamine is a drug currently used off label in the neonatal treatment of circulatory failure, a condition that leads to impaired organ perfusion that will likely cause brain injury and poor neurodevelopmental outcomes. No uniform criteria exist to define circulatory failure, or neonatal shock, and there is little evidence to support current intervention strategies which vary widely. Recently, flow in the 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.
The NEO-CIRC consortium was established in 2011 to conduct trials to provide safety and efficacy data for dobutamine as a first line inotrope in neonates, based on a new age-appropriate neonatal formulation, and with the intention to progress towards a Paediatric Use Marketing Authorisation (PUMA) supported by the trials’ results. Additional aims were to develop improved biomarkers of circulatory impairment, with a focus on SVC-flow; and to conduct pre-clinical, pharmacokinetic, pharmacodynamic and pharmacogenetic studies to better understand the mode of action of dobutamine. The consortium included international experts in neonatal medicine, pharmacology, pharmacogenetics, drug formulation, pre-clinical neonatal models and a group of NICUs experienced in multicentre clinical trials.
The project has effectively led to the development and testing of a new neonatal formulation of dobutamine, producing novel pharmacokinetic (PK) data on the half-life of the drug in human preterm infants. Other pre-clinical PK results have established the suitability of the neonate piglet as an animal model to study dobutamine, showing an encouraging pattern of changes in response to the new formulation of dobutamine that justify long-term studies in human neonates. Parallel results of genetics studies from the German neonatal network (GNN) indicate that dobutamine treatment should be done in a personalized way and include clinical and genetic risk factor assessment, to help reduce complications that may lead to disability or death.
Despite various challenges that precluded the opening of the main clinical trial to ultimately test the efficacy and safety of dobutamine, the project has been educational in the assessment of newborns with circulatory failure. It has created awareness about neonatologist-performed echocardiography and has enabled successful training in the clinical centres. The multifaceted nature of neonatal circulation in the early days of life has been acknowledged and the necessity of a combination of biomarkers to guide treatment has been emphasized.
The consensus on the biomarkers to define circulatory impairment in the first days of life in preterm infants, together with the half-life PK results that help inform timing aspects of the application and evaluation of dobutamine, have laid the foundation for a well-designed clinical trial on the efficacy and safety of dobutamine. The trial protocol has been finalised and will be implemented by Spain, Turkey and UK. Novel aspects of the proposed trial will lead to better designed clinical trials with more relevant results and to better selection of patients who would actually benefit from treatment; ultimately contributing to a new definition of neonatal shock that can be used by clinicians treating this highly vulnerable population.
Project Context and Objectives:
Many medicines used in children, especially neonates, have never been tested to the level seen in adult healthcare. This population is often treated with drugs that are unlicensed or off-label, with age-related differences in drug absorption or metabolism resulting in the use of suboptimal drug regimens with a weak evidence-base. The lack of formal studies in babies and children also means that adverse events are poorly understood and safety is compromised. An urgent need to resolve this unsatisfactory state of affairs was recognised by the European Medicines Agency (EMA) for off-label drugs of common use in neonates.
Dobutamine for circulatory failure was identified as a priority drug and the FP7 funded NEO-CIRC Consortium was established with a threefold remit: to produce an age-appropriate formulation with the bare minimum of excipients and avoiding dilutions if possible; to generate data on efficacy and safety in neonates; and the need for international consensus on a definition for circulatory failure or neonatal shock. New EU and US Paediatric Drug Regulations require the industry to provide age-appropriate formulations of medicines for children. In Europe, new drugs produced for children must have a Paediatric Investigation Plan (PIP) as part of their development. As an incentive the company obtaining a Paediatric Use Marketing Authorisation (PUMA) after a PIP will receive an extension of the patent period.
Why circulatory failure?
Circulatory failure has been recognised as a risk factor for disability in very preterm babies, with studies indicating a strong association between the condition in the days after birth and adverse outcomes including death. Failure of the circulation is manifest in several ways including low blood pressure and poor blood supply to key organs, such as the brain; thus sick newborn babies with this condition are at risk of brain injury and poor neurodevelopmental outcomes. Many sick newborn babies grow up with disability and handicap which lead to significant burdens on themselves, their families and society. It has been estimated that the cost to the public sector of looking after all babies born each year with these problems, until they are 18 years old, could amount to approximately €9 billion in the European Union. This all shows that very preterm infants with circulatory failure is a group with priority needs for research; and that the condition is an important target for treatments that aim to reduce disability.
The special case of helping very preterm infants soon after birth
The first hours after birth differ markedly from all other periods in human life and are characterised by a unique and dynamically changing anatomy. This is accompanied by striking changes in function as the circulatory system of the healthy newborn adapts rapidly to life outside the womb. Haemodynamic physiology and pathophysiology changes are specific to this age-group and generate unique clinical challenges. In current clinical practice, diagnostic and therapeutic approaches are different when managing neonates born very prematurely than with older infants. There are anatomic features of the cardiovascular system, relating to both the myocardium and neural control, which render very premature babies unique. Specific physiological features of the adaptation to birth of these babies include: a likely patent ductus arteriosus with left-to-right or bidirectional shunt; lower ventricular distensibility affecting preload; and a reduced reserve for ventricular contractility.
If other major types of shock (hypovolemic, distributive or obstructive) are discarded, then the main determinants leading to compromised organ blood flow after birth are myocardial dysfunction (causing decreased cardiac output) or abnormal peripheral vasoregulation (producing changes in systemic vascular resistance). Given that blood pressure is the product of both cardiac output and systemic vascular resistance, the impact of central blood pressure on actual tissue blood flow is unpredictable. Blood pressure is thus a poor surrogate of systemic and organ (including brain) blood flow during the transitional period from intra- to extra-uterine life. There is evidence that the correlation between systemic blood flow and blood pressure in the preterm infant is rather poor; and that impaired organ perfusion or shock can occur with normal, low or high blood pressure.
To overcome the limitations of assessing circulatory failure in very preterm babies soon after birth, NEO-CIRC proposes to use, in addition to blood pressure, a combination of clinical and biochemical parameters as biomarkers to determine the status of blood flow distribution and poor perfusion; including the use of functional echocardiography, particularly SVC-flow, to assess systemic and cerebral blood flow. SVC-flow has been highlighted as a potentially useful tool by a handful of studies that, although not conclusively due to their medium sample-size, have revealed that: SVC-flow is unaffected by the presence of intra- or extra-cardiac shunts; SVC-flow is the only functional echocardiographic measure that correlates with a marker of cerebral blood flow based on NIRS; low SVC-flow is associated with surrogate markers of adverse long-term outcomes like intraventricular haemorrhage; and low SVC-flow is associated with poor long term outcomes.
With respect to implementation, functional echocardiography has been adopted by physicians working with critically ill patients; and formal educational interventions that allow novices to acquire competence have been defined and assessed. A simplified method, focusing on measures of circulatory function, has been implemented in NEO-CIRC centres. The method, originally described in Australia in 2000 by Kluckow and Evans, has been successfully applied by neonatal units worldwide. In our experience, a well-structured training program allows accurate and reproducible measurements with low intra- and inter-observer variability, with most studies doable in less than 5 minutes by trained individuals. Thus, a NEO-CIRC developed training course enabled clinicians to measure SVC-flow in real time without learning the full set of echocardiography skills.
Why dobutamine?
Dobutamine is unique among proposed treatments for the neonatal circulation in that there is evidence that the use of this drug is likely to reduce the incidence of disability. This evidence relates to the use of dobutamine to treat low SVC-flow. Pharmacological attempts to prevent low SVC-flow have so far been unsuccessful. One clinical trial involving 42 babies born at less than 30 weeks’ gestation with low SVC-flow found that dobutamine increased SVC-flow and was associated with a reduced incidence of a key surrogate outcome. Parenchymal brain haemorrhage was seen in 5% of neonates treated with dobutamine, compared to 35% of neonates treated with dopamine. This raises the possibility that a dobutamine-mediated increase in SVC-flow will improve neurodevelopmental outcome. That is, dobutamine treatment seems to increase SVC-flow and may reduce disability.
There’s a pressing need for effective therapies for disturbances to the transitional circulation and dobutamine seems to be a good candidate that merits formal testing in the context of a well-designed clinical trial.
A large scale trial is justified
According to the finally agreed PIP with the EMA, an international, multicentre, randomized, placebo-controlled, double blind three arm trial is to be conducted; to investigate the efficacy of dobutamine with two different starting doses in the treatment of haemodynamic insufficiency in the immediate postnatal period.
A placebo group is justified in conditions such as circulatory failure in preterm infants; where widespread uncertainty amongst neonatologists justifies testing a particular treatment approach within all the safeguards of a high quality randomised clinical trial. There is currently no standard method of diagnosis or treatment for circulatory failure and there is evidence that preterm infants may be at risk of overtreatment with current approaches which may be unnecessary or even harmful. The clinical community and individual clinicians are at “clinical” equipoise on this question and placebo treatment is justifiable in the context of an agreed approach to managing comorbidities such as protracted hypotension, persistently low SVC flow, prolonged capillary refill time or worsening biochemical parameters.
Additional work needed to strengthen the knowledge base around this area of research
• Pharmacology: The pharmacokinetics (PK) of dobutamine in the population of interest is not well defined. This information is needed to establish adequate evidence-based timings for dosing and pharmacodynamic (PD) assessment. It would also be of value to establish the possible relationship between the plasma concentration of dobutamine and its efficacy or toxicity, as well as the factors that could explain the interindividual variability of this relationship (Pop-PK/PD modelling). This could help determine an optimal dosing regimen of dobutamine in infants, based on the individual characteristics explaining the between-subject differences in the efficacy and toxicity of this drug (dose-finding).
• Pharmacogenetics: It is well established that the individual response of preterm newborn babies to dobutamine treatment varies from an extremely good response to total resistance even if high doses are given. Genetic factors alter the individual response to many medications including dobutamine. However, no data were available so far for the pharmacogenetics of dobutamine in preterm newborn infants. NEO-CIRC set up a biobank of maternal and infant DNA (including infant umbilical cord tissue, which will be available for further metabolomic and proteomic studies). Genome wide array studies in more than 2000 preterm infants were done since 2011 by the German Neonatal Network (GNN), a consortium which was led by ULU. Since blood pressure on day one of life is an outcome parameter of the GNN, this reference group would add substantial information to the analysis of the well characterized NEOCIRC cohort, which at the end of NEOCIRC-003 would have contributed important pharmacokinetic and pharmacodynamic data.
• Pre-clinical (animal) work: The performance of experimental studies in suitable animal species is a common practice, given the difficulties of conducting pharmacological research in children and more specifically in the neonatal population. Preclinical findings, and especially juvenile animal data, can be useful to generate information to support the use of a specific drug in pediatric populations. Specifically, it is important that unlike models in adult animals, those based on juvenile and in particular neonatal animals allow for the fact that drug concentration (PK) and drug response (PD) may be different in immature and developing organs. Moreover, it is important to obtain information on PK/PD and potentially different safety profiles on juvenile and, in particular neonatal animals, from those seen in adults, because there are a number of developmental variations of structure and function of the organs, an in particular of the cardiovascular system, that suggest a different response to the drug.
• Definition of neonatal shock: Low blood pressure is widely used to diagnose neonatal shock but there is no clearly established link between low blood pressure, or its treatment and long-term outcome. The threshold of blood pressure at which treating hypotension has an impact on long-term outcomes has not been defined. Other markers have been described (SVC-flow, NIRS, EEG, Cerebral Blood Flow Autoregulation, other cardiovascular indices) but the effects of treating abnormal values of these markers have not been established. Thus there is a necessity to define shock in neonates so that dobutamine can be targeted appropriately; and to develop evidence-based guidelines for the assessment of the neonatal circulation that can be applied in clinical practice leading to wider experience in innovative methodological approaches in the evaluation of medicinal products in neonates.
Based on the project context described in this section, NEO-CIRC worked towards the aims and objectives outlined below.
Aim 1 - Work towards PUMA for dobutamine: Deliver pharmaceutical, pre-clinical and clinical work that will contribute to a PUMA for dobutamine as treatment for circulatory failure after birth.
Aim 1 Objectives:
• Develop a PIP for dobutamine.
• Develop an age-appropriate formulation for dobutamine.
• Optimise a dosage-regimen for dobutamine in neonates.
• Conduct preclinical studies to investigate the safety and mechanism of action of dobutamine.
• Develop consistent approaches to measuring SVC flow and other markers of neonatal shock, with a training package to ensure that SVC flow is measured consistently in the clinical trials.
• Conduct a large Phase 3 therapeutic confirmatory clinical trial of the efficacy and safety of dobutamine to treat circulatory failure in very premature neonates after birth.
Aim 2 - Definition of neonatal shock: Derive a new definition of neonatal shock as the basis for international guidelines for the assessment and treatment of neonatal shock.
Aim 2 Objectives:
• Standardise measurements.
• Conduct observational studies in parallel to trials.
• Develop a consensus definition and guidelines to ensure the results of the research change clinical practice.
Project Results:
The NEO-CIRC project (Dobutamine for NEOnatal CIRCulatory failure defined by novel biomarkers) was funded under the EU’s 7th Framework Programme (FP7) to address the FP7 HEALTH call topic “Investigator-driven clinical trials on off-patent medicines for children”.
