Dual thrombolytic therapy with mutant pro-urokinase and small bolus alteplase for ischemic stroke (DUMAS): study protocol for a multicenter randomized controlled phase II trial

Abstract

Background: The effectiveness of alteplase for ischemic stroke treatment is limited, partly due to the occurrence of intracranial and extracranial hemorrhage. Mutant pro-urokinase (m-proUK) does not deplete fibrinogen and lyses fibrin only after induction with alteplase. Therefore, this treatment has the potential to be safer and more efficacious than treatment with alteplase alone. The aim of this study is to assess the safety and efficacy of thrombolytic treatment consisting of a small bolus alteplase followed by m-proUK compared with standard thrombolytic treatment with alteplase in patients presenting with ischemic stroke.

Methods: DUMAS is a multicenter, phase II trial with a prospective randomized open-label blinded end-point (PROBE) design, and an adaptive design for dose optimization. Patients with ischemic stroke, who meet the criteria for treatment with intravenous (IV) alteplase can be included. Patients eligible for endovascular thrombectomy are excluded. Patients are randomly assigned (1:1) to receive a bolus of IV alteplase (5mg) followed by a continuous IV infusion of m-proUK (40 mg/h during 60 min) or usual care with alteplase (0.9 mg/kg). Depending on the results of interim analyses, the dose of m-proUK may be revised to a lower dose (30 mg/h during 60 min) or a higher dose (50 mg/h during 60 min). We aim to include 200 patients with a final diagnosis of ischemic stroke. The primary outcome is any post-intervention intracranial hemorrhage (ICH) on neuroimaging at 24 h according to the Heidelberg Bleeding Classification, analyzed with binary logistic regression. Efficacy outcomes include stroke severity measured with the National Institutes of Health Stroke Scale (NIHSS) at 24 h and 5-7 days, score on the modified Rankin scale (mRS) assessed at 30 days, change (pre-treatment vs. post-treatment) in abnormal perfusion volume, and blood biomarkers of thrombolysis at 24 h. Secondary safety endpoints include symptomatic intracranial hemorrhage, death, and major extracranial hemorrhage. This trial will use a deferred consent procedure.

Discussion: When dual thrombolytic therapy with a small bolus alteplase and m-proUK shows the anticipated effect on the outcome, this will lead to a 13% absolute reduction in the occurrence of ICH in patients with ischemic stroke.

Trial registration: NL7409 (November 26, 2018)/NCT04256473 (February 5, 2020).

Keywords: Alteplase; Ischemic stroke; Mutant pro-urokinase; Randomized controlled trial; Thrombolytic treatment.

Fig. 1

Trial logo

Fig. 2

SPIRIT figure. mRS indicates modified Rankin scale; NIHSS, National Institutes of Health Stroke Scale; SAE, serious adverse events. *t₋₁: directly before randomization, t₀: randomization, t₁ = directly after randomization; t₂ = at 1 h; t₃ = at 3 h; t₄ = at 24 h; t₅ = at 5–7 days or at discharge if earlier; t₆ = at 30 days. **Informed consent: as early as deemed possible after IV thrombolysis. ***Administration of IV thrombolytic therapy directly after randomization. ****Neuro-imaging at baseline consists of non-contrast CT, CT-perfusion, and CT-angiography or brain MRI and MRA. Neuro-imaging at 24 h consists preferably of a brain MRI