Acute Ischemic Stroke
Conditions
Keywords
Recombinant human prourokinase (rhPro-UK), Posterior circulation ischemic stroke, Extended-window thrombolysis, Intravenous thrombolytic therapy
Brief summary
This study aims to evaluate whether, in patients with imaging-confirmed acute ischemic stroke of the posterior circulation presenting within 4.5-24 hours after symptom onset and not scheduled for endovascular thrombectomy, intravenous thrombolysis with recombinant human prourokinase (rhPro-UK), compared with standard medical treatment, can achieve superior 90-day functional outcomes with a higher level of safety.
Detailed description
Stroke is the second leading cause of death and the third leading cause of disability worldwide. Posterior circulation ischemic stroke (PCIS) accounts for approximately 20% of all ischemic strokes. Due to involvement of critical structures such as the brainstem and cerebellum, PCIS is associated with rapid neurological deterioration, high disability and mortality rates, and often presents with atypical clinical manifestations, leading to frequent misdiagnosis and delayed treatment. Consequently, many patients miss the conventional 4.5-hour intravenous thrombolysis window. However, the posterior circulation possesses relatively abundant collateral circulation and stronger ischemic tolerance, resulting in a lower risk of intracranial hemorrhage after thrombolysis and suggesting the potential feasibility of an extended therapeutic window. In recent years, multiple studies have promoted a paradigm shift in acute ischemic stroke management from a "time window"-based strategy to a "tissue window"-based strategy. Trials including EXTEND, TRACE-III, HOPE, and OPTION demonstrated that intravenous thrombolysis administered within 4.5-24 hours after symptom onset, guided by perfusion imaging selection, could still improve functional outcomes. The EXPECTS study further showed that patients with posterior circulation stroke who were not candidates for endovascular thrombectomy could benefit from alteplase treatment within 4.5-24 hours, with a relatively low risk of symptomatic intracranial hemorrhage. Nevertheless, limitations such as a high proportion of mild stroke cases, non-randomized study design, and baseline imbalance indicate that stronger evidence is still required. Recombinant human prourokinase (rhPro-UK), a novel fibrin-specific thrombolytic agent independently developed in China, has advantages over rt-PA, including lower systemic fibrinolytic activation and reduced bleeding risk, making it potentially more suitable for extended-window thrombolysis. The PROST-2 trial demonstrated that rhPro-UK was non-inferior to rt-PA in efficacy among patients treated within 4.5 hours after acute ischemic stroke onset, while significantly reducing symptomatic intracranial hemorrhage and systemic bleeding events, highlighting its favorable safety profile and potential for extended-window application. Therefore, this study aims to evaluate whether intravenous thrombolysis with rhPro-UK, compared with standard medical therapy, can achieve better 90-day functional outcomes and improved safety in patients with imaging-confirmed posterior circulation acute ischemic stroke presenting within 4.5-24 hours after symptom onset and not scheduled for endovascular thrombectomy.
Interventions
DRUGrhPro-UK
rhPro-UK (5 mg/vial), to maximum of 35mg
DRUGplacebo
Asprin (placebo)
DRUGAspirin
Asprin (300mg)
DRUGPlacebo
rhPro-UK(placebo)
Sponsors
The First Affiliated Hospital of Zhengzhou University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Experimental group: On Day 1 after randomization, recombinant human prourokinase (rhPro-UK) plus placebo for aspirin (300 mg). On Day 2, standard treatment as recommended by the Chinese Guidelines for Diagnosis and Treatment of Acute Ischemic Stroke (2023). Control group: On Day 1 after randomization, rhPro-UK placebo plus aspirin (300 mg). On Day 2, standard treatment as recommended by the Chinese Guidelines for Diagnosis and Treatment of Acute Ischemic Stroke (2023).
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥ 18 years; 2. AIS with symptom onset 4.5-9 hours before enrollment, including wake-up stroke and unwitnessed stroke (onset time defined as when symptoms were first noticed); 3. Imaging criteria: 1. DWI-FLAIR mismatch: visible lesion on DWI with no marked visible lesion on FLAIR; 2. DWI infarct core not exceeding one-third of the middle cerebral artery territory, one-half of the anterior cerebral artery territory, or one-half of the posterior cerebral artery territory; 4. NIHSS score 4-25; 5. First-ever stroke or previous stroke without significant disability (pre-stroke mRS ≤ 1); 6. Signed informed consent from the patient or legally authorized representative.
Exclusion criteria
1. Planned endovascular treatment; 2. Contradictory to MRI examination; 3. MRI image not qualified for evaluation; 4. Serious neurological deficits before onset (mRS≥2); 5. Obvious head injuries or strokes within 3 months; 6. Subarachnoid or intracranial hemorrhage; 7. History of intracranial hemorrhage; 8. Intracranial tumor, arteriovenous malformation or aneurysm; 9. Intracranial or spinal cord surgery within 3 months; 10. Active internal hemorrhage; 11. platelet count of \<100000/mm3; 12. Aortic arch dissection; 13. Heparin therapy within 24 hours; 14. Oral warfarin is being taken and INR\>1.6 or APTT abnormal; 15. Oral anticoagulation therapy; 16. Systolic pressure≥185 mmHg or diastolic pressure≥110 mmHg; 17. Blood glucose \< 50 mg/dl (2.7mmol/L); 18. Pregnancy; 19. Neurological deficit after epileptic seizures; 20. Major surgery within 1 month; 21. Gastrointestinal or urinary tract hemorrhage within the previous 30 days; 22. Myocardial infarction within 3 months; 23. Allergy to study drugs; 24. Unlikely to adhere to the trial protocol or follow-up; 25. Any condition that, in the judgment of the investigator could impose hazards to the patient if study therapy is initiated or affect the participation of the patient in the study; 26. Participation in other interventional clinical trials within the previous 3 months.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Modified Rankin Scale (mRS) | 90 ± 7 days] | Proportion of subjects of excellent outcome defined as mRS (0-1) at 90 ± 7 days. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Modified Rankin Scale (mRS) | 90 ± 7 days | Proportion of subjects of excellent outcome defined as mRS (0-2) at 90 ± 7 days. |
| National Institutes of Health Stroke Scale (NIHSS) | 24 hours and 7 days | NIHSS change from baseline at 24 hours and 7 days. |
| Barthel (BI) | 90 ± 7 days | Barthel Index score at 90 ± 7 days. |
| EuroQol 5-Dimension (EQ-5D) | 90 ± 7 days | Quality of life measured by EQ-5D scale at 90 ± 7 days. |
Countries
China
Contacts
CONTACTBo Song, MD
Outcome results
None listed