​​​Safeguarding the brain oour smallest children – a phase III randomised clinical trial on near-infrared spectroscopy monitoring combined with a treatment guideline in premature infants​ with patient relevant outcomes

The phase-II trial was successful in reducing the burden of cerebral hypoxia to less than half. Therefore we wanted to conduct a large pragmatic trial. The purpose is to examine if this can reduce the risk of death or severe brain injury at 36 weeks of age from about 34% in the control group to about 26% in the experimental group.
First we formed a group of 93 neonatal units in 17 European countries and applied to the Horizon2020 research programme.

This call received applications for 113 projects in stage-1 of which 36 were allowed to submit an application to stage-II – among these SafeBoosC-III. But we were not funded. 
Next we formed a consortium with 10 national partners and applied to the Irish Heath Research Board in 2016. Again we were shortlisted, but in March 2017 we learned that we were not funded.
We then considered a cluster randomized design. The SafeBoosC intervention is complex: Monitoring of cerebral oxygenation by NIRS from 3 hours after birth until 72 hours and adequate implementation of the treatment guideline whenever cerebral oxygenation drop below the threshold. This means that many clinical staff members are involved and therefore a cluster design would be more efficient in terms of training and equipment. Also, since the phase-III trial is pragmatic, only outcomes that are routinely reported to neonatal networks are used, such as mortality, major brain injury as detected by routine cerebral ultrasound, and other major neonatal morbidities. But such a design would require the participation of approximately 140 NICUs. Furthermore, the research ethics is less clear, since parental choice would be reduced.
In September 2017 we applied to the NovoNordicFoundation for a trial planning to involve 50 NICUs to enroll 1600 infants in a pragmatic, individually randomized clinical trial over a period of two years. This was not granted.
In April 2018 the initial trial center costs were funded by Elsass Fonden and we started the work with the goal to start patient recruitment in April 2019. Twenty national coordinators have been identified and 125 NICUs from Europe, China and the US have shown their interest and was included in a application to the medtronics foundation, to cover local GCP expenses and insurance. This was not granted. 
The protocol has been reviewed and approved by all national coordinators, who are now in the process of applying for ethics approval in their respective countries. As for now, 11 NICUs have obtained ethics approval and more will come within the next weeks. 
Oxyprem will have their NIRS devices CE-marked before end of June, and they will have 100 monitors with reusable sensors, availabe for NICUs participating in SafeBoosC. Oxyprem will make direct agreements with principal investgators. 
We are also developing a web-based training and certification system to ensure the competence of clinical staff before the start of the trial.