A Phase 4 interventional study of Kallikrein in Stroke, Acute, sponsored by The Second Hospital of Hebei Medical University. Completed at 1 site in China. Open to participants aged 18 Years to 80 Years. Per ClinicalTrials.gov, last updated 2021-03-01.
Sponsored by The Second Hospital of Hebei Medical University · Phase 4, Interventional, and Treatment
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.
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.
7,286 studies on the registry are indexed under Stroke; 2,007 are open to participants now.
This study's enrollment of 80 is above the median of 50 across 5,369 interventional studies indexed under Stroke.
Browse Stroke studies →The Second Hospital of Hebei Medical University is the lead sponsor of 21 studies on the registry; 4 are open to participants now.
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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;
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
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.
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.
Also known as: Human urinary kallidinogenase
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: After 14 ± 5 days of treatment
| Milestone | Kallikrein+Standard Treatment Group | Standard Treatment Group |
|---|---|---|
| Started | 42 | 38 |
| Completed | 42 | 38 |
| Not completed | 0 | 0 |
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.
| pg/ml | Kallikrein+Standard Treatment Group | Standard Treatment Group |
|---|---|---|
| Prior treatment | 0.42 (0.23 to 0.80) | 0.64 (0.15 to 1.36) |
| After treatment | 0.41 (0.18 to 0.82) | 0.71 (0.27 to 1.35) |
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.
| ng/ml | Kallikrein+Standard Treatment Group | Standard Treatment Group |
|---|---|---|
| Prior treatment | 22.42 (10.25 to 50.43) | 22.56 (16.06 to 55.24) |
| After treatment | 29.53 (17.31 to 59.68) | 22.91 (9.97 to 47.62) |
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.
| score on a scale | Kallikrein+Standard Treatment Group | Standard Treatment Group |
|---|---|---|
| Changes of Barthel Index(BI) Before and After Treatment in the Two Groups | 17.5 (10 to 30) | 12.5 (5 to 20) |
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.
| score on a scale | Kallikrein+Standard Treatment Group | Standard Treatment Group |
|---|---|---|
| Changes in Muscle Strength of the Kallikrein+Standard Treatment Group and the Standard Treatment Group Before and After Treatment | 1 (0 to 1) | 1 (1 to 2) |
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.
| score on a scale | Kallikrein+Standard Treatment Group | Standard Treatment Group |
|---|---|---|
| Changes of National Institute of Health Stroke Scale(NIHSS) Before and After Treatment in the Two Groups | 2.88 ± 1.35 | 2.16 ± 1.59 |
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.
| percentage of decline rate | Kallikrein+Standard Treatment Group | Standard Treatment Group |
|---|---|---|
| Change of Fractional Anisotropy Valuev Decline Rate† (FA Decline Rate†) | 0.036 (-0.001 to 0.099) | 0.09 (0.05 to 0.16) |
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.
| percentage of decline rate | Kallikrein+Standard Treatment Group | Standard Treatment Group |
|---|---|---|
| Change of Apparent Diffusion Coefficient Value Decline Rate‡（ADC Decline Rate‡） | -0.02 (-0.06 to 0.01) | 0.03 (-0.02 to 0.07) |
Collected over During the hospitalization of all participants within 14 ± 5 days. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Kallikrein+Standard Treatment Group | 0/42 (0%) | 0/42 (0%) | 0/42 (0%) |
| Standard Treatment Group | 0/38 (0%) | 0/38 (0%) | 0/38 (0%) |
| Age, Continuous(years) | Kallikrein+Standard Treatment Group | Standard Treatment Group | Total |
|---|---|---|---|
| Mean | 56.762 ± 11.096 | 60.789 ± 9.376 | 58.675 ± 10.4479 |
| Sex: Female, Male(Participants) | Kallikrein+Standard Treatment Group | Standard Treatment Group | Total |
|---|---|---|---|
| Female | 12 | 16 | 28 |
| Male | 30 | 22 | 52 |
| Race and Ethnicity Not Collected(Participants) | Kallikrein+Standard Treatment Group | Standard Treatment Group | Total |
|---|---|---|---|
| Count of participants | — | — | 0 |
| Hypertension (number, %)(Participants) | Kallikrein+Standard Treatment Group | Standard Treatment Group | Total |
|---|---|---|---|
| Have hypertension | 33 | 29 | 62 |
| Without hypertension | 9 | 9 | 18 |
| Diabetes (number, %)(Participants) | Kallikrein+Standard Treatment Group | Standard Treatment Group | Total |
|---|---|---|---|
| Diabetes | 15 | 13 | 28 |
| Without diabetes | 27 | 25 | 52 |
| Coronary heart disease (number, %)(Participants) | Kallikrein+Standard Treatment Group | Standard Treatment Group | Total |
|---|---|---|---|
| With coronary heart disease | 3 | 5 | 8 |
| Without coronary heart disease | 39 | 33 | 72 |
| Hyperhomocysteinemia (number, %)(Participants) | Kallikrein+Standard Treatment Group | Standard Treatment Group | Total |
|---|---|---|---|
| Hyperhomocysteinemia | 18 | 14 | 32 |
| without hyperhomocysteinemia | 24 | 24 | 48 |
| Previous history of cerebral infarction (number, %)(Participants) | Kallikrein+Standard Treatment Group | Standard Treatment Group | Total |
|---|---|---|---|
| Previous history of cerebral infarction | 7 | 7 | 14 |
| Without the history of cerebral infarction | 35 | 31 | 66 |
10 further baseline measures are reported on the registry.
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The Second Hospital of Hebei Medical University