Human Urinary Kallidinogenase Improve Short Term Motor Functional Outcome of Acute Ischemia Stroke Patients

Study Overview
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Brief Summary
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Acute cerebral infarction is a common type of ischemic stroke, causing brain dysfunction in patients with high morbidity and disability. With the changes in people's diet, lifestyle patterns and population aging, the incidence of acute cerebral infarction has increased year by year, which has become an important cause of disability and death in middle-aged and elderly patients. The human urinary kallidinogenase (HUK) was used in China in the management of acute ischemic stroke (AIS) in recent years. However, the mechanism of HUK on AIS has not been systematically investigated. This study aimed to assess the effect of HUK on motor functional outcome and relative corticospinal tract recovery in the patients with AIS. Diffusion tensor imaging(DTI) and diffusion tensor tractography(DTT) have all been used to observe features of cerebral white matter fibrous structures. In addition, diffusion tensor tractography which is used to trace fiber bundle and evaluate white matter fiber bundle integrity and direction is the only non-invasive imaging method to display the corticospinal tract in vivo.

Detailed Description
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A total of 80 AIS patients with the unilateral corticospinal tract damage who were matched for inclusion criterion were enrolled in this randomized controlled trial. The HUK group was administered with HUK and standard treatment(general treatment for anti-platelet, lipid-lowering and improving circulation,etc.), the control group received only standard treatment. Kallikrein+Standard Treatment Group (general Treatment for anti-platelet, lipid-lowering and improving circulation,etc.) and Standard Treatment Group were randomly selected. At admission and discharge, National Institute of Health Stroke Scale(NIHSS), Barthel Index(BI), muscle strength were scored; The DTI were performed and DTT were utilized to reconstruct corticospinal tract to observe its direction and appearance changes then to evaluate the integrity and impairment degree of the corticospinal tract which was divided into four grades according to DTT presented compression, deformation, or rupture. Fractional anisotropy(FA) and apparent diffusion coefficient(ADC) of infarct region and corresponding contralateral normal regions were measured. Blood samples were collected to test serum myelin basic protein(MBP) and vascular endothelial growth factor (VEGF) by enzyme-linked immunosorbent assay (ELISA). The primary endpoint is the short-term motor function prognosis of the AIS patients, we also evaluated the recovery of corticospinal tract and the serum MBP and VEGF changes during treatment in two groups.

Official Title
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Human Urinary Kallidinogenase Improve Short Term Motor Functional Outcome by Reducing the Corticospinal Tract Damage in Acute Ischemia Stroke Patients

Conditions
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Stroke, Acute

Intervention / Treatment
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* Drug: Kallikrein


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years old ≤ age <80 years old; Within 72 hours of onset; Diagnosed as acute cerebral infarction, and confirmed by magnetic resonance imaging as an acute infarct in the unilateral corticospinal tract; The patient's onset muscle strength grade <4; No history of cerebral infarction or residual physical activity disorder; No other intracranial lesions; Patients or their legal representatives voluntarily Sign the informed consent form; Exclusion Criteria: Intracranial hemorrhagic disease: cerebral hemorrhage, subarachnoid hemorrhage, etc.; Transient ischemic attack; Intravenous thrombolysis and interventional thrombectomy; Serious physical illness affects limb movement before enrollment ; Apply other drugs with nutritional nerves and regeneration during the study period; Unstable vital signs, severe liver and kidney diseases or malignant tumors; Incomprehensible or incapable of obeying the research procedure or being unable to follow up due to mental illness, cognitive or emotional disorders;

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Kallikrein+Standard treatment group<br>The Kallikrein+Standard treatment group was given kallikrein through intravenous injection to treatment for 0.15 PNA/day+standard treatment medicine based on the guidelines for the treatment of acute ischemic stroke for 14 ± 5 days. | Drug: Kallikrein<br>* HUK has been approved by China's State Food and Drug Administration as a state category I new drug for the treatment of stroke patients. Based on the available evidence, HUK injection ameliorates neurological deficits and improves long-term outcomes.<br>* Other names: Human urinary kallidinogenase;|
| No Intervention: Standard treatment group<br>The Standard treatment group was only given standard treatment medicine based on the guidelines for the treatment of acute ischemic stroke for 14 ± 5 days. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Myelin Basic Protein (MBP) Comparison Between the Two Groups Before and After Treatment | The effect of Kallikrein on myelin basic protein (MBP) was determined by comparing the changes of MBP before and after treatment between the Kallikrein+Standard treatment group and the standard treatment group. | before (baseline) and after treatment (14 ± 5 days) | 
| Comparison of Vascular Endothelial Growth Factor (VEGF) Before and After Treatment Between the Kallikrein+Standard Treatment Group and Standard Treatment Group | The effect of Kallikrein on vascular endothelial growth factor (VEGF) was judged by comparing the changes of VEGF before and after treatment in the Kallikrein+Standard treatment group and the standard treatment group. | before (baseline) and after treatment (14 ± 5 days) | 
| Changes of Barthel Index(BI) Before and After Treatment in the Two Groups | The Barthel Index(BI) is 0 to 100 points. The higher the score, the better the patient's motor function and behavior. The effect of Kallikrein on Barthel Index was judged by comparing the changes of Barthel Index before and after treatment in the Kallikrein+Standard treatment group and the standard treatment group. | before (baseline) and after treatment (14 ± 5 days) | 
| Changes in Muscle Strength of the Kallikrein+Standard Treatment Group and the Standard Treatment Group Before and After Treatment | Using the recording method of grade 6 muscle strength of 0-5 grade, grade 0 means no muscle contraction, grade 5 means normal muscle strength. The effect of Kallikrein on muscle strength was judged by comparing the changes of muscle strength before and after treatment in the Kallikrein+Standard treatment group and the standard treatment group. | before (baseline) and after treatment (14 ± 5 days) | 
| Changes of National Institute of Health Stroke Scale(NIHSS) Before and After Treatment in the Two Groups | The NIHSS score is 0 to 42 points. The higher the score, the more severe the nerve damage. The change of NIHSS score is calculated as the value at the earlier time point minus the value at the later time point, that is, the value at the time of admission minus the value after the end of treatment, and then the comparison between groups is performed to obtain the current result. | before (baseline) and after treatment (14 ± 5 days) | 
| Change of Fractional Anisotropy Valuev Decline Rate† (FA Decline Rate†) | The FA value is used to express the anisotropy, which indicates the anisotropic component of water molecules accounts for the total value of diffusion tensor,and ranges from 0 to 1, the closer the value is to 1, the better the fiber bundle integrity. †FA decline rate = (FA contralateral- FA ipsilateral) / FA contralateral， Used to compare the FA decline rate† of the two groups after treatment. A more substantial decrease of FA values is believed to represent the most severely ischemic tissue. | After 14 ± 5 days of treatment | 
| Change of Apparent Diffusion Coefficient Value Decline Rate‡（ADC Decline Rate‡） | The ADC value of normal brain tissue is in the range of 0.7-0.9×10﹣³m㎡/s. When the brain tissue is acutely affected, it is mostly decreased, and it is mostly increased in subacute or chronic disease. The upper and lower limits of abnormal changes in ADC value are 0.4-2.5×10﹣³m㎡/s. ‡ ADC decline rate = (ADCcontralateral- ADCipsilateral) / ADCcontralateral；Used to compare the ADC decline rate‡ of the two groups after treatment. A more substantial decrease of ADC values is believed to represent the most severely ischemic tissue. | After 14 ± 5 days of treatment |