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

Phase 2

Completed

• Conditions: Ischemic Stroke
• Interventions: Drug: mutant pro-urokinase; Drug: Alteplase

• Registration Number: NCT04256473
• Lead Sponsor: Erasmus Medical Center

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2019-08-10
• Study First Submitted: 2020-02-03
• Study First Submitted QC: 2020-02-04
• Study First Posted: 2020-02-05
• Primary Completion: 2022-03-26
• Study Completion: 2022-05-26
• Status Verified: 2023-09
• Last Update Submitted: 2023-09-05
• Last Update Posted: 2023-09-07

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 200

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).

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Intervention	mutant pro-urokinase	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).
Control	Alteplase	Usual care with alteplase 0.9 mg/kg in 60 minutes

Primary Outcome Measures

Name	Time	Method
Any intracranial hemorrhage according to the Heidelberg Bleeding Classification on MRI	24-48 hours post-treatment

Secondary Outcome Measures

Name	Time	Method
Infarct volume on MRI	at 24-48 hours
Score on the National Institutes of Health Stroke Scale (NIHSS)	at 24 hours and 5-7 days post-treatment	The NIHSS measures neurological deficit, ranging from 0 to 42, with higher scores indicating more severe neurological deficit.
Score on the modified Rankin Scale (mRS)	at 30 days	The mRS is an ordinal scale ranging from 0 (no symptoms) to 6 (death) measuring the degree of disability or dependence in everyday life.
Symptomatic intracranial hemorrhage (sICH) according to the Heidelberg Bleeding Classification	within 30 days	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.
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,
Death from any cause	Within 30 days
Major extracranial hemorrhage according to the ISTH criteria	within 24 hours of study drug administration

Trial Locations

Locations (1)

DUMAS trial office; 🇳🇱 Rotterdam, Netherlands