Pro-urokinase for Extended-Window Posterior Circulation Stroke (PROMISE)

Pro-urokinase for Reperfusion in Acute pOsterior Circulation ischeMIc Stroke in the Extended Window (the PROMISE Trail): A Randomized, Double-blind, Baseline Treatment-controlled Study

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Acute Ischemic Stroke
• Intervention / Treatment: Drug: Aspirin; Drug: rhPro-UK; Drug: placebo; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Estimated): 586
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Bo Song, MD; Phone Number: +86-371-66278068; Email: fccsongb@zzu.edu.cn

Study Locations

• China
  • Henan
    • Zhengzhou, Henan, China
      • Department of Neurology, the First Affiliated Hospital of Zhengzhou University
      • Contact: Bo Song, MD; Phone Number: +86-371-66278068; Email: fccsongb@zzu.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: rhPro-UK group; On Day 1 after randomization, patients will receive intravenous rhPro-UK plus aspirin placebo (300 mg). From day 2 to day 90, patients will receive standard care according to the Chinese Guidelines for Diagnosis and Treatment of Acute Ischemic Stroke (2023).	Drug: rhPro-UK; rhPro-UK (5 mg/vial), to maximum of 35mg; Drug: placebo; Asprin (placebo)
Active Comparator: Control group; On Day 1 after randomization, patients will receive rhPro-UK placebo plus oral aspirin (300 mg). From day 2 to day 90, patients will receive standard care according to the Chinese Guidelines for Diagnosis and Treatment of Acute Ischemic Stroke (2023).	Drug: Aspirin; Asprin (300mg); Drug: Placebo; rhPro-UK(placebo)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Modified Rankin Scale (mRS)	Proportion of subjects of excellent outcome defined as mRS (0-1) at 90 ± 7 days.	90 ± 7 days]

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Modified Rankin Scale (mRS)	Proportion of subjects of excellent outcome defined as mRS (0-2) at 90 ± 7 days.	90 ± 7 days
Modified Rankin Scale (mRS)	Ordinal shift analysis of mRS at 90 days	90 ± 7 days
National Institutes of Health Stroke Scale (NIHSS)	NIHSS change from baseline at 24 hours and 7 days.	24 hours and 7 days
Barthel (BI)	Barthel Index score at 90 ± 7 days.	90 ± 7 days
EuroQol 5-Dimension (EQ-5D)	Quality of life measured by EQ-5D scale at 90 ± 7 days.	90 ± 7 days
Modified Rankin Scale (mRS)	Proportion of subjects of excellent outcome defined as mRS (0-2) at 90 ± 7 days.; Ordinal distribution of mRS at 90 ± 7 days	90 ± 7 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Death	Overall mortality rate at 90 days.	90 days
Symptomatic intracranial hemorrhage (sICH)	Proportion of subjects with symptomatic intracranial hemorrhage (sICH) at 36 hours (according to the ECASS III criteria).	36 hours
Systemic bleeding	Systemic bleeding at 90 days (according to the GUSTO criteria)	90 days
Adverse events (AEs)/ serious adverse events (SAEs)	Proportion of patients with adverse events (AEs)/ serious adverse events (SAEs) within 90 days.	90 days

Collaborators and Investigators

• Sponsor: The First Affiliated Hospital of Zhengzhou University

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): June 30, 2028

Study Registration Dates

• First Submitted: May 26, 2026
• First Submitted That Met QC Criteria: May 26, 2026
• First Posted (Actual): June 1, 2026

Study Record Updates

• Last Update Posted (Actual): June 1, 2026
• Last Update Submitted That Met QC Criteria: May 26, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Recombinant human prourokinase (rhPro-UK); Posterior circulation ischemic stroke; Extended-window thrombolysis; Intravenous thrombolytic therapy
• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Stroke; Ischemic Stroke; Organic Chemicals; Hydrocarbons; Hydrocarbons, Cyclic; Hydrocarbons, Aromatic; Phenols; Benzene Derivatives; Salicylates; Hydroxybenzoates; Aspirin
• Other Study ID Numbers: PROMISE-001

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No