Efficacy and Safety of Human Urinary Kallidinogenase Combined With Reteplase Intravenous Thrombolysis in the Treatment of Acute Ischemic Stroke (KREATE)

This study is a multicentre, randomized, blinded-endpoint trial that aims to evaluate the efficacy and safety of human urinary kallidinogenase combined with reteplase intravenous thrombolysis in the treatment of acute ischemic stroke

Study Overview

• Status: Not yet recruiting
• Conditions: Acute Ischemic Stroke
• Intervention / Treatment: Other: Clinical Routine Treatment; Drug: Human Urinary Kallidinogenase

Detailed Description

Reteplase intravenous thrombolysis for acute ischemic stroke (AIS) owing to a prolonged half-life and bolus dosing. However, some patients still do not achieve favorable outcomes, likely due to complex pathophysiological processes such as oxidative stress, inflammation, and apoptosis triggered after stroke. Human urinary kallidinogenase primarily acts through the kallikrein-kinin system (KKS). It can improve oxygen supply to ischemic brain tissue, promote the establishment of collateral circulation, alleviate ischemic reperfusion injury, and exert anti-inflammatory and antioxidant effects. Whether its combination with reteplase can further improve neurological recovery in patients without increasing the risk of hemorrhage remains unreported. Therefore, this study aims to investigate the efficacy and safety of combining human urinary kallidinogenase with reteplase in the treatment of AIS.

• Study Type: Interventional
• Enrollment (Estimated): 220
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Guangxian Nan, MD, Ph.D; Phone Number: +86 13404320500; Email: nangx@jlu.edu.cn
• Study Contact Backup: Name: Lumei Chi; Phone Number: +86 181 8681 6316; Email: chilm@jlu.edu.cn

Study Locations

• China
  • Jilin
    • Changchun, Jilin, China, 130033
      • China-Japan Union Hospital of Jilin University
      • Contact: Guangxian Nan; Phone Number: +86 13404320500; Email: nangx@jlu.edu.cn
      • Principal Investigator: Guangxian Nan, MD, Ph.D
      • Sub-Investigator: Lumei Chi

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Meet the diagnostic criteria of the Chinese Guidelines for the Diagnosis and Treatment of Acute Ischemic Stroke 2023
2. Age ≥ 18 years
3. The time from last known well to treatment is within 4.5 hours
4. First-ever ischemic stroke or have history of ischemic stroke but mRS≤1 before onset
5. 6 ≤NIHSS≤ 16
6. Meet the clinical thrombolysis indications in the Chinese Guidelines for the Diagnosis and Treatment of Ischemic Stroke and receive reteplase intravenous thrombolysis
7. Have provided signed written informed consent from the patient or the patient's legal representative

Exclusion Criteria:

1. Preoperative non-contrast head CT shows Alberta Stroke Program Early CT Score (ASPECTS) ≤ 6
2. Presence of contraindications to intravenous thrombolysis
3. Patients who have been on angiotensin-converting enzyme inhibitor (ACEI) drugs and within 5 half-lives (according to the specific drug instructions) before initiate Human Urinary Kallidinogenase treatment
4. Planed for endovascular treatment
5. Patients with fracture, claudication and other factors affecting functional outcome score upon admission
6. Use of Edaravone Injection, Edaravone Dexborneol Injection, Sublingual Edaravone Dexborneol, Butylphthalide Injection or Capsules after the onset of the current episode
7. Severe uncontrolled hypertension: systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 110 mmHg
8. History of severe food or drug allergies, or prior allergy or intolerance to urinary kallidinogenase for injection
9. Pregnant or lactating women, or patients planning pregnancy within 90 days
10. Renal failure or severe renal impairment (creatinine clearance < 30 mL/min) at screening
11. Liver function impairment: Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 times the upper limit of normal, or liver diseases (e.g., acute/chronic hepatitis, cirrhosis)
12. Heart failure (NYHA Class III or IV), unstable angina, acute myocardial infarction, severe arrhythmia, or second/third-degree cardiac conduction obstruction within 6 months before randomization
13. Drug abuse or addiction in the past year
14. Concurrent malignant tumors or severe systemic diseases with an expected survival < 90 days
15. Severe mental disorders or dementia unable to complete the informed consent and follow-up
16. Participation in any interventional drug or device clinical trial within 3 months before screening
17. Patients deemed unsuitable for the study by the investigator

