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Penumbral Rescue by Normobaric O=O Administration in Patients With Ischaemic Stroke and Target Mismatch ProFile: A Phase II Proof-of-Concept Trial

Periodic Reporting for period 3 - PROOF (Penumbral Rescue by Normobaric O=O Administration in Patients With Ischaemic Stroke and Target Mismatch ProFile: A Phase II Proof-of-Concept Trial)

Reporting period: 2020-01-01 to 2021-06-30

An ischaemic stroke is the most common type of stroke and a leading cause of mortality and morbidity in the world. The arteries that supply the brain with blood become clogged by clots. This kills the cells at the centre of the stroke and puts those nearby at great risk. The longer the brain suffers from oxygen and blood deficiency, the more serious the consequences, and the more brain tissue will die. Emergency treatment must therefore get rid of the blocked arteries as quickly as possible.
Within PROOF twelve clinical centres in eight European countries will test whether the consequences of stroke can be reduced by rapidly applying high-dose oxygen therapy.
The high-dose oxygen therapy is very simple and low-cost. The patient, after having been diagnosed with an ischemic stroke after their scan, wears a mask through which they inhale almost pure oxygen at a flow of 40 litres per minute. This keeps the oxygen content in the blood as high as it can be.
The aim is to ensure that the surrounding brain tissue at risk, which will have less oxygen but is not yet dead, is stabilized by the high oxygen content coming in. This continues until the clot is removed and the blood circulation is improved again. The treatment therefore aims at the so-called “shadow zones” of the stroke, sometimes called the “rescue zones”. These may include the entire stroke area in some patients.
PROOF is the first trial to thoroughly investigate high-dose oxygenation in stroke patients. If it proves that the brain can be saved by this, it could also bring great benefits to patients who are not near a clinic where stroke can be treated and who have longer access times to emergency care.
The main work performed in the third period of the project were two adaptions of the clinical trial protocol and related documents in order to facilitate recruitment as well as the prepara-tion of the trial infrastructure in all participating European PROOF centers as well as the initia-tion of those study centers that received ethical approval for study participation.
The first study initiation visit, i.e. of Tübingen University Hospital, was conducted on 19.07.2019. The majority of German centers were initiated between July 2019 and October 2019 followed by one last initiation in July 2020 (Heidelberg). The study centers in Belgium, Czech, Finland and Spain were initiated between July 2020 and October 2020.
In order to address Covid-19 pandemic associated restrictions and to further improve the better-than-before but still not sufficient recruitment with protocol version 1.3 the PROOF Scientific Advisory Board was consulted and a subsequent amendment with inclusion criteria adapted to incorporate the most recent European and inter-national acute ischemic stroke guideline recommendations of the European Society of Minimal-ly Invasive Neurological Therapy (ESMINT) and European Stroke Organisation (ESO) as well as the American Heart Association / American Stroke Association (AHA/ASA). Above all, the chang-es made to the protocol included the possibility of enrolling patients with wake-up stroke, pa-tients with ASPECTS of 6, patients with a modified Rankin Scale score of 2, and the no longer mandatory perfusion imaging at baseline, a simplified trial schedule (including the biomarker sub-study), a less strict definition of the impartial witness and the possibility of remote monitoring in order to allow the study conduct during the Covid-19 pandemic. Besides, the risk benefit section was updated considering the most recent literature including a Chinese study on post-thrombectomy normobaric hyperoxygenation that showed highly promising results.

Main results achieved in period 3:
- Extensive risk-benefit-analysis conducted. Country-specific adapted complex ICF development
- All regulatory and ethical approvals obtained so far - only the approval for Switzerland is pending
- Monitoring Concept has been updated; Online-Moitoring-Visits have been added
- Revision of the eCRF
- Preparation of complex worksheets to simplify the enrolment of patients for the study sites and to improve the process of data generation
- Update of all training materials
- Regular Newsletter have been sent out
- Online-Consortium-Meetings and Board-Meetings have been carried out
The trial’s overall objective can be summarised as follows: to demonstrate in a prospective, multicentre adaptive phase IIb, parallel-group, randomised (1:1), standard treatment-controlled, open-label, clinical trial with blinded endpoint assessment (PROBE design) that NBHO-treatment in the setting of ischaemic stroke with imaging-based identification of salvageable penumbra will lead to a decrease in infarct growth from baseline to 24h follow up (as compared with the control group) and will not be associated with an increased rate of clinically significant adverse events.
The specific objectives of the project depend on the trial protocol; therefore, only when the recruitment phase has started any achievements can be obtained.
Based on a successful trial, it can be foreseen that PROOF will create a scale of impacts comprising:
- Improvement of health and quality of life for stroke patients,
- Scientific impacts for the researchers and clinicians working in the field - the PROOF trial results will be published in a peer reviewed journal with high impact (e.g. Neurology or higher)
- Healthcare impact for clinicians and rehabilitation professionals treating stroke patients – NBHO treatment will generate better treatment and rehabilitation outcomes, and
- Socio-economic impact on the health care system – improved patient outcomes will reduce healthcare costs and will also benefit society through early return of people with stroke to work
At this stage of the project these scale of impacts are still valid and there is no need to change them in any way.