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

Study Overview
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Brief Summary
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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.

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

Conditions
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Ischemic Stroke

Intervention / Treatment
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* Drug: mutant pro-urokinase
* Drug: Alteplase


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention<br>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<br>* Intravenous administration<br>* Other names: HisproUK;|
| Active Comparator: Control<br>Usual care with alteplase 0.9 mg/kg in 60 minutes | Drug: Alteplase<br>* Intravenous administration<br>* Other names: Actilyse;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Randomized Controlled Trial, Thrombolytic treatment, Intracranial hemorrhage, Mutant pro-urokinase, Ischemic stroke