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 group:Human Urinary Kallidinogenase + Clinical Routine Treatment; Intravenous injections of Human urinary kallidinogenase (0.15 PNA units) dissolved in 100 ml of normal saline once a day for 8±1 days	Drug: Human Urinary Kallidinogenase; Intravenous injections of urinary kallidinogenase (0.15 PNA units) dissolved in 100 ml of normal saline, administered via slow intravenous drip over no less than 50 minutes,once a day. The solvent can be increased and/or slowed down according to the patient's condition for 8±1 days; Other Names: KLK; HUK
Other: Control group: Clinical Routine Treatment; Conventional therapy of acute ischemic stroke after based on Chinese guidelines	Other: Clinical Routine Treatment; Conventional therapy of acute ischemic stroke after based on Chinese guidelines

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients with modified Rankin Scale (mRS) 0-1	mRS scores range from 0 to 6. 0=no symptoms,1 = symptoms without clinically significant disability,2 = slight disability,3 = moderate disability,4 = moderately severe disability,5 = severe disability; and 6 = death	90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stroke recurrence rate	Stroke recurrence rate within 90 days	90 days
ordinal distribution of modified Rankin Scale (mRS)	The minimum and maximum values of mRS are 0 and 6, respectively; higher score mean a worse outcome	90 days
Proportion of patients with modified Rankin Scale (mRS) 0-2	The minimum and maximum values of mRS are 0 and 6, respectively; higher score mean a worse outcome	90 days
occurrence of early neurological improvement (ENI)	ENI is defined as more than 4-point decrease in National Institute of Health stroke scale score or NIHSS score ≤ 1	24 、24-48 hours
change of National Institute of Health stroke scale (NIHSS) score	NIHSS ranges from 0 to 42, a low value represents a better outcome	24 、24-48 hours
change in National Institute of Health stroke scale (NIHSS) score	NIHSS ranges from 0 to 42, a low value represents a better outcome	8±1 days
Changes of Barthel index from baseline	Barthel Index is used to assess patients' activities of daily living (ADL), with a total score of 100 points. A higher score indicates better self-care ability	90 days
Proportion of patients with Barthel Index (BI) ≥ 95	Barthel Index is used to assess patients' activities of daily living (ADL), with a total score of 100 points. A higher score indicates better self-care ability	90 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of symptomatic intracranial hemorrhage (sICH)	sICH was defined as any evidence of bleeding on the head computed tomographic scan associated with clinically significant neurological deterioration	48 hours
Rate of any bleeding events	Including skin and mucosal bleeding, gingival bleeding, bleeding at other organ sites, and other types of hemorrhage	8±1 days

Collaborators and Investigators

• Sponsor: China-Japan Union Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2026
• Primary Completion (Estimated): March 1, 2028
• Study Completion (Estimated): June 18, 2028

Study Registration Dates

• First Submitted: March 16, 2026
• First Submitted That Met QC Criteria: March 16, 2026
• First Posted (Actual): March 19, 2026

Study Record Updates

• Last Update Posted (Actual): March 30, 2026
• Last Update Submitted That Met QC Criteria: March 25, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Acute Ischemic Stroke; Human Urinary Kallidinogenase; KLK; Intravenous Thrombolysis; Reteplase; HUK
• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Stroke; Ischemic Stroke
• Other Study ID Numbers: KLK-S029

Drug and device information, study documents

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