The project was coordinated by BSUH (UK) and the original Consortium comprised 18 partners, including four research intensive SME organisations, located in 8 different countries. SERMAS (Spain) acted as the sponsor of the Clinical Trials with 11 trial sites originally planned in the UK (BSUH, Brighton and ULIV, Liverpool), Spain (OSA, Bilbao and SERMAS, Madrid), Germany (ULU, Lubeck and VKJK, Datteln), Turkey (GUSM, Ankara), Hungary (SU, Budapest and UOP, Pecs), Romania (UMF CLUJ, Cluj-Napoca) and the US (TMC, Boston). ONO (UK) were responsible for managing the clinical monitoring of the trials, MHH (Germany) for the trial statistics and data management and analysis and PRO (UK) for producing the new formulation of dobutamine. In addition, INSERM (France) was responsible for pharmacokinetics and pharmacodynamic studies, ULU (Germany) for pharmacogenetics studies, OSA and DYNA (Spain) for animal model studies and GUSM (Turkey) [initially ULIV (Liverpool)] for biomarker studies. Finally, KIE and MOD (UK) were responsible for supporting BSUH in the overall management of the NEO-CIRC project.
At the start of the project, two independent boards were established, the Expert Advisory Board and the Ethics Advisory and Data Monitoring Board, which were comprised of leading international experts in relevant fields. The aim of the Expert Advisory Board was to ensure that the decisions taken by the Consortium were consistently aimed at and optimised to maximise the impact of the research on neonatal circulation and more generally off patent paediatric medicines. The aim of the Ethics advisory and Data Monitoring Board was to safeguard the interests of trial participants, monitor the main outcome measures including safety and efficacy, and monitor the overall conduct of the trial.
The NEO-CIRC project comprised 8 work packages, 6 of which are research focussed (WP1-WP6).
WP1 aimed to determine the pharmacokinetics (PK) and to model the PK/pharmacodynamic (PD) relationships of dobutamine in preterm infants.
WP2 aimed to define clinical and genetic risk factors for different response to dobutamine in preterm infants, by pharmacogenetic studies on genetic polymorphisms regarding inotrope use.
WP3 aimed to define the biomarkers indicating neonatal shock and their relationship to important clinical outcomes; and to implement training on SVC-flow.
WP4 aimed to conduct pre-clinical studies in animals to support the development of a new age-appropriate formulation of dobutamine to be used in preterm neonatal patients, through the study of the effect of different dobutamine doses and a complete PK/PD study in a neonatal animal model.
The objective of WP5 was to conduct 3 clinical trials and 1 systematic review requested by the approved PIP according to GCP guidelines and to the highest ethical standards. These were to assess: the prevalence of low systemic blood flow during transitional circulation in neonates; the PD effects of dobutamine using clinical, biochemical and non-invasive monitoring (Echo-D, NIRS and aEEG); and the efficacy and safety of dobutamine on long term neurodevelopmental outcome. The latter was planned as the NEOCIRC-003 trial: An international multicentre randomized placebo-controlled, double blind three arm trial to investigate the efficacy and safety of dobutamine with two different starting doses in the treatment of haemodynamic insufficiency of very preterm babies in the immediate postnatal period.
The main aim of WP6 was to develop an age-appropriate neonatal formulation of dobutamine and gather the necessary portfolio of information to enable submission of a Paediatric Use Marketing Authorisation (PUMA) application.
WP7 concentrated on the effective dissemination of the project results, both to the clinical community and parents, and training of the wider clinical community.
The objective of WP8 was to ensure the smooth running of the project including good communications with all partners and financial management, setting up relevant committees and communicating with and providing reports to the European Commission.
The main scientific and technological results of each of these work packages are described next.
Work Package 1: Pharmacokinetic (PK) and Pharmacodynamic (PD) models
Work Package 1 developed and validated an analytical method for the quantification of dobutamine in plasma, according to EMA guidelines. This method was subsequently used to determine the concentration of dobutamine in the plasma samples in infants in order to determine the elimination half-life of dobutamine in relevant the population. Ten infants were included in this pharmacokinetic study. The calculated elimination half-lives in these 10 subjects ranged from 3 to 36 minutes.
Work Package 1 evidenced the important interindividual pharmacokinetic variability in the population of interest. However, it did not fully achieve its objectives because the NEOCIRC-003 clinical trial, that was to generate the data to investigate the concentration-effect relationship of dobutamine, was not conducted before the end of the funding. The trial will be conducted with national funding support in the future.
The important pharmacokinetic variability that was evidenced must be taken into account for the evaluation of the efficacy of dobutamine in the future. Indeed, for a given dose, the maximal efficacy will be reached when the plasma concentration of dobutamine will reach the plateau, which occurs after an infusion duration of at least 5 elimination half-lives. Based on the elimination half-lives determined in the study, it can be concluded that the true effect of a dose can be observed 3 hours after the beginning its administration, and not a few minutes as it was previously thought. These new data should now be taken into consideration for the evaluation of dobutamine in preterm infants in the future.
Work Package 2: Pharmacogenetics of dobutamine
Work Package 2 was designed to identify specific groups of infants who will have particular benefits of a treatment with dobutamine. If such groups are identified, their clinical and genetic background will provide additional information how catecholamine treatment can be optimized in preterm infants. The main objective of this Work Package was to define clinical and genetic risk factors for different response to dobutamine in preterm infants.
Clinical and genetic data from a large German cohort study were used. Clinical and genetic factors predictive for low blood pressure in preterm infants were analyzed, since low blood pressure was one of the main inclusion criteria for the planned NEOCIRC-003 clinical trial. Clinical risk factors for low blood pressure in preterm infants, which were published in previous studies, were confirmed and quantified. Furthermore, it was demonstrated that low blood pressure in preterm infants is associated with a high mortality rate and a high rate of intracranial bleeding in preterm infants. These results are already published (Arch Dis Child Fetal Neonatal Ed 2015; 100:F388-92). In addition, genetic risk factors for low blood pressure in preterm infants were analysed.
Genetic factors may affect dosage regimens. Appropriate material was collected, a biobank was developed and polymorphisms for dobutamine receptors were researched, which could lead to individualised medication in the future.
Work Package 3: Non-invasive biomarkers to measure/define shock in neonates
As part of Work Package 3, the NEO-CIRC Clinical Trial Partners developed standardised approaches for the use of the various biomarkers in the NEO-CIRC Clinical Trials. Standard Operating Procedures were produced to ensure the reliable monitoring and recording of the following:
• Invasive and non-invasive blood pressure.
• Capillary refill time
• Lactate and base excess
• Pulse oximetry
• Urine output
• Functional echocardiography performed by neonatologists with a focus on Superior Vena Cava flow measurement training. Considering that echocardiography is quickly becoming an important part of haemodynamic examination in the newborn this ensured a high quality assessment tool.
• Cranial-Doppler ultrasound in newborns to assess early neurological outcome
• Electroencephalography (EEG/aEEG) for the newborn
• Brain oxygenation using near infrared spectroscopy (NIRS). The value of cerebral oxygenation monitoring and its impact on decision making has also guided clinicians to perform more research on this topic.
In preparation for the clinical trials, NEO-CIRC Clinical Trial Partners participating as clinical sites performed assessments using biomarkers such as lactate and base deficit level, capillary refilling time, urine output, oxygen saturation, echocardiographic findings, aEEG and NIRS on a local basis. However, the interruption of the NEOCIRC-001 trial and subsequent delay in opening the NEOCIRC-003 confirmatory trial prevented prospective data for analysis being obtained.
The results of a pilot study on biomarkers by SERMAS played a pivotal role in the design of the NEOCIRC-003 randomized controlled trial, with SVC-flow, BP and lactate levels being relevant as inclusion criteria for circulatory failure. Results from the NEOCIRC-001A PK sub-study involving BSUH and SERMAS also informed the design of this trial, particularly with respect to timings for PD assessment.
The ULIV HAPI-PDA study was adopted by the NEO-CIRC consortium and finished recruitment in December 2016 after recruiting 52 preterm infants <29 weeks gestational age. The first data analyses were presented at numerous national and international conferences including EAPS 2016 (Switzerland), Neonatal Society Meetings 2016-2017 (UK), XXV Biennial Meeting of the International Perinatal Collegium (Scotland), 6th European Society for Developmental Perinatal and Paediatric Congress (Belgium) and JENS 2017 (Italy). Also, whilst preparing for the NEOCIRC trials, UMF CLUJ carried out a study to evaluate the potential role of SVC flow in premature infants and the results were presented at national and international congresses including EAPS 2016 and JENS 2017.
The BSUH NeoAdapt studies were also adopted by the NEO-CIRC consortium, consisting of three observational cohort studies that included infants >33 weeks gestational age who received special care (NeoAdapt1, n=50, trial closed July 2015), intensive care (NeoAdapt2, n=25, trial closed May 2016) and total body cooling (NeoAdapt3, n=18, trial closed September 2016). Results were presented at numerous national and international conferences including jENS 2015 (Hungary), Neonatal Society Meeting 2015 (UK), Neonatal Cardiology & Haemodynamics Conference 2015 (UK), Pediatric Academic Societies Meeting 2016 (USA) and EAPS 2018 (France).
Clinical practice and research are currently hampered by the lack of a shared definition of neonatal shock. The platform for research that the consortium developed to work on the PIP for dobutamine allowed us to develop a definition of neonatal shock and embed it in clinical guidelines. A working definition of neonatal shock based on the results of the clinical trial was not possible due to the delay to the start of NEOCIRC-003, however a consensus meeting was held between members of the NEO-CIRC consortium (BSUH, ULIV, MHH, SERMAS, UMF CLUJ, OSA and GUSM) and members of the HIP Trial consortium which was designed to test Dopamine for the hypotension in preterm. The following biomarkers were agreed upon as the parameters to be used for deciding circulatory support in preterm in the first 48 hours of life:
• Mean blood pressure < gestational age
• Lactate > 4mmol/l
• Echocardiographic assessment of heart with emphasis on contractility
• Cerebral oxygenation assessment by NIRS
Overall, the training obtained during preparation for the Clinical Trial has helped the NEO-CIRC Clinical Partners to develop a better understanding of circulatory failure in newborns. In addition, a Methodology for assessment of neurodevelopmental outcomes was developed in preparation for the main clinical trial.
WP4 - Neonatal / juvenile animal models
Firstly OSA, with the help of BSUH, conducted and published a systematic review on the use of dobutamine in juvenile animal models, using MEDLINE (the U.S. National Library of Medicine® (NLM) premier bibliographic database) and EMBASE (a biomedical and pharmacological bibliographic database) as databases, to summarize and assess the preclinical evidence of the use of dobutamine in juvenile/neonatal animals. The conclusion from this systematic review was that although there was enough preclinical evidence to conclude that dobutamine improves cardiac output it was necessary to perform more studies because the heterogeneity across studies in juvenile/neonatal animals made it difficult to obtain clear evidence to better understand the effects of dobutamine in peripheral organs, above all in the brain.
Based on the systematic review, a preclinical study was planned, in a well-established hypoxic neonatal pig model, to measure the effects of different doses of the new NEO-CIRC pediatric formulation of dobutamine on hemodynamic and oxygen metabolism; and to perform a complete PK/PD study on the short term effects of the new formulation in other organs with a focus on the brain. The study was conducted in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals in the experimental research unit of Cruces University Hospital (OSA). The experimental protocol met European and Spanish regulations for protection of experimental animals (2010/63/UE and RD53/2013)).
In the hypoxic neonatal pig animal study different biomarkers to assess circulatory status and tissue oxygen delivery and perfusion, mainly focused on the brain, were used at different dobutamine doses. Near infrared spectroscopy (NIRS) was used to measure the changes on systemic and brain oxygenation; a perivascular flow probe placed in the carotid artery was used to measure carotid blood flow as a surrogated of cerebral perfusion; mean arterial blood pressure, heart rate, cardiac output, stroke volume and systemic vascular resistance, among others, were measured through a multiparameter hemodynamic monitor to assess circulatory status and blood gas analysis was performed to assess the ventilator and acid-base status. Also, blood hepatocellular enzymes (aspartate transferase (AST) and aminoalanine transferase (ALT)) as markers of hepatic injury, blood creatinine concentration as a marker of renal injury and troponin as a marker myocardial injury were determined. Finally, complete pharmacokinetic and pharmacodynamics study and tissue damage analyses were performed.
The pharmacokinetic study allowed the suitability of neonate piglet to be established as an animal model to study dobutamine in human neonates, as the estimated dobutamine clearance in the animal model (that reflects the rate of drug elimination divided by plasma concentration) is of the same magnitude of the clearance reported for the drug in humans. Taking all the results together, the study allowed us to conclude that the new pediatric dobutamine formulation improved hemodynamic status in hypoxic neonatal piglets, with dose-specific differences in metabolic response, with an improvement in cerebral oxygenation and perfusion at higher dobutamine doses with less histological injury. So, the pattern of changes seen in response to the new dobutamine was encouraging and justifies long-term studies in human neonates.
