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FP7

NEUROSIS Sintesi della relazione

Project ID: 223060
Finanziato nell'ambito di: FP7-HEALTH
Paese: Germany

Periodic Report Summary 3 - NEUROSIS (Efficacy and Safety of Inhaled Budesonide in Very Preterm Infants at Risk for Bronchopulmonary Dysplasia)



Project Context and Objectives:

The Neonatal European Study of Inhaled Steroids (Neurosis) is an international multi-center randomised controlled blinded study in a population of preterm infants. NEUROSIS is powered to provide clinical evidence on a relevant efficacy outcome, survival without BPD at 36 weeks gestational age. NEUROSIS includes a follow-up phase of the infants up to a corrected age of 18-22 months in order to assess their neurodevelopmental profile, the main and most important safety outcome in preterms. The study protocol has been developed by a panel of neonatologists from all over Europe. After development, it was critically reviewed by external experts and has received a consistent very high rating which led to funding by the EU. NEUROSIS is one of the largest randomised controlled studies in preterm neonates ever conducted in Europe. The sponsor of NEUROSIS is the University Children’s Hospital of Tuebingen, at which the two principal investigators are based.

HYPOTHESIS:

Early prophylactic inhalation of Budesonide reduces the absolute risk of developing bronchopulmonary dysplasia (BPD) or death in preterm infants born <28 weeks gestational age (GA) by 10%.

PRIMARY OBJECTIVE:

To determine whether early inhalation of Budesonide improves survival without BPD at 36 weeks GA in infants born between 23 and 27 weeks GA.

STUDY DESIGN:

Randomised placebo-controlled, multi-centre clinical trial.

RESEARCH PLAN:

Within the study period, 850 infants of 23-27 weeks GA will be randomised during the first 12 hours of life to Budesonide or placebo to prevent BPD. Study drugs will be administered via Aerochamber and continued until infants are either off supplementary oxygen and positive pressure support or have reached a GA of 32 0/7 weeks regardless of ventilatory status. The primary outcome of survival without BPD will be determined at 36 weeks GA and BPD will be defined according to the physiological definition. Study patients will be followed and neurodevelopmental outcomes will be assessed at a corrected age of 18-22 months.

STUDY PROGRESS:

The funding phase started in March 2009 and the study has already been approved by ethics boards and national competent authorities in seven countries; patient recruitment started in April 2010 and as of April 23rd 2012, a total of 1097 preterm infants have been screened and 455 of them were randomized. The Neurosis consortium submitted a Pediatric Investigation Plan to the European Medicines Agency (EMEA-001120-PIP01-10). On November 30. 2011, the European Medicines Agency agreed on our paediatric investigation plan, which can be considered a major achievement.

Project Results:

Since the Neonatal European Study of Inhaled Steroids (Neurosis) started in March 2009, the foundations for the effective functioning of the clinical study have been laid. The main goals of the initial study period were the development of the central infrastructure as well as the setting up of infrastructure for local participating centers.

Regarding the central infrastructure, the development of essential study documents (e.g. case report forms, study operating manual, data management plan), the development of a GCP-conform trial data system together with the development of standard operating procedures (SOPs) for using the system has been completed. An internet site has been set up for Neurosis (www.neurosis-study.eu), which is extendable, and will be extended as the study progresses.

Approvals from the national competent authorities and the research ethics boards have been obtained in all countries and patient recruitment has started on April 1st 2010. The main goal of the second period of the project was to increase patient recruitment. As of April 23rd 2012, only 455 infants were randomized. Thus the main objective for the third period of the project was to achieve the targeted sample size of 850 patients. This objective has been met and in August 2013 the last patient has been randomized. For the remaining time of the project, focus should be on the cleaning of the data and the achievement of the highest follow-up rate possible.

The FP7 Cooperation Work Programme “Health” lists two essential impacts for the call that led to the funding of Neurosis: (1) Evidence for better use in paediatric populations; and (2) to aim at eventual new Paediatric Use marketing authorisations (PUMAs). Since Neurosis has finished patient recruitment, it will lead to evidence for better use of inhaled steroids in preterm infants. Based on the most recent review from the Data Monitoring Committee, this could mean that inhaled steroids should not be used fort he prophylaxis of Bronchopulmonary Dysplasia in preterm infants with a gestational age of less than 28 weeks. However, final results need to be awaited before definite conclusions can be made. Regarding the other impact listed in the programme, a major breakthrough has been achieved in period 2 of the project: Together with Chiesi Farmaceutical the Neurosis consortium submitted a Pediatric Investigation Plan to the European Medicines Agency (EMEA-001120-PIP01-10). On November 30. 2011, the European Medicines Agency agreed on our paediatric investigation plan.

Potential Impact:

Clinical significance and wider societal implications

Considering the recent progress of the study, it is very likely that Neurosis will achieve its targeted sample size of 850 preterm infants over the next 17 months. NEUROSIS is powered to provide clinical evidence on a relevant efficacy outcome, survival without bronchopulmonary dysplasia (BPD) at 36 weeks gestational age. BPD not only contributes to the mortality of preterm infants but is also associated with impaired neurosensory development in Extremely Low Birth Weight (ELBW) survivors, frequent readmission to hospital in the first 2 years of life, as well as with an increased risk of asthma, lung function abnormalities and persistent respiratory symptoms in adolescence and young adulthood. Systemic corticosteriods are effective in preventing BPD, but their use is practically prohibited given their adverse effects on neurodevelopment. Early inhalation of corticosteroids has been shown to be associated with secondary pulmonary benefits, but its effect on survival without BPD and on neurodevelopment remains unclear. In order to address this issue, NEUROSIS also includes a follow-up phase of the infants up to a corrected age of 18-22 months with an assessment of the neurodevelopmental profile, the main and most important safety outcome in preterms.

Socio-economic impact

We are not aware of a reliable estimate of the cost of treating preterm infants with chronic lung disease in Europe. In the United States, the overall yearly costs of treating infants with BPD are estimated to be $2.4 billion. This amount is second only to the costs for treating asthma (Source: National Institutes of Health). A safe therapy that would lead to a difference in BPD incidence, even if the difference is relatively small, would be extremely valuable, not only from an individual patient perspective but also from an economic health care perspective. To be able to demonstrate such a relatively small, statistically significant difference, a large number of preterm infants is required. Such a study needs to be multicentre accross different nations. NEUROSIS is one of the largest randomised controlled studies in preterm neonates ever conducted in Europe and its results have the potential to make an important impact on the economics of health care in Europe and other parts of the world.

List of Websites:

http://www.neurosis-study.eu


Informazioni correlate

Contatto

Christian Poets, (Professor of Paediatrics / Director)
Tel.: +49 7071 2984742
Fax: +49 7071 293969