Research Design and Approach
The core of this project was a multi-centre, multi-factorial, randomised, controlled, open-label clinical trial with blinded outcome assessment (PROBE) of ceftriaxone, paracetamol, and metoclopramide in at least 2500 elderly patients with acute ischaemic stroke or intracerebral haemorrhage. The trial was 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 consisted 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 24 hours of symptom onset; and written informed consent. Exclusion criteria were very limited and included known allergies and contra-indications to the study drugs. The trial explicitly aimed to enrol equal numbers of women and men.
Centres, countries, and local investigators
Patients were recruited in 68 centres in 9 countries in Europe over a period of 75 months. To increase the generalisability of the findings, these countries were proportionally distributed over Europe, and included Estonia, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, and the United Kingdom. For the same reason, the trial recruited patients both in academic and regional hospitals.
Before the opening of their site for patient recruitment, each investigator received training in trial-specific procedures by the national coordinator and/or trial manager. Investigators were trained in the mRS assessment using a validated web-based training programme hosted at UGLA.
Randomisation and blinding
Patients were 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 was assessed using a video clip of the mRS interview by three independent adjudicators who were unaware of the treatment allocation.
Treatment allocation was based on proportional minimisation.