As part of this Work Package, OSA, BSUH and DYNA published three articles in peer reviewed journals. In addition, the Animal model established in the experimental research unit of Cruces University Hospital (OSA) is currently being used to study neonatal hypoxic condition and could help with future pre-clinical studies in the Management of Circulatory Failure in newborns.
Work Package 5: Clinical Trials
Work Package 5 was one of the main pillars of NEO-CIRC because neither of the two main project aims are achievable without results from the clinical trials; it therefore involved the participation of most of NEO-CIRC Project Partners.
The clinical trial activity required to answer the variety of research questions in this project, meant that several studies and sub-studies, with different methodologies, needed to be planned and designed as part of this work package.
Unfortunately, this work package has not been able to fully achieve its objectives due to difficulties encountered in setting-up the studies, in particular the final clinical trial (NEOCIRC-003), which was designed to provide answers to the questions regarding the efficacy and safety of dobutamine. This trial has not yet started, as the first country regulatory approvals were only received in the final months of the project.
The various studies developed as part of Work Package 5 were part of the Paediatric Investigational Plan (PIP) from the European Medicines Agency’s Paediatric Committee (EMA/PDCO) negotiated to develop a “New Paediatric Formulation of Dobutamine” suitable for neonates. According to Human Regulatory R&D indications from the European Medicines Agency:
“A paediatric investigation plan (PIP) is a development plan aimed at ensuring that the necessary data are obtained through studies in children, to support the authorisation of a medicine for children. All applications for marketing authorisation for new medicines have to include the results of studies as described in an agreed PIP, unless the medicine is exempt because of a deferral or waiver. This requirement also applies when a marketing-authorisation holder wants to add a new indication, pharmaceutical form or route of administration for a medicine that is already authorised and covered by intellectual property rights”.
This requirement meant that the NEOCIRC clinical trials could not start until an agreed PIP was in place with the EMA PDCO. Unfortunately, as described in Work Package 6, this was a lengthy and time-consuming process which delayed the start of the NEOCIRC clinical trials.
NEOCIRC-001 – Therapeutic Exploratory Trial
This pilot study, performed in Spain and the UK, was an 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. The pilot study had embedded PK and PK/PD sub-studies NEOCIRC-001A and NEOCIRC-001B respectively.
During this pilot study samples were collected from 15 new-born infants, of which samples from 10 infants provided valid PK data, to estimate the elimination half-life, and consequently the time to steady-state of dobutamine in extremely premature neonates. From the patients enrolled in this trial, it was determined that a delay of 3 hours should be respected before measuring the pharmacodynamic endpoints for each dose. Since this delay is not compatible with the standards of care, maintaining it would have led to the frequent use of rescue medication during the trial, which would have precluded the evaluation of dobutamine efficacy.
These conclusions formed the basis for the design of the PK/PD sub study for NEOCIRC-003:
• The 1st sample should be drawn at the pharmacodynamics evaluation of the 1st dose.
• The delay until a dose increase should be based on the decision of the physician according to clinical data and not on the PK of dobutamine. However, a delay of at least 2 to 3 hours should be respected before drawing the blood sample for the efficient dose (2nd blood sample).
• Finally, an optional 3rd blood sample could be drawn 15-30 min after the end of the last infusion in order to have an estimation of the elimination half-life in the population.
With the data from this study and other information provided by published studies carried out by SERMAS, the NEO-CIRC Consortium decided to reduce the number of studies from 3 to 2. This required a change to the PIP which had to be approved by the EMA PDCO. The approval of the proposed PIP modifications was a lengthy process with the approval finally received in July 2017.
NEOCIRC-003 Clinical Trial
This was an international, multicentre, randomized, placebo-controlled, double blind three arm trial to be conducted to investigate the efficacy of dobutamine with two different starting doses in the treatment of haemodynamic insufficiency in the immediate postnatal period. A clinical study protocol for the NEOCIRC-003 trial was developed based on the modified PIP, including requirements demanded by the EMA PDCO, and the protocol was approved by the relevant NEO-CIRC Partners in November 2017.
The Consortium carried out the preparatory activities for the NEOCIRC-003 trial in accordance with clinical trials regulation, including applying for Ethics approvals and National Competent Authorities authorisations. However, the process took much longer than it would normally do as an extensive set of questions related to the new neonatal formulation of dobutamine were received which were quite unusual for a clinical trial application. Responses required the input of the active substance manufacturer, the finished product manufacturer and the clinical trial supplies contractor and an updated Investigational Medicinal Product (IMP) Dossier and new IMP Management Guideline Manual were also required. After submission of the responses a further round of questions was received, and responses provided. As a result of the delays caused by the extensive questioning the first national approval was not received until July 2018; this precluded the opening of the trial within the timeframe of the FP7 project.
Although the trial was not opened within the timeframe of the FP7 project, the work performed by the consortium in the design and medical writing of the NEOCIRC-003 Protocol has achieved the following key milestones to allow the project to continue in the future:
• Internal approval of a complex study: the main study; a PK/PD sub study; a Pharmacogenetics sub study and a nested trial for the evaluation of advanced biomarkers.
• Ethics/regulatory approval in Spain.
• Establishment of a sound basis for the continuity of the trial, contingent on applications for local / national funding to execute the trial.
The Consortium members are still committed to carrying out the NEOCIRC-003 study and are in the process of applying for local / national grants to fund this. The intention is to perform the study initially in Spain (where the study is already authorised and local funding has been awarded), Turkey and the UK (where national leaders are currently actively seeking local funding). The rest of the countries have been encouraged to also seek national funding to contribute to the required sample size.
NEOCIRC-004 – Literature Review
A structured literature reviews on inotropes was carried out and published: "A Literature Review of the Pharmacokinetics and Pharmacodynamics of Dobutamine in Neonates". Mahoney L, Shah G, Crook D, Rojas-Anaya H, Rabe H. Pediatr Cardiol (2016) 37: 14. doi:10.1007/s00246-015-1263-9.
The achievements of Work Package 5 have influenced:
• The methods used for the assessment and follow up of these patients in a clinical trial setting, particularly with respect to their standardisation, which could then permeate into standard of care when the evidence of their utility is confirmed by the trial results.
• The future research agenda to be continued in Spain, Turkey and UK, that will result in the eventual execution of the NEOCIRC-003 study.
• Advances in the design of clinical trials for the assessment of the transitional circulation in preterm infants, which could be incorporated by future trials in this field.
Work Package 6: PIP and PUMA
As previously highlighted, the NEOCIRC clinical trials could not start until an agreed PIP was in place with the EMA. PRO were responsible for compiling and submitting all regulatory procedures with the EMA with the body of the required documentation being prepared by BSUH and SERMAS.
In the first instance scientific advice was sought from EMA. The outcome of the procedure was adopted by the NEO-CIRC Consortium and a PIP was submitted with a clinical programme that included two pilot studies (NEOCIRC-001 and NEOCIRC-002) followed by a randomised controlled trial (NEOCIRC-003). Following the submission of modifications requested by the EMA, the PIP was granted.
The program commenced and following the review of outcomes from the initial biomarkers pilot study by SERMAS and literature reviews, clinical strategy discussions were held to identify a restructured clinical program that would provide the best outcome for NEO-CIRC and the wider research community given the remaining project resources. A request for PIP modification was filed which included updates on progress against the agreed measures to date, a proposal to stop the ongoing therapeutic exploratory study (NEOCIRC-001) after completion of the embedded PK sub-study NEOCIRC-001A as justified in Work Package 5 above, and a proposal for a sole clinical trial that could provide clinically relevant safety and efficacy information on the use of dobutamine during circulatory failure in preterm neonates; but at the same time answer many of the other research questions from the original PIP agreed with the EMA. Whilst the PDCO issued a positive opinion, it did not however agree to the removal of the dose finding study. This represented a major challenge as project timelines did not allow for the extra time required to conduct a dose finding study and therefore rendered the PIP unachievable within the scope of the project. After much discussion, the PIP sub-group partners agreed that the NEOCIRC-003 trial could be adapted to address the concerns of the PDCO by inclusion of a second starting dose. This resulted in the need for a further PIP Modification and study protocol re-design. After consultation with the PDCO the 3rd PIP modification was prepared, filed and subsequently granted a positive opinion.
At the outset of the pharmaceutical development program, PRO conducted a literature review and patent search from which outline presentations for the new dobutamine product were identified. A questionnaire was devised to gain feedback from the Consortium clinicians on current practices and on the proposed presentations. Several formulation prototypes were developed and subjected to accelerated stability evaluation. These proved to be unsuitable candidates so modification to the formulations and the method of manufacture were subsequently made. In addition, feedback received as part of the initial PIP request for modification resulted in the need to evaluate alternative antioxidants. As a result, a series of new prototypes were developed and subjected to accelerated stability testing and a final formulation was selected. The formulation of the investigational medicinal product (IMP) was developed to minimise the level of sodium metabisulphite in the product, to enable use in newborn babies, where metabisulphite is toxic. The manufacturing process is also novel, using nitrogen infusion and blanketing to limit dissolved oxygen and oxygen in the headspace of the vial, thereby limiting the rate of degradation of the dobutamine.
Alongside the formulation development work, analytical method development and qualification was undertaken.
A pilot batch of the selected formulation was manufactured and set down on stability according to ICH guidelines. This batch formed part of the formal validation programme which would be incorporated in the PUMA application and was also used for supply to the clinics. At 16 months real time stability, significant discolouration of the batch was identified. Discolouration of dobutamine in aqueous solution due to oxidation was not unexpected and is well documented in published literature. The oxidation is limited by the inclusion of an antioxidant in the formulation, sodium metabisulphite, but at the low level requested by the PDCO it has a limited effect and therefore a limitation on the shelf life of the product.
The batch was withdrawn and following assessment it was concluded there was no impact on patients. It did however cause a delay in the continuation of the clinical study. The formulation and manufacturing process were reviewed to identify possible optimisation steps as part of the on-going development of the product. The eventual optimisation focused on the manufacturing process and further reduction in exposure to oxygen to slow the rate of oxidation of the dobutamine. An update of the Investigational Medicinal Product Dossier was required and submission of a regulatory amendment. A fresh batch of IMP was manufactured and following quality control analysis, labelling and Qualified Person release, supplies were made available to the clinics to re-start the trial. ICH stability studies were then initiated.
Following the conclusion of the NEOCIRC-001 pilot study, the review of the clinical program and subsequent PIP modification, a fresh batch of IMP was required and also 2 new study drugs; a half strength dobutamine product and a saline placebo. Development work was undertaken with the contract manufacturer and a batch of each of the 3 study drugs was produced for the start of the NEOCIRC-003 trial and ICH stability studies were initiated.
As NEOCIRC-003 was to be a blinded trial, it was necessary to blind the vials as differential colour change was expected due to differing rates of change between the two active drugs vs no change for the saline. A blinding device for the vials was devised. A similar device was designed for the syringes for transfer of the drug from the vials to the infusion solution.
An IMP Management Guideline Manual for the clinical trial sites was created to provide the necessary information for safe and effective management of the study medication at sites including, ordering, receipt, storage and accountability for the IMP supplies.
Multilingual booklet labels were devised (5 languages) to maximise supply chain flexibility.
At the time of project closure, 24 months successful real time data had been generated on the new formulation.
In order to complete a pharmaceutical dossier for PUMA submission, further batch manufacture and validation activities would be required. The delays in the project meant that these could not be completed within the project timeframe. In addition, although some of the content for the PUMA has been generated from the work conducted during the project, it can only be compiled when the clinical trials have been completed in accordance with the agreed PIP measures and the study reports closed.
Work Package 7: Knowledge Translation and Training
Training of partners was promoted by BSUH throughout the life of the project. With respect to Good Clinical Practice (GCP), clinical partners had the responsibility to train their research staff locally. In addition, ONO conducted neonatal specific refresher sessions during Consortium Meetings. All partners responsible for trial specific training were heavily involved in the training design and delivery. In particular, SERMAS hosted the functional echocardiography hands-on sessions in Madrid which were attended by various neonatologists from the clinical sites.
With respect to Public and Patient Involvement (PPI), BSUH reviewed all parent information and consent forms for the clinical trials in collaboration with their local Neonatal Parents’ Forum; and sought advice from the European Forum for Care of the Newborn Infants (EFCNI) before releasing the final versions. In the same fashion partners involved their local parent groups, when available, to produce their country specific documentation. Additionally, a PPI related sub-study protocol was designed to explore parents’ perceptions of antenatal and deferred consent but couldn’t be executed.
Conclusion
Even though the large clinical trial was unable to be carried out, the consortium has been able to deliver a range of benefits. Work on the definition of neonatal shock and the development of guidelines for the assessment of the neonatal circulation has been conducted as a formal knowledge translation process. That is, the process of knowledge creation (PK work, biomarker work etc.) was conducted in parallel to work that engages with people who will use the knowledge.
The overall strategy of the work plan was to conduct a tightly integrated programme of work that leads to the submission and completion of a PIP. This required information about dobutamine that is specific for the intended indication on the PIP and PUMA.
The platform provided by work on the PIP has allowed the consortium to start deriving a new definition of neonatal shock, with a view to embed a future definition in guidelines for the assessment and treatment of the circulatory failure in the newborn.
