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
Authors: van der Ende Nadinda A. M. , Roozenbeek Bob , Smagge Lucas E. M. , Luijten Sven P. R. , Aerden Leo A. M. , Kraayeveld Petra , van den Wijngaard Ido R. , Lycklama à Nijeholt Geert J. , den Hertog Heleen M. , Flach H. Zwenneke , Wallace Alexis C. , Gurewich Victor , del Zoppo Gregory J. , Meurer William J. , Lingsma Hester F. , van der Lugt Aad , Dippel Diederik W. J. ,   on behalf of the DUMAS Investigators, Dippel Diederik , van der Lugt Aad , van der Ende Nadinda , Roozenbeek Bob , de Maat Moniek , Aerden Leo , van den Wijngaard Ido , den Hertog Heleen , Kraayeveld Petra , Lycklama a Nijeholt Geert , Flach Zwenneke , Hill Michael , Rempel Jeremy , Lowe Ann , Lingsma Hester , Nieboer Daan , del Zoppo Gregory , Rijken Dingeman , Cohen Adam , Gurewich Victor , van der Lugt Aad , Smagge Lucas , Sterrenberg Martin , El Ghannouti Naziha , Priem Debby , Batenburg Monique , Ponjee Eva , Eilander Rieke , de Meris Joke , Dofferhoff-Vermeulen Tamara , den Hartog Sanne , Kremer Stijn , Heiligers Leontien , Lansbergen-Engel Angela 
Published: August 2022

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)