Research Design and Approach
The core of this programme is a multi-centre, multi-factorial, randomised, controlled, open-label clinical trial with blinded outcome assessment (PROBE) of ceftriaxone, paracetamol, and metoclopramide in 3800 elderly patients with acute ischaemic stroke or intracerebral haemorrhage. The trial will be performed according to ICH-GCP principles, the Declaration of Helsinki as most recently amended in 2013, and national and international regulatory requirements.
The study population will consist of patients aged 66 years or older with a clinical diagnosis of ischaemic stroke or intracerebral haemorrhage, confirmed with CT or MRI; a score on the National Institutes of Health Stroke Scale (NIHSS) ≥ 6, indicating moderately severe to severe stroke; the possibility to start treatment within 12 hours of symptom onset; and written informed consent. Exclusion criteria are very limited and will include known allergies and contra-indications to the study drugs. The trial will explicitly aim to enrol equal numbers of women and men.
Centres, countries, and local investigators
Patients will be recruited in 80 centres in 9 countries in Europe over a period of three years and 10 months. To increase the generalisability of the findings, these countries are proportionally distributed over Europe, and include Estonia, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, and the United Kingdom. For the same reason, the trial will recruit patients both in academic and regional hospitals.
Before the opening of their site for patient recruitment, each investigator will receive training in trial-specific procedures by the national coordinator and/or trial manager. Investigators will be trained in the mRS assessment using a validated web-based training programme hosted at UGLA.
Randomisation and blinding
Patients will be randomly allocated in a 2x2x2 factorial design to ceftriaxone, paracetamol, metoclopramide, any combination of these, or to ‘standard’ treatment, based on proportional minimisation through a web-based allocation service. To allow blinded assessment of the primary outcome and to enhance statistical power, the score on the mRS at three months will be assessed using a video clip of the mRS interview by three independent adjudicators who are unaware of the treatment allocation.