Finally, as a result of having conducted this project, the NEO-CIRC management group has the following observations/recommendations:
1. Apart from reviews by the European Commission (EC), which are useful to help steer this kind of project, it would be beneficial to implement a critical appraisal by experts from a similar area of research and application, who have previously participated or are finalising similar large scale EU funded projects. A mid-project “health-check” by “fresh” expert eyes could help foresee certain key problems and allow the implementation of targeted mitigation strategies in good time, e.g. prioritising certain tasks, or joining efforts with other similar EU projects early. This could improve the overall productivity of EU projects in relation to the funding already assigned.
2. It is well known that the problem with currently used off label / off licence old drugs in paediatrics, is that the pharmaceutical industry has little incentive to invest in such studies. As a consequence the European Commission specifically allocated funding for studying frequently used off label drugs in newborns and children in order to achieve a Paediatric Use Marketing Authorisation (PUMA) for age-appropriate formulations that have minimal toxicity. This funding was targeted at drugs on a priority list issued by EMA/FDA like dobutamine. However NEO-CIRC has sensed that, at least in the case of this drug, the likelihood of prescribers transferring across to a new licensed IMP product from cheaper existing licensed dobutamine products is relatively low. This hinders the ability of networks like NEO-CIRC to continue into the originally planned PIP-PUMA pathway in which substantial time and resources have been invested. We believe it is in the best interest of the EC/EMA to explore this issue further.
Potential Impact:
Potential Impact
Impact can be measured based upon knowledge creation, informing policy, direct health benefits and economic and societal benefits. The actual and potential impacts of the NEO-CIRC project are as follows:
The results of the genetics studies have shown that catecholamine and volume treatment of preterm infants, and dobutamine treatment in particular, should be done in a personalized way and include clinical and genetic risk factor assessment. This will help to reduce complications which are more frequent in preterm infants who are prone to low blood pressure values and to protect these infants from early death and complications of premature birth like intracranial haemorrhage.
The project has been educational in the assessment of newborns with circulatory failure by creating a broader perspective for the evaluation. It has created an awareness and enthusiasm amongst neonatologists about neonatologist-performed echocardiography and has enabled successful training in the NEO-CIRC clinical centers. The difficulties in performing neonatal echocardiography and the variability between measurements have been recognized. The multifaceted nature of neonatal circulation in the early days of life has been acknowledged and the necessity of a combination of biomarkers to guide treatment has been emphasized.
The work performed may lead to more in depth evaluation of neonatal circulation before starting a medication and may lead to more clinical trials to assess short and long-term impact. More centers will probably perform echocardiography and NIRS to have a better understanding of circulation and combine the results with those of blood pressure, lactate, capillary refilling time which are currently used to decide treatment. The introduction of NIRS technique to assess cerebral oxygenation will result in closer monitoring of brain injury and hopefully will result in better neurological outcome which will undoubtedly lead to less burden on society.
The consensus on the biomarkers to define circulatory impairment in the first days of life in preterm infants will lead to better designed clinical trials and hopefully with more relevant results in the end. It will also lead to better selection of the patients who would actually require treatment. The project results will contribute to a new definition of circulatory failure and or shock in the new-born period which can be used by all clinicians treating this highly vulnerable population. The new definition will support a better outcome for affected newborn infants through targeted and individualized treatments based on the results of the genetics and clinical studies.
The pharmacokinetic study has established the suitability of neonate piglet as animal model to study dobutamine in human neonates, as the estimated dobutamine clearance in the animal model (that reflects the rate of drug elimination divided by plasma concentration) is of the same magnitude of the clearance reported for the drug in humans. Taking all the results together, the study allowed us to conclude that the new pediatric dobutamine formulation improved hemodynamic status in hypoxic neonatal piglets, with dose-specific differences in metabolic response, with an improvement in cerebral oxygenation and perfusion at higher dobutamine doses with less histological injury. So, the pattern of changes seen in response to the new dobutamine was encouraging and justifies long-term studies in human neonates.
The project has laid the foundation for a clinical study on the efficacy and safety of dobutamine on long-term neurodevelopmental outcome. It has provided a better understanding of the low systemic blood flow, in particular it has provided a wealth of information on the biomarkers that can be used in non-invasive way to define this status, and a well-designed protocol, that will be implemented in Spain, Turkey and UK.
An age appropriate formulation of dobutamine, with 24 month shelf life, has been developed and stability studies successfully completed. Whilst further data are required to support the pharmaceutical development section of a PUMA application, the outcome is positive, and it has demonstrated there is significant potential for a new, paediatric formulation with reduced toxicity effects, to be brought to market for the benefit of preterm babies with circulatory failure. This would replace the need for off label use of the currently marketed dobutamine products, and the inherent risks this brings for prescribers and patients. There is significant potential for this new dobutamine formulation and following the grant of a successful PUMA application there is the opportunity for the product to be commercialised across the 27 EU countries. Further pharmaceutical development studies, along with the fully completed clinical program, would be required to complete the PUMA.
Better neurodevelopmental outcome will reduce the economic on-cost of prematurity beyond the stay in hospital thereby reducing health care costs across EU member states and beyond. This will be a benefit to all EU citizens.
The consortium has brought together academic partners from European and American institutes and industry working together on a common goal. These collaborations can be used in the future to develop other new products and scientific knowledge for the treatment of conditions affecting the new-born infants. The industry partners should also benefit from these collaborations by growing their expertise and business portfolio.
Further international collaborations through the participation in the International Neonatal Consortium should strengthen the links between different continents and improve the care of the new-born infants around the world.
Dissemination activities
The project has been widely disseminated and promoted to the scientific research community, clinicians and the general public. The main outreach to the research community and clinicians has been through publications in scientific journals, presentations at scientific meetings and conferences, workshops and the NEO-CIRC project WEB site.
The NEO-CIRC Chief investigator and members of the consortium have attended and presented at numerous scientific meetings across the world, creating awareness of the NEO-CIRC project and highlighting the importance of this study and the challenges posed. These meetings have included the Pediatric Academic Society, European Society for Paediatric Research, European Neonatal Brain Club, Recent Advances in Neonatal Medicine, International Perinatal Collegium and at many national meetings including UK, Turkey and Romania.
The NEO-CIRC Consortium has also collaborated extensively with other groups in this area: the EU FP7 funded HIP consortium, the SafeBoosC consortium, the European Forum for Care of the Newborn Infants (EFCNI), the network of paediatric research at European Medicines Agency (EnprEMA) and the International Neonatal Consortium (INC). The NEO-CIRC Consortium believes that these collaborations will lead to the production of evidence for the neonatologists to support circulation in the preterm during transitional period.
The NEO-CIRC consortium has published more than 50 abstracts at various national and international conferences and meetings, in particular the biennial Congress of the European Academy of Paediatric Societies (EAPS) and Congress of joint European Neonatal Societies (jENS). This has involved a combination of invited talks, presentations and posters communicating the objectives of the NEO-CIRC project and results achieved.
To date, members of the NEO-CIRC Consortium have also published 11 articles related to the NEO-CIRC project. These include the major speciality specific journals such as European Journal of Paediatrics, Pediatric Research, Pediatric Drugs, Archives of Diseases in Childhood Fetal and Neonatal edition, Pediatric Cardiology amongst others.
General information about the NEO-CIRC research and clinical study is available through the project WEB site www.neocirculation.eu.
The Parent Information page includes background information for parents related to the NEOCIRC study, copies of the Patient Information Leaflets and links to other independent organisations involved in the support of parents and families of premature and sick babies. The Publications and Presentations page is aimed at the research community and includes links to the relevant journal WEB sites where copies of the NEO-CIRC scientific papers can be downloaded as well as a list of all NEO-CIRC Conference presentations and posters.
Exploitation of results
The results of the NEO-CIRC project can / will be exploited in several ways:
Information from NEO-CIRC Echo-D, NIRS and aEEG SOPs
Information from Echo-D, NIRS and aEEG SOPs generated during the NEO-CIRC project has been incorporated into Medical Guidelines for the Management of Circulatory Failure in newborns. These guidelines are used by professional staff at the Brighton and Sussex University Hospitals (BSUH) Trevor Mann Baby Unit to assess newborns with circulatory failure, identify the cause and determine the appropriate treatment. The guidelines have been written primarily for use within the BSUH neonatal service and are available online as a stimulus for the exchange of knowledge and ideas in the field of neonatology. The guidelines take into account the best available evidence at the time of their creation, as well as current recommended best practice. Other NICUs could potentially use these guidelines for the benefit of their neonatal services.
Training course in measurement of SVC-flow
The capability for measurement of SVC-flow generated during the NEO-CIRC project has been incorporated into local hospital activity for the Management of Circulatory Failure in newborns. Not only will this help improve on the Management of Circulatory Failure in newborns but it will also be an enabler to participate in future clinical trials.
Neonatal echocardiography and cranial ultrasound training
The training on neonatal echocardiography and cranial ultrasound developed during the NEO-CIRC project has created an awareness regarding the value of neonatologist performed echocardiography and cranial ultrasound in NICUs especially for preterm infants with circulatory problems. This will improve patient care and will enable neonatologists and neonatal fellows to discuss treatment with pediatric cardiologists in more detail. They will also be able to assess myocardial contractility early on to guide their treatment. Being able to recognize IVH will enable the clinician to take more appropriate decisions in time.
More frequent use of Near-Infrared Spectroscopy (NIRS)
The use of NIRS more frequently in NICU has helped to achieve a more comprehensive monitoring of critical patients in NICU. This will also enable NEO-CIRC partners to participate in future clinical trials in Europe.
Awareness of biomarkers other than blood pressure or capillary refilling time to define circulatory failure and guide treatment accordingly
The awareness created about the advanced biomarkers and the knowledge gathered has resulted in more critical evaluation of preterm infants with regards to circulatory failure. The decision making for inotropes based on blood pressure, capillary refilling time or urine output is now regarded as a simplistic approach in the NEO-CIRC NICUs and more advanced tests are searched by clinicians.
Pre-clinical studies in neonatal/juvenile animals
The systematic review of the use of dobutamine in juvenile animal models and the experimental protocol developed during the NEO-CIRC project could help streamline trial design for future pre-clinical studies in the Management of Circulatory Failure in newborns.
Quantification of dobutamine levels in newborn pig plasma
The bioanalytical technique developed can be used to determine dobutamine plasma levels in subsequent preclinical studies to gain further knowledge in dobutamine PK/PD relationships. Although, the bioanalytical technique was primarily developed to quantify dobutamine in the preclinical studies conducted within the NEO-CIRC project, it can be used to support any additional pre-clinical study that might be conducted in pre-clinical studies in neonatal/juvenile animals to further characterise the PK/PD of dobutamine.
Dobutamine elimination half-life in pre-term neonates
This will be used to determine how long a dobutamine infusion must last until the evaluation of the efficacy of the administered dose. This will optimize the use of dobutamine and the evaluation of its efficacy in the future clinical trials.
Clinical risk factor score for low blood pressure in preterm infants
This score is a very simple tool to identify preterm infants with a high risk for hypotension and treatment with catecholamines who need umbilical lines at birth. The score will soon be published in a manuscript concerning genetic risk factors for low blood pressure in preterm infants.
Application of Bauer and Köhne Design for sample size calculation for a three-arm trial
The Bauer and Köhne design for stopping a trial after interim analysis was applied to a three-arm trial in conjunction with further multiplicity adjustments in the setting of rare diseases. The design structure can be re-used and/ or adapted for future trials.
Standard Operating Procedures (SOPs) and Informed Consent Forms
The SOP design, review and approval process is a highly time-consuming activity. The SOPs designed as part of the NEO-CIRC project could be used in future commercial and/or academic trials by the NEO-CIRC partner NICUs. Similarly, the Informed Consent Forms designed as part of the NEO-CIRC project would also provide a solid base for future studies carried out by the NEO-CIRC partners using local funding.
NEOCIRC-003 Study Protocol
Several of the NEO-CIRC partners will submit requests for national funding based on an adapted version of the NEOCIRC-003 study protocol to carry out a clinical trial to produce data on the efficacy and safety on the use of dobutamine as a treatment for early haemodynamic insufficiency in the preterm infant. The results of this study will help redefine neonatal shock and improve existing medical guidelines for the Management of Circulatory Failure in this population. SERMAS has already been successful in securing funding for this purpose.
Age appropriate formulation of dobutamine
The market size is likely small and, due to the unique manufacturing process, the cost of manufacture is significantly higher than for currently marketed dobutamine products. However, the new formulation has been significantly improved over current products. For commercial viability, it would however need to be positioned as the only paediatric licensed product for this indication and secure majority market share. As some of the current dobutamine products cover the indication in broad terms, and in many cases have posology for paediatric patients, it would be necessary for this legacy paediatric wording to be removed from those licences that do not have supporting clinical paediatric data. There would need to be a legal mechanism in place to ensure automatic switch to the PUMA licensed product and that prescribers could no longer prescribe existing products because they are cheaper. It is possible that patent protection could be sought for the formulation and orphan designation may also be possible.
