MR ASAP Study design
Design
MR ASAP is a phase III, multicentre, prospective, randomised, open-label clinical trial with blinded endpoint assessment (PROBE) of transdermal GTN in a dose of 5 mg/day for one day in 1400 patients with suspected stroke.
Patient population
The study population will consist of adult patients in whom the attending paramedic makes the probable diagnosis of acute stroke with a moderately severe to severe deficit. Eligibility criteria are listed below. These criteria are checked by the paramedic in the ambulance and the exclusion criteria should be checked again upon arrival to the hospital, by the treating physician. If an exclusion criterion appears to have been missed by the paramedic, the GTN patch (if randomised to GTN) should be removed.
| Inclusion criteria |
| Age ≥ 18 years |
| Probable diagnosis of acute stroke, as assessed by the paramedics in the prehospital setting |
| Score of 2 or 3 on the Face Arm Speech Test (FAST) |
| Systolic blood pressure ≥ 140 mm Hg |
| Possibility to start the trial treatment within 3 hours of symptom onset |
| Intention to transport the patient to one of the participating hospitals |
| Wirtten informed consent (deferred) |
| Exclusion criteria |
| Considerable pre-stroke dependency in activities of daily living, defined as staying in a chronic nursing home or rehabilitation centre |
| Known pregnancy or lactation |
| Indication for acute treatment with nitroglycerin or knwon use of nitroglycerin in the previous 12 hours |
| Known hypersensitivity to nitroglycerin, nitrates in general or adhesiv used in the past |
| Glasgow Coma Scale < 8 |
| Known with any of the following heart disorders: myocardial insufficiency due tot obstruction; aortis or mitral valve stenosis; constrictive pericarditis; hypertrophic obstructive cardiomyopathy; cardiac tamponade |
| Known marked anaemia, defined as haemoglobin < 5 mmol/l |
| Known closed angle glaucoma |
| Known use of phosphodiesterase type-5 inhibitors (e.g. sildenafil) |
Randomisation and treatment
Patients will be randomly allocated to open-label GTN (5 mg/24 hours) administered as a transdermal patch by paramedics in the prehospital setting within 3 hours of stroke onset and continued for 24 hours in addition to standard care, or to standard care alone. Randomisation will be through a secure web-based electronic application, which has real-time data validation. If patients are randomised to treatment with GTN but prove not to have a transient ischaemic attack (TIA) or stroke after examination in the hospital, the patch will be removed.
Primary outcome
The main study outcome is the score for functional outcome on the modified Rankin Scale (mRS) at 90 (± 14) days, analysed with ordinal logistic regression.
Informed consent
This study evaluates a treatment initiated by paramedics as soon as possible after stroke onset. Since most patients with acute neurological deficits are not capable of decision making, and to reduce treatment delays, MR ASAP uses a deferred informed consent procedure, in line with Dutch law (Dutch Medical Research (Human Subjects) Act: 6,4). This implicates that patients are included and may receive the GTN patch in the ambulance before consent is obtained. Written informed consent should be obtained as soon as possible, preferably within 24 hours after hospital admission. In patients randomised to GTN who decline to participate, study medication will be stopped immediately.