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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 2 - 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: 2018-07-01 to 2019-12-31

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 first phase of the project was the preparation of the clinical trial protocol and the related documents as well as the preparation of the trial infrastructure. An appropriately designed trial protocol serves as the basis for a well conducted clinical trial. Therefore, lots of effort has been spent to write the trial protocol properly. Diverse precious suggestions have been discussed intensively within the project management team and have been implemented respectively. In total the trial protocol has been spread within the PROOF consortium for review three times. As especially the informed / deferred consent procedure is quite complex due to the patient population studied within the PROOF trial, discussion focused on risk-benefit assessment.
The protocol was pre-finalized in January 2018 and sent to the ECRIN Scientific Board (SB) for review. SB’s review has been received in March 2018 and the trial protocol has been adapted and finalized accordingly. As soon as the trial protocol was finalized, submission to the regulatory authorities has been performed. Submission has been done within the Voluntary Harmonization Procedure (VHP) including all European Competent Authorities. VHP has been accepted by all countries except for France. In Sweden, deferred consent procedure was not possible due to Swedish law and therefore, Swedish competent authority did not approve the PROOF trial. Regulatory approval within the international step of the VHP could be obtained on 18-JUN-2018 for Germany, Spain, Czech Republic, Belgium and Finland. Afterwards, national submissions have been done within the timeframe of 20 days and by now; regulatory approval has been obtained for Germany and Belgium in early July 2018.
In parallel to the regulatory submission, the PROOF trial has been submitted to the German Ethics Committees in April 2018 and the Spanish Ethics Committee in July 2018. Ethical approval has not been obtained yet.
An electronic case report form has been designed to assess the trial data accordingly and is already available in a prefinal version. Additionally, a prefinal version of the monitoring plan has been set up. To meet the requirements of the Integrated Addendum to Good Clinical Practice (ICH-GCP E6 R2) a risk-based quality management (RBQM) strategy has been implemented. Furthermore a Safety Manual (pharmacovigilance conception) was set up to assure an in-time reporting to the competent authorities and ethics committees if applicable according to local laws and regulations and a permanent and efficient safety monitoring.
Besides the effort put in the design of the trial protocol and the related concepts the following tasks have been performed:
- Kick-off Meeting in Tübingen on January 29th – 30th 2017
- the Project Manual has been created
- the project website has been set up
- the project Risk Management Plan, the PROOF communication and dissemination tools as well as the GEN Requirements were established
- the data collection and reading manual has been finalized
- the SOP for the blood sampling management protocol as well as an educational video were distributed within the consortium
- tender were carried out to choose additional clinical trial units for the PROOF study in Europe
- CTU contracts between Tübingen University Hospital and the Beneficiaries respectively the Beneficiaries and the additional Clinical Trial Units were set up. A Responsibility Split between ECRIN/KKS and the SPONSOR was signed

In summary, all preparations were made to start patient recruitment immediately once the positive ethics vote is received, which we expect in October at the latest. As a high percentage of the stroke patients in our clinics fulfil the inclusion criteria for the trial it is still safe at this time that the number of patients envisaged for the trial will be recruited within the project duration.
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.