List of Websites:
Coordinator
Dr Heike Rabe
Brighton and Sussex University Hospitals NHS Trust
Brighton, BN2 5BE
United Kingdom
Website: www.neocirculation.eu
Dobutamine is a drug currently used off label in the neonatal treatment of circulatory failure, a condition that leads to impaired organ perfusion that will likely cause brain injury and poor neurodevelopmental outcomes. No uniform criteria exist to define circulatory failure, or neonatal shock, and there is little evidence to support current intervention strategies which vary widely. Recently, flow in the 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.
The NEO-CIRC consortium was established in 2011 to conduct trials to provide safety and efficacy data for dobutamine as a first line inotrope in neonates, based on a new age-appropriate neonatal formulation, and with the intention to progress towards a Paediatric Use Marketing Authorisation (PUMA) supported by the trials’ results. Additional aims were to develop improved biomarkers of circulatory impairment, with a focus on SVC-flow; and to conduct pre-clinical, pharmacokinetic, pharmacodynamic and pharmacogenetic studies to better understand the mode of action of dobutamine. The consortium included international experts in neonatal medicine, pharmacology, pharmacogenetics, drug formulation, pre-clinical neonatal models and a group of NICUs experienced in multicentre clinical trials.
The project has effectively led to the development and testing of a new neonatal formulation of dobutamine, producing novel pharmacokinetic (PK) data on the half-life of the drug in human preterm infants. Other pre-clinical PK results have established the suitability of the neonate piglet as an animal model to study dobutamine, showing an encouraging pattern of changes in response to the new formulation of dobutamine that justify long-term studies in human neonates. Parallel results of genetics studies from the German neonatal network (GNN) indicate that dobutamine treatment should be done in a personalized way and include clinical and genetic risk factor assessment, to help reduce complications that may lead to disability or death.
Despite various challenges that precluded the opening of the main clinical trial to ultimately test the efficacy and safety of dobutamine, the project has been educational in the assessment of newborns with circulatory failure. It has created awareness about neonatologist-performed echocardiography and has enabled successful training in the clinical centres. The multifaceted nature of neonatal circulation in the early days of life has been acknowledged and the necessity of a combination of biomarkers to guide treatment has been emphasized.
The consensus on the biomarkers to define circulatory impairment in the first days of life in preterm infants, together with the half-life PK results that help inform timing aspects of the application and evaluation of dobutamine, have laid the foundation for a well-designed clinical trial on the efficacy and safety of dobutamine. The trial protocol has been finalised and will be implemented by Spain, Turkey and UK. Novel aspects of the proposed trial will lead to better designed clinical trials with more relevant results and to better selection of patients who would actually benefit from treatment; ultimately contributing to a new definition of neonatal shock that can be used by clinicians treating this highly vulnerable population.
Project Context and Objectives:
Many medicines used in children, especially neonates, have never been tested to the level seen in adult healthcare. This population is often treated with drugs that are unlicensed or off-label, with age-related differences in drug absorption or metabolism resulting in the use of suboptimal drug regimens with a weak evidence-base. The lack of formal studies in babies and children also means that adverse events are poorly understood and safety is compromised. An urgent need to resolve this unsatisfactory state of affairs was recognised by the European Medicines Agency (EMA) for off-label drugs of common use in neonates.
Dobutamine for circulatory failure was identified as a priority drug and the FP7 funded NEO-CIRC Consortium was established with a threefold remit: to produce an age-appropriate formulation with the bare minimum of excipients and avoiding dilutions if possible; to generate data on efficacy and safety in neonates; and the need for international consensus on a definition for circulatory failure or neonatal shock. New EU and US Paediatric Drug Regulations require the industry to provide age-appropriate formulations of medicines for children. In Europe, new drugs produced for children must have a Paediatric Investigation Plan (PIP) as part of their development. As an incentive the company obtaining a Paediatric Use Marketing Authorisation (PUMA) after a PIP will receive an extension of the patent period.
Why circulatory failure?
Circulatory failure has been recognised as a risk factor for disability in very preterm babies, with studies indicating a strong association between the condition in the days after birth and adverse outcomes including death. Failure of the circulation is manifest in several ways including low blood pressure and poor blood supply to key organs, such as the brain; thus sick newborn babies with this condition are at risk of brain injury and poor neurodevelopmental outcomes. Many sick newborn babies grow up with disability and handicap which lead to significant burdens on themselves, their families and society. It has been estimated that the cost to the public sector of looking after all babies born each year with these problems, until they are 18 years old, could amount to approximately €9 billion in the European Union. This all shows that very preterm infants with circulatory failure is a group with priority needs for research; and that the condition is an important target for treatments that aim to reduce disability.
The special case of helping very preterm infants soon after birth
The first hours after birth differ markedly from all other periods in human life and are characterised by a unique and dynamically changing anatomy. This is accompanied by striking changes in function as the circulatory system of the healthy newborn adapts rapidly to life outside the womb. Haemodynamic physiology and pathophysiology changes are specific to this age-group and generate unique clinical challenges. In current clinical practice, diagnostic and therapeutic approaches are different when managing neonates born very prematurely than with older infants. There are anatomic features of the cardiovascular system, relating to both the myocardium and neural control, which render very premature babies unique. Specific physiological features of the adaptation to birth of these babies include: a likely patent ductus arteriosus with left-to-right or bidirectional shunt; lower ventricular distensibility affecting preload; and a reduced reserve for ventricular contractility.
If other major types of shock (hypovolemic, distributive or obstructive) are discarded, then the main determinants leading to compromised organ blood flow after birth are myocardial dysfunction (causing decreased cardiac output) or abnormal peripheral vasoregulation (producing changes in systemic vascular resistance). Given that blood pressure is the product of both cardiac output and systemic vascular resistance, the impact of central blood pressure on actual tissue blood flow is unpredictable. Blood pressure is thus a poor surrogate of systemic and organ (including brain) blood flow during the transitional period from intra- to extra-uterine life. There is evidence that the correlation between systemic blood flow and blood pressure in the preterm infant is rather poor; and that impaired organ perfusion or shock can occur with normal, low or high blood pressure.
To overcome the limitations of assessing circulatory failure in very preterm babies soon after birth, NEO-CIRC proposes to use, in addition to blood pressure, a combination of clinical and biochemical parameters as biomarkers to determine the status of blood flow distribution and poor perfusion; including the use of functional echocardiography, particularly SVC-flow, to assess systemic and cerebral blood flow. SVC-flow has been highlighted as a potentially useful tool by a handful of studies that, although not conclusively due to their medium sample-size, have revealed that: SVC-flow is unaffected by the presence of intra- or extra-cardiac shunts; SVC-flow is the only functional echocardiographic measure that correlates with a marker of cerebral blood flow based on NIRS; low SVC-flow is associated with surrogate markers of adverse long-term outcomes like intraventricular haemorrhage; and low SVC-flow is associated with poor long term outcomes.
With respect to implementation, functional echocardiography has been adopted by physicians working with critically ill patients; and formal educational interventions that allow novices to acquire competence have been defined and assessed. A simplified method, focusing on measures of circulatory function, has been implemented in NEO-CIRC centres. The method, originally described in Australia in 2000 by Kluckow and Evans, has been successfully applied by neonatal units worldwide. In our experience, a well-structured training program allows accurate and reproducible measurements with low intra- and inter-observer variability, with most studies doable in less than 5 minutes by trained individuals. Thus, a NEO-CIRC developed training course enabled clinicians to measure SVC-flow in real time without learning the full set of echocardiography skills.
Why dobutamine?
Dobutamine is unique among proposed treatments for the neonatal circulation in that there is evidence that the use of this drug is likely to reduce the incidence of disability. This evidence relates to the use of dobutamine to treat low SVC-flow. Pharmacological attempts to prevent low SVC-flow have so far been unsuccessful. One clinical trial involving 42 babies born at less than 30 weeks’ gestation with low SVC-flow found that dobutamine increased SVC-flow and was associated with a reduced incidence of a key surrogate outcome. Parenchymal brain haemorrhage was seen in 5% of neonates treated with dobutamine, compared to 35% of neonates treated with dopamine. This raises the possibility that a dobutamine-mediated increase in SVC-flow will improve neurodevelopmental outcome. That is, dobutamine treatment seems to increase SVC-flow and may reduce disability.
There’s a pressing need for effective therapies for disturbances to the transitional circulation and dobutamine seems to be a good candidate that merits formal testing in the context of a well-designed clinical trial.
A large scale trial is justified
According to the finally agreed PIP with the EMA, an international, multicentre, randomized, placebo-controlled, double blind three arm trial is to be conducted; to investigate the efficacy of dobutamine with two different starting doses in the treatment of haemodynamic insufficiency in the immediate postnatal period.
A placebo group is justified in conditions such as circulatory failure in preterm infants; where widespread uncertainty amongst neonatologists justifies testing a particular treatment approach within all the safeguards of a high quality randomised clinical trial. There is currently no standard method of diagnosis or treatment for circulatory failure and there is evidence that preterm infants may be at risk of overtreatment with current approaches which may be unnecessary or even harmful. The clinical community and individual clinicians are at “clinical” equipoise on this question and placebo treatment is justifiable in the context of an agreed approach to managing comorbidities such as protracted hypotension, persistently low SVC flow, prolonged capillary refill time or worsening biochemical parameters.
Additional work needed to strengthen the knowledge base around this area of research
• Pharmacology: The pharmacokinetics (PK) of dobutamine in the population of interest is not well defined. This information is needed to establish adequate evidence-based timings for dosing and pharmacodynamic (PD) assessment. It would also be of value to establish the possible relationship between the plasma concentration of dobutamine and its efficacy or toxicity, as well as the factors that could explain the interindividual variability of this relationship (Pop-PK/PD modelling). This could help determine an optimal dosing regimen of dobutamine in infants, based on the individual characteristics explaining the between-subject differences in the efficacy and toxicity of this drug (dose-finding).
• Pharmacogenetics: It is well established that the individual response of preterm newborn babies to dobutamine treatment varies from an extremely good response to total resistance even if high doses are given. Genetic factors alter the individual response to many medications including dobutamine. However, no data were available so far for the pharmacogenetics of dobutamine in preterm newborn infants. NEO-CIRC set up a biobank of maternal and infant DNA (including infant umbilical cord tissue, which will be available for further metabolomic and proteomic studies). Genome wide array studies in more than 2000 preterm infants were done since 2011 by the German Neonatal Network (GNN), a consortium which was led by ULU. Since blood pressure on day one of life is an outcome parameter of the GNN, this reference group would add substantial information to the analysis of the well characterized NEOCIRC cohort, which at the end of NEOCIRC-003 would have contributed important pharmacokinetic and pharmacodynamic data.
• Pre-clinical (animal) work: The performance of experimental studies in suitable animal species is a common practice, given the difficulties of conducting pharmacological research in children and more specifically in the neonatal population. Preclinical findings, and especially juvenile animal data, can be useful to generate information to support the use of a specific drug in pediatric populations. Specifically, it is important that unlike models in adult animals, those based on juvenile and in particular neonatal animals allow for the fact that drug concentration (PK) and drug response (PD) may be different in immature and developing organs. Moreover, it is important to obtain information on PK/PD and potentially different safety profiles on juvenile and, in particular neonatal animals, from those seen in adults, because there are a number of developmental variations of structure and function of the organs, an in particular of the cardiovascular system, that suggest a different response to the drug.
• Definition of neonatal shock: Low blood pressure is widely used to diagnose neonatal shock but there is no clearly established link between low blood pressure, or its treatment and long-term outcome. The threshold of blood pressure at which treating hypotension has an impact on long-term outcomes has not been defined. Other markers have been described (SVC-flow, NIRS, EEG, Cerebral Blood Flow Autoregulation, other cardiovascular indices) but the effects of treating abnormal values of these markers have not been established. Thus there is a necessity to define shock in neonates so that dobutamine can be targeted appropriately; and to develop evidence-based guidelines for the assessment of the neonatal circulation that can be applied in clinical practice leading to wider experience in innovative methodological approaches in the evaluation of medicinal products in neonates.
Based on the project context described in this section, NEO-CIRC worked towards the aims and objectives outlined below.
Aim 1 - Work towards PUMA for dobutamine: Deliver pharmaceutical, pre-clinical and clinical work that will contribute to a PUMA for dobutamine as treatment for circulatory failure after birth.
Aim 1 Objectives:
• Develop a PIP for dobutamine.
• Develop an age-appropriate formulation for dobutamine.
• Optimise a dosage-regimen for dobutamine in neonates.
• Conduct preclinical studies to investigate the safety and mechanism of action of dobutamine.
• Develop consistent approaches to measuring SVC flow and other markers of neonatal shock, with a training package to ensure that SVC flow is measured consistently in the clinical trials.
• Conduct a large Phase 3 therapeutic confirmatory clinical trial of the efficacy and safety of dobutamine to treat circulatory failure in very premature neonates after birth.
Aim 2 - Definition of neonatal shock: Derive a new definition of neonatal shock as the basis for international guidelines for the assessment and treatment of neonatal shock.
Aim 2 Objectives:
• Standardise measurements.
• Conduct observational studies in parallel to trials.
• Develop a consensus definition and guidelines to ensure the results of the research change clinical practice.
Project Results:
The NEO-CIRC project (Dobutamine for NEOnatal CIRCulatory failure defined by novel biomarkers) was funded under the EU’s 7th Framework Programme (FP7) to address the FP7 HEALTH call topic “Investigator-driven clinical trials on off-patent medicines for children”.
