DUMAS is a multicenter, phase II, randomized clinical trial with open-label treatment, adaptive design for dose optimization and blinded outcome assessment, comparing a low dose IV alteplase followed by IV m-pro-urokinase with usual thrombolytic treatment of alteplase alone.
We aim to enroll 200 patients with a discharge diagnosis of ischemic stroke. To account for inclusion of patients with a discharge diagnosis other than ischemic stroke (e.g. stroke mimic), we will include one extra patient for each included patient with a discharge diagnosis other than ischemic stroke. Eligibility criteria are listed below.
DUMAS Inclusion criteria
- A clinical diagnosis of ischemic stroke
- A score of at least 1 on the NIH Stroke Scale
- CT or MRI ruling out intracranial hemorrhage
- Treatment possible for patients who: 1) can be treated within 4.5 hours from symptom onset or last seen well, or 2) can be treated between 4.5 to 12 hours from symptom onset or last seen well and have an infarct core ≤ 25 mL and have a penumbra of at least the same size as the infarct core (i.e. total ischemic volume/infarct core mismatch ≥ 2.0), or 3) have an unknown time of onset and a mismatch between diffusion-weighted imaging and FLAIR
- Meet the criteria for standard treatment for IV alteplase according to national guidelines
- Written informed consent (deferred)
A potential subject who meets any of the following criteria will be excluded from participation in this study:DUMAS exclusion criteria
|- Candidate for endovascular thrombectomy (i.e., a proximal intracranial large artery occlusion on CTA)|
|- Contra-indication for treatment with IV alteplase according to national guidelines:|
- Arterial blood pressure exceeding 185/110 mmHg and not responding to treatment
- Blood glucose less than 2.7 or over 22.2 mmol/L
- Cerebral infarction in the previous 6 weeks with residual neurological deficit or signs of recent infarction on neuro-imaging
- concussionHead trauma in the previous 4 weeks
- Major surgery or serious trauma in the previous 2 weeks
- Gastrointestinal or urinary tract hemorrhage in the previous 2 weeks
- Previous intracerebral hemorrhage
- Use of anticoagulant with INR exceeding 1.7 or APTT exceeding 50 seconds
- Known thrombocyte count less than 90 x 109/L. When the treating physician suspects a thrombocyte count below 90x109/L (e.g. suspected hemorrhagic diathesis), the thrombocyte count in the laboratory should be awaited prior to inclusion in DUMAS.
- Treatment with direct thrombin or factor X inhibitors, unless specific antidotum has been given, i.e. idarucizumab in case of dabigatran use.
|- Pre-stroke disability which interferes with the assessment of functional outcome at 90 days, i.e. mRS > 2|
|- Known pregnancy or if pregnancy cannot be excluded, i.e. did not have intercourse for > 6 months and no clinical signs of pregnancy, adequate use of any contraceptive method (e.g. intrauterine devices) or sterilization of the subject herself.|
|- Contra-indication for an MRI scan, i.e.:|
- an MRI incompatible pacemaker, ICD, pacing wires and loop records
- metallic foreign bodies (e.g. intra-ocular)
- prosthetic heart valves
- blood vessel clips, coils or stents
- an implanted electronic and/or magnetic implant or pump (e.g. neurostimulator)
- cochlear implants
- mechanical implants (implanted less than 6 weeks ago)
- a copper intrauterine device
|- Current Participation in any medical or surgical therapeutic trial other than DUMAS (or MR ASAP or ARTEMIS).|
Randomisation and treatment
Patients will be randomly allocated to dual thrombolytic treatment with low dose alteplase followed by mutant pro-urokinase or alteplase alone (standard care) by a computer- and web-based procedure.
The primary outcome is any post-intervention intracranial hemorrhage on MRI according to the Heidelberg Bleeding Classification within 24-48 hours of study drug administration.