Dual Thrombolytic Therapy With Mutant Pro-urokinase and Low Dose Alteplase for Ischemic Stroke (DUMAS)

Dual Thrombolytic Therapy With Mutant Pro-urokinase (M-pro-urokinase, HisproUK) and Low Dose Alteplase for Ischemic Stroke

Randomized controlled phase II trial to test the safety and preliminary efficacy of a dual thrombolytic treatment consisting of a small intravenous (IV) bolus of alteplase followed by IV infusion of mutant pro-urokinase against usual treatment with IV alteplase in patients presenting with ischemic stroke.

Study Overview

• Status: Completed
• Conditions: Ischemic Stroke
• Intervention / Treatment: Drug: mutant pro-urokinase; Drug: Alteplase

• Study Type: Interventional
• Enrollment (Actual): 200
• Phase: Phase 2

Contacts and Locations

Study Locations

• Netherlands
  • Rotterdam, Netherlands, 3000 CA
    • DUMAS trial office

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• A clinical diagnosis of ischemic stroke;
• A score of at least 1 on the NIH Stroke Scale;
• CT ruling out intracranial hemorrhage;
• Treatment possible within 4.5 hours from symptom onset or last seen well;
• Meet the criteria for standard treatment for IV alteplase according to national guidelines27;
• Age of 18 years or older;
• Written informed consent (deferred).

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 guidelines27:

  • 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
  • Head 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
  • 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention; Bolus of IV alteplase (5 mg) followed by continuous infusion of HisproUK 40 mg/hr during 60 minutes. Depending on results of interim analyses, the alternate dose may be revised to a lower dose (30mg/hr during 60 minutes) or a higher dose (50mg/hr during 60 minutes).	Drug: mutant pro-urokinase; Intravenous administration; Other Names: HisproUK
Active Comparator: Control; Usual care with alteplase 0.9 mg/kg in 60 minutes	Drug: Alteplase; Intravenous administration; Other Names: Actilyse

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Any intracranial hemorrhage according to the Heidelberg Bleeding Classification on MRI	24-48 hours post-treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Score on the National Institutes of Health Stroke Scale (NIHSS)	The NIHSS measures neurological deficit, ranging from 0 to 42, with higher scores indicating more severe neurological deficit.	at 24 hours and 5-7 days post-treatment
Score on the modified Rankin Scale (mRS)	The mRS is an ordinal scale ranging from 0 (no symptoms) to 6 (death) measuring the degree of disability or dependence in everyday life.	at 30 days
Infarct volume on MRI		at 24-48 hours
Change (pre-treatment vs. post-treatment) in abnormal perfusion volume based on TTP/MTT maps measured with CT perfusion at baseline and MRI		at 24-48 hours post treatment.
Secondary blood biomarkers of thrombolysis: d-dimer levels and fibrinogen levels.		1 hour post-treatment, after 3 hours, and after 24 hours post-treatment,
Symptomatic intracranial hemorrhage (sICH) according to the Heidelberg Bleeding Classification	sICH is defined as any intracranial hemorrhage followed by a neurological deterioration that can be attributed to that hemorrhage, defined as an increase of >= 4 points on the NIHSS or >= 2 points on a specific NIHSS item.	within 30 days
Death from any cause		Within 30 days
Major extracranial hemorrhage according to the ISTH criteria		within 24 hours of study drug administration

Collaborators and Investigators

• Sponsor: Erasmus Medical Center
• Collaborators: DUMAS is sponsored by an unrestricted grant from Thrombolytic Science International, paid to the institution.

Publications and helpful links

General Publications

• van der Ende NAM, Roozenbeek B, Smagge LEM, Luijten SPR, Aerden LAM, Kraayeveld P, van den Wijngaard IR, Lycklama A Nijeholt GJ, den Hertog HM, Flach HZ, Wallace AC, Gurewich V, Del Zoppo GJ, Meurer WJ, Lingsma HF, van der Lugt A, Dippel DWJ; DUMAS Investigators. 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. Trials. 2022 Aug 9;23(1):641. doi: 10.1186/s13063-022-06596-z.

Helpful Links

• DUMAS website

Study record dates

Study Major Dates

• Study Start (Actual): August 10, 2019
• Primary Completion (Actual): March 26, 2022
• Study Completion (Actual): May 26, 2022

Study Registration Dates

• First Submitted: February 3, 2020
• First Submitted That Met QC Criteria: February 4, 2020
• First Posted (Actual): February 5, 2020

Study Record Updates

• Last Update Posted (Actual): September 7, 2023
• Last Update Submitted That Met QC Criteria: September 5, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Randomized Controlled Trial; Ischemic stroke; Intracranial hemorrhage; Thrombolytic treatment; Mutant pro-urokinase
• Additional Relevant MeSH Terms: Pathologic Processes; Necrosis; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Brain Ischemia; Infarction; Brain Infarction; Stroke; Ischemic Stroke; Ischemia; Cerebral Infarction; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Tissue Plasminogen Activator; Saruplase
• Other Study ID Numbers: DUMAS-1.1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No