The project was coordinated by BSUH (UK) and the original Consortium comprised 18 partners, including four research intensive SME organisations, located in 8 different countries. SERMAS (Spain) acted as the sponsor of the Clinical Trials with 11 trial sites originally planned in the UK (BSUH, Brighton and ULIV, Liverpool), Spain (OSA, Bilbao and SERMAS, Madrid), Germany (ULU, Lubeck and VKJK, Datteln), Turkey (GUSM, Ankara), Hungary (SU, Budapest and UOP, Pecs), Romania (UMF CLUJ, Cluj-Napoca) and the US (TMC, Boston). ONO (UK) were responsible for managing the clinical monitoring of the trials, MHH (Germany) for the trial statistics and data management and analysis and PRO (UK) for producing the new formulation of dobutamine. In addition, INSERM (France) was responsible for pharmacokinetics and pharmacodynamic studies, ULU (Germany) for pharmacogenetics studies, OSA and DYNA (Spain) for animal model studies and GUSM (Turkey) [initially ULIV (Liverpool)] for biomarker studies. Finally, KIE and MOD (UK) were responsible for supporting BSUH in the overall management of the NEO-CIRC project.
At the start of the project, two independent boards were established, the Expert Advisory Board and the Ethics Advisory and Data Monitoring Board, which were comprised of leading international experts in relevant fields. The aim of the Expert Advisory Board was to ensure that the decisions taken by the Consortium were consistently aimed at and optimised to maximise the impact of the research on neonatal circulation and more generally off patent paediatric medicines. The aim of the Ethics advisory and Data Monitoring Board was to safeguard the interests of trial participants, monitor the main outcome measures including safety and efficacy, and monitor the overall conduct of the trial.
The NEO-CIRC project comprised 8 work packages, 6 of which are research focussed (WP1-WP6).
WP1 aimed to determine the pharmacokinetics (PK) and to model the PK/pharmacodynamic (PD) relationships of dobutamine in preterm infants.
WP2 aimed to define clinical and genetic risk factors for different response to dobutamine in preterm infants, by pharmacogenetic studies on genetic polymorphisms regarding inotrope use.
WP3 aimed to define the biomarkers indicating neonatal shock and their relationship to important clinical outcomes; and to implement training on SVC-flow.
WP4 aimed to conduct pre-clinical studies in animals to support the development of a new age-appropriate formulation of dobutamine to be used in preterm neonatal patients, through the study of the effect of different dobutamine doses and a complete PK/PD study in a neonatal animal model.
The objective of WP5 was to conduct 3 clinical trials and 1 systematic review requested by the approved PIP according to GCP guidelines and to the highest ethical standards. These were to assess: the prevalence of low systemic blood flow during transitional circulation in neonates; the PD effects of dobutamine using clinical, biochemical and non-invasive monitoring (Echo-D, NIRS and aEEG); and the efficacy and safety of dobutamine on long term neurodevelopmental outcome. The latter was planned as the NEOCIRC-003 trial: An international multicentre randomized placebo-controlled, double blind three arm trial to investigate the efficacy and safety of dobutamine with two different starting doses in the treatment of haemodynamic insufficiency of very preterm babies in the immediate postnatal period.
The main aim of WP6 was to develop an age-appropriate neonatal formulation of dobutamine and gather the necessary portfolio of information to enable submission of a Paediatric Use Marketing Authorisation (PUMA) application.
WP7 concentrated on the effective dissemination of the project results, both to the clinical community and parents, and training of the wider clinical community.
The objective of WP8 was to ensure the smooth running of the project including good communications with all partners and financial management, setting up relevant committees and communicating with and providing reports to the European Commission.
The main scientific and technological results of each of these work packages are described next.
Work Package 1: Pharmacokinetic (PK) and Pharmacodynamic (PD) models
Work Package 1 developed and validated an analytical method for the quantification of dobutamine in plasma, according to EMA guidelines. This method was subsequently used to determine the concentration of dobutamine in the plasma samples in infants in order to determine the elimination half-life of dobutamine in relevant the population. Ten infants were included in this pharmacokinetic study. The calculated elimination half-lives in these 10 subjects ranged from 3 to 36 minutes.
Work Package 1 evidenced the important interindividual pharmacokinetic variability in the population of interest. However, it did not fully achieve its objectives because the NEOCIRC-003 clinical trial, that was to generate the data to investigate the concentration-effect relationship of dobutamine, was not conducted before the end of the funding. The trial will be conducted with national funding support in the future.
The important pharmacokinetic variability that was evidenced must be taken into account for the evaluation of the efficacy of dobutamine in the future. Indeed, for a given dose, the maximal efficacy will be reached when the plasma concentration of dobutamine will reach the plateau, which occurs after an infusion duration of at least 5 elimination half-lives. Based on the elimination half-lives determined in the study, it can be concluded that the true effect of a dose can be observed 3 hours after the beginning its administration, and not a few minutes as it was previously thought. These new data should now be taken into consideration for the evaluation of dobutamine in preterm infants in the future.
Work Package 2: Pharmacogenetics of dobutamine
Work Package 2 was designed to identify specific groups of infants who will have particular benefits of a treatment with dobutamine. If such groups are identified, their clinical and genetic background will provide additional information how catecholamine treatment can be optimized in preterm infants. The main objective of this Work Package was to define clinical and genetic risk factors for different response to dobutamine in preterm infants.
Clinical and genetic data from a large German cohort study were used. Clinical and genetic factors predictive for low blood pressure in preterm infants were analyzed, since low blood pressure was one of the main inclusion criteria for the planned NEOCIRC-003 clinical trial. Clinical risk factors for low blood pressure in preterm infants, which were published in previous studies, were confirmed and quantified. Furthermore, it was demonstrated that low blood pressure in preterm infants is associated with a high mortality rate and a high rate of intracranial bleeding in preterm infants. These results are already published (Arch Dis Child Fetal Neonatal Ed 2015; 100:F388-92). In addition, genetic risk factors for low blood pressure in preterm infants were analysed.
Genetic factors may affect dosage regimens. Appropriate material was collected, a biobank was developed and polymorphisms for dobutamine receptors were researched, which could lead to individualised medication in the future.
Work Package 3: Non-invasive biomarkers to measure/define shock in neonates
As part of Work Package 3, the NEO-CIRC Clinical Trial Partners developed standardised approaches for the use of the various biomarkers in the NEO-CIRC Clinical Trials. Standard Operating Procedures were produced to ensure the reliable monitoring and recording of the following:
• Invasive and non-invasive blood pressure.
• Capillary refill time
• Lactate and base excess
• Pulse oximetry
• Urine output
• Functional echocardiography performed by neonatologists with a focus on Superior Vena Cava flow measurement training. Considering that echocardiography is quickly becoming an important part of haemodynamic examination in the newborn this ensured a high quality assessment tool.
• Cranial-Doppler ultrasound in newborns to assess early neurological outcome
• Electroencephalography (EEG/aEEG) for the newborn
• Brain oxygenation using near infrared spectroscopy (NIRS). The value of cerebral oxygenation monitoring and its impact on decision making has also guided clinicians to perform more research on this topic.
In preparation for the clinical trials, NEO-CIRC Clinical Trial Partners participating as clinical sites performed assessments using biomarkers such as lactate and base deficit level, capillary refilling time, urine output, oxygen saturation, echocardiographic findings, aEEG and NIRS on a local basis. However, the interruption of the NEOCIRC-001 trial and subsequent delay in opening the NEOCIRC-003 confirmatory trial prevented prospective data for analysis being obtained.
The results of a pilot study on biomarkers by SERMAS played a pivotal role in the design of the NEOCIRC-003 randomized controlled trial, with SVC-flow, BP and lactate levels being relevant as inclusion criteria for circulatory failure. Results from the NEOCIRC-001A PK sub-study involving BSUH and SERMAS also informed the design of this trial, particularly with respect to timings for PD assessment.
The ULIV HAPI-PDA study was adopted by the NEO-CIRC consortium and finished recruitment in December 2016 after recruiting 52 preterm infants <29 weeks gestational age. The first data analyses were presented at numerous national and international conferences including EAPS 2016 (Switzerland), Neonatal Society Meetings 2016-2017 (UK), XXV Biennial Meeting of the International Perinatal Collegium (Scotland), 6th European Society for Developmental Perinatal and Paediatric Congress (Belgium) and JENS 2017 (Italy). Also, whilst preparing for the NEOCIRC trials, UMF CLUJ carried out a study to evaluate the potential role of SVC flow in premature infants and the results were presented at national and international congresses including EAPS 2016 and JENS 2017.
The BSUH NeoAdapt studies were also adopted by the NEO-CIRC consortium, consisting of three observational cohort studies that included infants >33 weeks gestational age who received special care (NeoAdapt1, n=50, trial closed July 2015), intensive care (NeoAdapt2, n=25, trial closed May 2016) and total body cooling (NeoAdapt3, n=18, trial closed September 2016). Results were presented at numerous national and international conferences including jENS 2015 (Hungary), Neonatal Society Meeting 2015 (UK), Neonatal Cardiology & Haemodynamics Conference 2015 (UK), Pediatric Academic Societies Meeting 2016 (USA) and EAPS 2018 (France).
Clinical practice and research are currently hampered by the lack of a shared definition of neonatal shock. The platform for research that the consortium developed to work on the PIP for dobutamine allowed us to develop a definition of neonatal shock and embed it in clinical guidelines. A working definition of neonatal shock based on the results of the clinical trial was not possible due to the delay to the start of NEOCIRC-003, however a consensus meeting was held between members of the NEO-CIRC consortium (BSUH, ULIV, MHH, SERMAS, UMF CLUJ, OSA and GUSM) and members of the HIP Trial consortium which was designed to test Dopamine for the hypotension in preterm. The following biomarkers were agreed upon as the parameters to be used for deciding circulatory support in preterm in the first 48 hours of life:
• Mean blood pressure < gestational age
• Lactate > 4mmol/l
• Echocardiographic assessment of heart with emphasis on contractility
• Cerebral oxygenation assessment by NIRS
Overall, the training obtained during preparation for the Clinical Trial has helped the NEO-CIRC Clinical Partners to develop a better understanding of circulatory failure in newborns. In addition, a Methodology for assessment of neurodevelopmental outcomes was developed in preparation for the main clinical trial.
WP4 - Neonatal / juvenile animal models
Firstly OSA, with the help of BSUH, conducted and published a systematic review on the use of dobutamine in juvenile animal models, using MEDLINE (the U.S. National Library of Medicine® (NLM) premier bibliographic database) and EMBASE (a biomedical and pharmacological bibliographic database) as databases, to summarize and assess the preclinical evidence of the use of dobutamine in juvenile/neonatal animals. The conclusion from this systematic review was that although there was enough preclinical evidence to conclude that dobutamine improves cardiac output it was necessary to perform more studies because the heterogeneity across studies in juvenile/neonatal animals made it difficult to obtain clear evidence to better understand the effects of dobutamine in peripheral organs, above all in the brain.
Based on the systematic review, a preclinical study was planned, in a well-established hypoxic neonatal pig model, to measure the effects of different doses of the new NEO-CIRC pediatric formulation of dobutamine on hemodynamic and oxygen metabolism; and to perform a complete PK/PD study on the short term effects of the new formulation in other organs with a focus on the brain. The study was conducted in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals in the experimental research unit of Cruces University Hospital (OSA). The experimental protocol met European and Spanish regulations for protection of experimental animals (2010/63/UE and RD53/2013)).
In the hypoxic neonatal pig animal study different biomarkers to assess circulatory status and tissue oxygen delivery and perfusion, mainly focused on the brain, were used at different dobutamine doses. Near infrared spectroscopy (NIRS) was used to measure the changes on systemic and brain oxygenation; a perivascular flow probe placed in the carotid artery was used to measure carotid blood flow as a surrogated of cerebral perfusion; mean arterial blood pressure, heart rate, cardiac output, stroke volume and systemic vascular resistance, among others, were measured through a multiparameter hemodynamic monitor to assess circulatory status and blood gas analysis was performed to assess the ventilator and acid-base status. Also, blood hepatocellular enzymes (aspartate transferase (AST) and aminoalanine transferase (ALT)) as markers of hepatic injury, blood creatinine concentration as a marker of renal injury and troponin as a marker myocardial injury were determined. Finally, complete pharmacokinetic and pharmacodynamics study and tissue damage analyses were performed.
The pharmacokinetic study allowed the suitability of neonate piglet to be established as an animal model to study dobutamine in human neonates, as the estimated dobutamine clearance in the animal model (that reflects the rate of drug elimination divided by plasma concentration) is of the same magnitude of the clearance reported for the drug in humans. Taking all the results together, the study allowed us to conclude that the new pediatric dobutamine formulation improved hemodynamic status in hypoxic neonatal piglets, with dose-specific differences in metabolic response, with an improvement in cerebral oxygenation and perfusion at higher dobutamine doses with less histological injury. So, the pattern of changes seen in response to the new dobutamine was encouraging and justifies long-term studies in human neonates.
As part of this Work Package, OSA, BSUH and DYNA published three articles in peer reviewed journals. In addition, the Animal model established in the experimental research unit of Cruces University Hospital (OSA) is currently being used to study neonatal hypoxic condition and could help with future pre-clinical studies in the Management of Circulatory Failure in newborns.
Work Package 5: Clinical Trials
Work Package 5 was one of the main pillars of NEO-CIRC because neither of the two main project aims are achievable without results from the clinical trials; it therefore involved the participation of most of NEO-CIRC Project Partners.
The clinical trial activity required to answer the variety of research questions in this project, meant that several studies and sub-studies, with different methodologies, needed to be planned and designed as part of this work package.
Unfortunately, this work package has not been able to fully achieve its objectives due to difficulties encountered in setting-up the studies, in particular the final clinical trial (NEOCIRC-003), which was designed to provide answers to the questions regarding the efficacy and safety of dobutamine. This trial has not yet started, as the first country regulatory approvals were only received in the final months of the project.
The various studies developed as part of Work Package 5 were part of the Paediatric Investigational Plan (PIP) from the European Medicines Agency’s Paediatric Committee (EMA/PDCO) negotiated to develop a “New Paediatric Formulation of Dobutamine” suitable for neonates. According to Human Regulatory R&D indications from the European Medicines Agency:
“A paediatric investigation plan (PIP) is a development plan aimed at ensuring that the necessary data are obtained through studies in children, to support the authorisation of a medicine for children. All applications for marketing authorisation for new medicines have to include the results of studies as described in an agreed PIP, unless the medicine is exempt because of a deferral or waiver. This requirement also applies when a marketing-authorisation holder wants to add a new indication, pharmaceutical form or route of administration for a medicine that is already authorised and covered by intellectual property rights”.
This requirement meant that the NEOCIRC clinical trials could not start until an agreed PIP was in place with the EMA PDCO. Unfortunately, as described in Work Package 6, this was a lengthy and time-consuming process which delayed the start of the NEOCIRC clinical trials.
NEOCIRC-001 – Therapeutic Exploratory Trial
This pilot study, performed in Spain and the UK, was an 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. The pilot study had embedded PK and PK/PD sub-studies NEOCIRC-001A and NEOCIRC-001B respectively.
During this pilot study samples were collected from 15 new-born infants, of which samples from 10 infants provided valid PK data, to estimate the elimination half-life, and consequently the time to steady-state of dobutamine in extremely premature neonates. From the patients enrolled in this trial, it was determined that a delay of 3 hours should be respected before measuring the pharmacodynamic endpoints for each dose. Since this delay is not compatible with the standards of care, maintaining it would have led to the frequent use of rescue medication during the trial, which would have precluded the evaluation of dobutamine efficacy.
These conclusions formed the basis for the design of the PK/PD sub study for NEOCIRC-003:
• The 1st sample should be drawn at the pharmacodynamics evaluation of the 1st dose.
• The delay until a dose increase should be based on the decision of the physician according to clinical data and not on the PK of dobutamine. However, a delay of at least 2 to 3 hours should be respected before drawing the blood sample for the efficient dose (2nd blood sample).
• Finally, an optional 3rd blood sample could be drawn 15-30 min after the end of the last infusion in order to have an estimation of the elimination half-life in the population.
With the data from this study and other information provided by published studies carried out by SERMAS, the NEO-CIRC Consortium decided to reduce the number of studies from 3 to 2. This required a change to the PIP which had to be approved by the EMA PDCO. The approval of the proposed PIP modifications was a lengthy process with the approval finally received in July 2017.
NEOCIRC-003 Clinical Trial
This was an international, multicentre, randomized, placebo-controlled, double blind three arm trial to be conducted to investigate the efficacy of dobutamine with two different starting doses in the treatment of haemodynamic insufficiency in the immediate postnatal period. A clinical study protocol for the NEOCIRC-003 trial was developed based on the modified PIP, including requirements demanded by the EMA PDCO, and the protocol was approved by the relevant NEO-CIRC Partners in November 2017.
The Consortium carried out the preparatory activities for the NEOCIRC-003 trial in accordance with clinical trials regulation, including applying for Ethics approvals and National Competent Authorities authorisations. However, the process took much longer than it would normally do as an extensive set of questions related to the new neonatal formulation of dobutamine were received which were quite unusual for a clinical trial application. Responses required the input of the active substance manufacturer, the finished product manufacturer and the clinical trial supplies contractor and an updated Investigational Medicinal Product (IMP) Dossier and new IMP Management Guideline Manual were also required. After submission of the responses a further round of questions was received, and responses provided. As a result of the delays caused by the extensive questioning the first national approval was not received until July 2018; this precluded the opening of the trial within the timeframe of the FP7 project.
Although the trial was not opened within the timeframe of the FP7 project, the work performed by the consortium in the design and medical writing of the NEOCIRC-003 Protocol has achieved the following key milestones to allow the project to continue in the future:
• Internal approval of a complex study: the main study; a PK/PD sub study; a Pharmacogenetics sub study and a nested trial for the evaluation of advanced biomarkers.
• Ethics/regulatory approval in Spain.
• Establishment of a sound basis for the continuity of the trial, contingent on applications for local / national funding to execute the trial.
The Consortium members are still committed to carrying out the NEOCIRC-003 study and are in the process of applying for local / national grants to fund this. The intention is to perform the study initially in Spain (where the study is already authorised and local funding has been awarded), Turkey and the UK (where national leaders are currently actively seeking local funding). The rest of the countries have been encouraged to also seek national funding to contribute to the required sample size.
NEOCIRC-004 – Literature Review
A structured literature reviews on inotropes was carried out and published: "A Literature Review of the Pharmacokinetics and Pharmacodynamics of Dobutamine in Neonates". Mahoney L, Shah G, Crook D, Rojas-Anaya H, Rabe H. Pediatr Cardiol (2016) 37: 14. doi:10.1007/s00246-015-1263-9.
The achievements of Work Package 5 have influenced:
• The methods used for the assessment and follow up of these patients in a clinical trial setting, particularly with respect to their standardisation, which could then permeate into standard of care when the evidence of their utility is confirmed by the trial results.
• The future research agenda to be continued in Spain, Turkey and UK, that will result in the eventual execution of the NEOCIRC-003 study.
• Advances in the design of clinical trials for the assessment of the transitional circulation in preterm infants, which could be incorporated by future trials in this field.
Work Package 6: PIP and PUMA
As previously highlighted, the NEOCIRC clinical trials could not start until an agreed PIP was in place with the EMA. PRO were responsible for compiling and submitting all regulatory procedures with the EMA with the body of the required documentation being prepared by BSUH and SERMAS.
In the first instance scientific advice was sought from EMA. The outcome of the procedure was adopted by the NEO-CIRC Consortium and a PIP was submitted with a clinical programme that included two pilot studies (NEOCIRC-001 and NEOCIRC-002) followed by a randomised controlled trial (NEOCIRC-003). Following the submission of modifications requested by the EMA, the PIP was granted.
The program commenced and following the review of outcomes from the initial biomarkers pilot study by SERMAS and literature reviews, clinical strategy discussions were held to identify a restructured clinical program that would provide the best outcome for NEO-CIRC and the wider research community given the remaining project resources. A request for PIP modification was filed which included updates on progress against the agreed measures to date, a proposal to stop the ongoing therapeutic exploratory study (NEOCIRC-001) after completion of the embedded PK sub-study NEOCIRC-001A as justified in Work Package 5 above, and a proposal for a sole clinical trial that could provide clinically relevant safety and efficacy information on the use of dobutamine during circulatory failure in preterm neonates; but at the same time answer many of the other research questions from the original PIP agreed with the EMA. Whilst the PDCO issued a positive opinion, it did not however agree to the removal of the dose finding study. This represented a major challenge as project timelines did not allow for the extra time required to conduct a dose finding study and therefore rendered the PIP unachievable within the scope of the project. After much discussion, the PIP sub-group partners agreed that the NEOCIRC-003 trial could be adapted to address the concerns of the PDCO by inclusion of a second starting dose. This resulted in the need for a further PIP Modification and study protocol re-design. After consultation with the PDCO the 3rd PIP modification was prepared, filed and subsequently granted a positive opinion.
At the outset of the pharmaceutical development program, PRO conducted a literature review and patent search from which outline presentations for the new dobutamine product were identified. A questionnaire was devised to gain feedback from the Consortium clinicians on current practices and on the proposed presentations. Several formulation prototypes were developed and subjected to accelerated stability evaluation. These proved to be unsuitable candidates so modification to the formulations and the method of manufacture were subsequently made. In addition, feedback received as part of the initial PIP request for modification resulted in the need to evaluate alternative antioxidants. As a result, a series of new prototypes were developed and subjected to accelerated stability testing and a final formulation was selected. The formulation of the investigational medicinal product (IMP) was developed to minimise the level of sodium metabisulphite in the product, to enable use in newborn babies, where metabisulphite is toxic. The manufacturing process is also novel, using nitrogen infusion and blanketing to limit dissolved oxygen and oxygen in the headspace of the vial, thereby limiting the rate of degradation of the dobutamine.
Alongside the formulation development work, analytical method development and qualification was undertaken.
A pilot batch of the selected formulation was manufactured and set down on stability according to ICH guidelines. This batch formed part of the formal validation programme which would be incorporated in the PUMA application and was also used for supply to the clinics. At 16 months real time stability, significant discolouration of the batch was identified. Discolouration of dobutamine in aqueous solution due to oxidation was not unexpected and is well documented in published literature. The oxidation is limited by the inclusion of an antioxidant in the formulation, sodium metabisulphite, but at the low level requested by the PDCO it has a limited effect and therefore a limitation on the shelf life of the product.
The batch was withdrawn and following assessment it was concluded there was no impact on patients. It did however cause a delay in the continuation of the clinical study. The formulation and manufacturing process were reviewed to identify possible optimisation steps as part of the on-going development of the product. The eventual optimisation focused on the manufacturing process and further reduction in exposure to oxygen to slow the rate of oxidation of the dobutamine. An update of the Investigational Medicinal Product Dossier was required and submission of a regulatory amendment. A fresh batch of IMP was manufactured and following quality control analysis, labelling and Qualified Person release, supplies were made available to the clinics to re-start the trial. ICH stability studies were then initiated.
Following the conclusion of the NEOCIRC-001 pilot study, the review of the clinical program and subsequent PIP modification, a fresh batch of IMP was required and also 2 new study drugs; a half strength dobutamine product and a saline placebo. Development work was undertaken with the contract manufacturer and a batch of each of the 3 study drugs was produced for the start of the NEOCIRC-003 trial and ICH stability studies were initiated.
As NEOCIRC-003 was to be a blinded trial, it was necessary to blind the vials as differential colour change was expected due to differing rates of change between the two active drugs vs no change for the saline. A blinding device for the vials was devised. A similar device was designed for the syringes for transfer of the drug from the vials to the infusion solution.
An IMP Management Guideline Manual for the clinical trial sites was created to provide the necessary information for safe and effective management of the study medication at sites including, ordering, receipt, storage and accountability for the IMP supplies.
Multilingual booklet labels were devised (5 languages) to maximise supply chain flexibility.
At the time of project closure, 24 months successful real time data had been generated on the new formulation.
In order to complete a pharmaceutical dossier for PUMA submission, further batch manufacture and validation activities would be required. The delays in the project meant that these could not be completed within the project timeframe. In addition, although some of the content for the PUMA has been generated from the work conducted during the project, it can only be compiled when the clinical trials have been completed in accordance with the agreed PIP measures and the study reports closed.
Work Package 7: Knowledge Translation and Training
Training of partners was promoted by BSUH throughout the life of the project. With respect to Good Clinical Practice (GCP), clinical partners had the responsibility to train their research staff locally. In addition, ONO conducted neonatal specific refresher sessions during Consortium Meetings. All partners responsible for trial specific training were heavily involved in the training design and delivery. In particular, SERMAS hosted the functional echocardiography hands-on sessions in Madrid which were attended by various neonatologists from the clinical sites.
With respect to Public and Patient Involvement (PPI), BSUH reviewed all parent information and consent forms for the clinical trials in collaboration with their local Neonatal Parents’ Forum; and sought advice from the European Forum for Care of the Newborn Infants (EFCNI) before releasing the final versions. In the same fashion partners involved their local parent groups, when available, to produce their country specific documentation. Additionally, a PPI related sub-study protocol was designed to explore parents’ perceptions of antenatal and deferred consent but couldn’t be executed.
Conclusion
Even though the large clinical trial was unable to be carried out, the consortium has been able to deliver a range of benefits. Work on the definition of neonatal shock and the development of guidelines for the assessment of the neonatal circulation has been conducted as a formal knowledge translation process. That is, the process of knowledge creation (PK work, biomarker work etc.) was conducted in parallel to work that engages with people who will use the knowledge.
The overall strategy of the work plan was to conduct a tightly integrated programme of work that leads to the submission and completion of a PIP. This required information about dobutamine that is specific for the intended indication on the PIP and PUMA.
The platform provided by work on the PIP has allowed the consortium to start deriving a new definition of neonatal shock, with a view to embed a future definition in guidelines for the assessment and treatment of the circulatory failure in the newborn.
Finally, as a result of having conducted this project, the NEO-CIRC management group has the following observations/recommendations:
1. Apart from reviews by the European Commission (EC), which are useful to help steer this kind of project, it would be beneficial to implement a critical appraisal by experts from a similar area of research and application, who have previously participated or are finalising similar large scale EU funded projects. A mid-project “health-check” by “fresh” expert eyes could help foresee certain key problems and allow the implementation of targeted mitigation strategies in good time, e.g. prioritising certain tasks, or joining efforts with other similar EU projects early. This could improve the overall productivity of EU projects in relation to the funding already assigned.
2. It is well known that the problem with currently used off label / off licence old drugs in paediatrics, is that the pharmaceutical industry has little incentive to invest in such studies. As a consequence the European Commission specifically allocated funding for studying frequently used off label drugs in newborns and children in order to achieve a Paediatric Use Marketing Authorisation (PUMA) for age-appropriate formulations that have minimal toxicity. This funding was targeted at drugs on a priority list issued by EMA/FDA like dobutamine. However NEO-CIRC has sensed that, at least in the case of this drug, the likelihood of prescribers transferring across to a new licensed IMP product from cheaper existing licensed dobutamine products is relatively low. This hinders the ability of networks like NEO-CIRC to continue into the originally planned PIP-PUMA pathway in which substantial time and resources have been invested. We believe it is in the best interest of the EC/EMA to explore this issue further.
Potential Impact:
Potential Impact
Impact can be measured based upon knowledge creation, informing policy, direct health benefits and economic and societal benefits. The actual and potential impacts of the NEO-CIRC project are as follows:
The results of the genetics studies have shown that catecholamine and volume treatment of preterm infants, and dobutamine treatment in particular, should be done in a personalized way and include clinical and genetic risk factor assessment. This will help to reduce complications which are more frequent in preterm infants who are prone to low blood pressure values and to protect these infants from early death and complications of premature birth like intracranial haemorrhage.
The project has been educational in the assessment of newborns with circulatory failure by creating a broader perspective for the evaluation. It has created an awareness and enthusiasm amongst neonatologists about neonatologist-performed echocardiography and has enabled successful training in the NEO-CIRC clinical centers. The difficulties in performing neonatal echocardiography and the variability between measurements have been recognized. The multifaceted nature of neonatal circulation in the early days of life has been acknowledged and the necessity of a combination of biomarkers to guide treatment has been emphasized.
The work performed may lead to more in depth evaluation of neonatal circulation before starting a medication and may lead to more clinical trials to assess short and long-term impact. More centers will probably perform echocardiography and NIRS to have a better understanding of circulation and combine the results with those of blood pressure, lactate, capillary refilling time which are currently used to decide treatment. The introduction of NIRS technique to assess cerebral oxygenation will result in closer monitoring of brain injury and hopefully will result in better neurological outcome which will undoubtedly lead to less burden on society.
The consensus on the biomarkers to define circulatory impairment in the first days of life in preterm infants will lead to better designed clinical trials and hopefully with more relevant results in the end. It will also lead to better selection of the patients who would actually require treatment. The project results will contribute to a new definition of circulatory failure and or shock in the new-born period which can be used by all clinicians treating this highly vulnerable population. The new definition will support a better outcome for affected newborn infants through targeted and individualized treatments based on the results of the genetics and clinical studies.
The pharmacokinetic study has established the suitability of neonate piglet as animal model to study dobutamine in human neonates, as the estimated dobutamine clearance in the animal model (that reflects the rate of drug elimination divided by plasma concentration) is of the same magnitude of the clearance reported for the drug in humans. Taking all the results together, the study allowed us to conclude that the new pediatric dobutamine formulation improved hemodynamic status in hypoxic neonatal piglets, with dose-specific differences in metabolic response, with an improvement in cerebral oxygenation and perfusion at higher dobutamine doses with less histological injury. So, the pattern of changes seen in response to the new dobutamine was encouraging and justifies long-term studies in human neonates.
The project has laid the foundation for a clinical study on the efficacy and safety of dobutamine on long-term neurodevelopmental outcome. It has provided a better understanding of the low systemic blood flow, in particular it has provided a wealth of information on the biomarkers that can be used in non-invasive way to define this status, and a well-designed protocol, that will be implemented in Spain, Turkey and UK.
An age appropriate formulation of dobutamine, with 24 month shelf life, has been developed and stability studies successfully completed. Whilst further data are required to support the pharmaceutical development section of a PUMA application, the outcome is positive, and it has demonstrated there is significant potential for a new, paediatric formulation with reduced toxicity effects, to be brought to market for the benefit of preterm babies with circulatory failure. This would replace the need for off label use of the currently marketed dobutamine products, and the inherent risks this brings for prescribers and patients. There is significant potential for this new dobutamine formulation and following the grant of a successful PUMA application there is the opportunity for the product to be commercialised across the 27 EU countries. Further pharmaceutical development studies, along with the fully completed clinical program, would be required to complete the PUMA.
Better neurodevelopmental outcome will reduce the economic on-cost of prematurity beyond the stay in hospital thereby reducing health care costs across EU member states and beyond. This will be a benefit to all EU citizens.
The consortium has brought together academic partners from European and American institutes and industry working together on a common goal. These collaborations can be used in the future to develop other new products and scientific knowledge for the treatment of conditions affecting the new-born infants. The industry partners should also benefit from these collaborations by growing their expertise and business portfolio.
Further international collaborations through the participation in the International Neonatal Consortium should strengthen the links between different continents and improve the care of the new-born infants around the world.
Dissemination activities
The project has been widely disseminated and promoted to the scientific research community, clinicians and the general public. The main outreach to the research community and clinicians has been through publications in scientific journals, presentations at scientific meetings and conferences, workshops and the NEO-CIRC project WEB site.
The NEO-CIRC Chief investigator and members of the consortium have attended and presented at numerous scientific meetings across the world, creating awareness of the NEO-CIRC project and highlighting the importance of this study and the challenges posed. These meetings have included the Pediatric Academic Society, European Society for Paediatric Research, European Neonatal Brain Club, Recent Advances in Neonatal Medicine, International Perinatal Collegium and at many national meetings including UK, Turkey and Romania.
The NEO-CIRC Consortium has also collaborated extensively with other groups in this area: the EU FP7 funded HIP consortium, the SafeBoosC consortium, the European Forum for Care of the Newborn Infants (EFCNI), the network of paediatric research at European Medicines Agency (EnprEMA) and the International Neonatal Consortium (INC). The NEO-CIRC Consortium believes that these collaborations will lead to the production of evidence for the neonatologists to support circulation in the preterm during transitional period.
The NEO-CIRC consortium has published more than 50 abstracts at various national and international conferences and meetings, in particular the biennial Congress of the European Academy of Paediatric Societies (EAPS) and Congress of joint European Neonatal Societies (jENS). This has involved a combination of invited talks, presentations and posters communicating the objectives of the NEO-CIRC project and results achieved.
To date, members of the NEO-CIRC Consortium have also published 11 articles related to the NEO-CIRC project. These include the major speciality specific journals such as European Journal of Paediatrics, Pediatric Research, Pediatric Drugs, Archives of Diseases in Childhood Fetal and Neonatal edition, Pediatric Cardiology amongst others.
General information about the NEO-CIRC research and clinical study is available through the project WEB site www.neocirculation.eu.
The Parent Information page includes background information for parents related to the NEOCIRC study, copies of the Patient Information Leaflets and links to other independent organisations involved in the support of parents and families of premature and sick babies. The Publications and Presentations page is aimed at the research community and includes links to the relevant journal WEB sites where copies of the NEO-CIRC scientific papers can be downloaded as well as a list of all NEO-CIRC Conference presentations and posters.
Exploitation of results
The results of the NEO-CIRC project can / will be exploited in several ways:
Information from NEO-CIRC Echo-D, NIRS and aEEG SOPs
Information from Echo-D, NIRS and aEEG SOPs generated during the NEO-CIRC project has been incorporated into Medical Guidelines for the Management of Circulatory Failure in newborns. These guidelines are used by professional staff at the Brighton and Sussex University Hospitals (BSUH) Trevor Mann Baby Unit to assess newborns with circulatory failure, identify the cause and determine the appropriate treatment. The guidelines have been written primarily for use within the BSUH neonatal service and are available online as a stimulus for the exchange of knowledge and ideas in the field of neonatology. The guidelines take into account the best available evidence at the time of their creation, as well as current recommended best practice. Other NICUs could potentially use these guidelines for the benefit of their neonatal services.
Training course in measurement of SVC-flow
The capability for measurement of SVC-flow generated during the NEO-CIRC project has been incorporated into local hospital activity for the Management of Circulatory Failure in newborns. Not only will this help improve on the Management of Circulatory Failure in newborns but it will also be an enabler to participate in future clinical trials.
Neonatal echocardiography and cranial ultrasound training
The training on neonatal echocardiography and cranial ultrasound developed during the NEO-CIRC project has created an awareness regarding the value of neonatologist performed echocardiography and cranial ultrasound in NICUs especially for preterm infants with circulatory problems. This will improve patient care and will enable neonatologists and neonatal fellows to discuss treatment with pediatric cardiologists in more detail. They will also be able to assess myocardial contractility early on to guide their treatment. Being able to recognize IVH will enable the clinician to take more appropriate decisions in time.
More frequent use of Near-Infrared Spectroscopy (NIRS)
The use of NIRS more frequently in NICU has helped to achieve a more comprehensive monitoring of critical patients in NICU. This will also enable NEO-CIRC partners to participate in future clinical trials in Europe.
Awareness of biomarkers other than blood pressure or capillary refilling time to define circulatory failure and guide treatment accordingly
The awareness created about the advanced biomarkers and the knowledge gathered has resulted in more critical evaluation of preterm infants with regards to circulatory failure. The decision making for inotropes based on blood pressure, capillary refilling time or urine output is now regarded as a simplistic approach in the NEO-CIRC NICUs and more advanced tests are searched by clinicians.
Pre-clinical studies in neonatal/juvenile animals
The systematic review of the use of dobutamine in juvenile animal models and the experimental protocol developed during the NEO-CIRC project could help streamline trial design for future pre-clinical studies in the Management of Circulatory Failure in newborns.
Quantification of dobutamine levels in newborn pig plasma
The bioanalytical technique developed can be used to determine dobutamine plasma levels in subsequent preclinical studies to gain further knowledge in dobutamine PK/PD relationships. Although, the bioanalytical technique was primarily developed to quantify dobutamine in the preclinical studies conducted within the NEO-CIRC project, it can be used to support any additional pre-clinical study that might be conducted in pre-clinical studies in neonatal/juvenile animals to further characterise the PK/PD of dobutamine.
Dobutamine elimination half-life in pre-term neonates
This will be used to determine how long a dobutamine infusion must last until the evaluation of the efficacy of the administered dose. This will optimize the use of dobutamine and the evaluation of its efficacy in the future clinical trials.
Clinical risk factor score for low blood pressure in preterm infants
This score is a very simple tool to identify preterm infants with a high risk for hypotension and treatment with catecholamines who need umbilical lines at birth. The score will soon be published in a manuscript concerning genetic risk factors for low blood pressure in preterm infants.
Application of Bauer and Köhne Design for sample size calculation for a three-arm trial
The Bauer and Köhne design for stopping a trial after interim analysis was applied to a three-arm trial in conjunction with further multiplicity adjustments in the setting of rare diseases. The design structure can be re-used and/ or adapted for future trials.
Standard Operating Procedures (SOPs) and Informed Consent Forms
The SOP design, review and approval process is a highly time-consuming activity. The SOPs designed as part of the NEO-CIRC project could be used in future commercial and/or academic trials by the NEO-CIRC partner NICUs. Similarly, the Informed Consent Forms designed as part of the NEO-CIRC project would also provide a solid base for future studies carried out by the NEO-CIRC partners using local funding.
NEOCIRC-003 Study Protocol
Several of the NEO-CIRC partners will submit requests for national funding based on an adapted version of the NEOCIRC-003 study protocol to carry out a clinical trial to produce data on the efficacy and safety on the use of dobutamine as a treatment for early haemodynamic insufficiency in the preterm infant. The results of this study will help redefine neonatal shock and improve existing medical guidelines for the Management of Circulatory Failure in this population. SERMAS has already been successful in securing funding for this purpose.
Age appropriate formulation of dobutamine
The market size is likely small and, due to the unique manufacturing process, the cost of manufacture is significantly higher than for currently marketed dobutamine products. However, the new formulation has been significantly improved over current products. For commercial viability, it would however need to be positioned as the only paediatric licensed product for this indication and secure majority market share. As some of the current dobutamine products cover the indication in broad terms, and in many cases have posology for paediatric patients, it would be necessary for this legacy paediatric wording to be removed from those licences that do not have supporting clinical paediatric data. There would need to be a legal mechanism in place to ensure automatic switch to the PUMA licensed product and that prescribers could no longer prescribe existing products because they are cheaper. It is possible that patent protection could be sought for the formulation and orphan designation may also be possible.
List of Websites:
Coordinator
Dr Heike Rabe
Brighton and Sussex University Hospitals NHS Trust
Brighton, BN2 5BE
United Kingdom
Website: www.neocirculation.eu
