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

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

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04102956

Enrollment

Registered

2019-09-25

Start date

2017-07-01

Completion date

2019-08-25

Last updated

2021-03-01

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Stroke, Acute

Brief summary

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

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.

Interventions

DRUGKallikrein

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.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 80 Years

Healthy volunteers

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;

Design outcomes

Primary

Measure	Time frame	Description
Change of Fractional Anisotropy Valuev Decline Rate† (FA Decline Rate†)	After 14 ± 5 days of treatment	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.
Myelin Basic Protein (MBP) Comparison Between the Two Groups Before and After Treatment	before (baseline) and after treatment (14 ± 5 days)	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.
Comparison of Vascular Endothelial Growth Factor (VEGF) Before and After Treatment Between the Kallikrein+Standard Treatment Group and Standard Treatment Group	before (baseline) and after treatment (14 ± 5 days)	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.
Changes of Barthel Index(BI) Before and After Treatment in the Two Groups	before (baseline) and after treatment (14 ± 5 days)	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.
Changes in Muscle Strength of the Kallikrein+Standard Treatment Group and the Standard Treatment Group Before and After Treatment	before (baseline) and after treatment (14 ± 5 days)	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.
Changes of National Institute of Health Stroke Scale(NIHSS) Before and After Treatment in the Two Groups	before (baseline) and after treatment (14 ± 5 days)	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.
Change of Apparent Diffusion Coefficient Value Decline Rate‡（ADC Decline Rate‡）	After 14 ± 5 days of treatment	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.

Countries

China

Participant flow

Participants by arm

Arm	Count
Kallikrein+Standard Treatment Group 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.	42
Standard Treatment Group 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.	38
Total	80

Baseline characteristics

Characteristic	Total	Standard Treatment Group	Kallikrein+Standard Treatment Group
ADC value at admission ( Mean±SD)	0.831 m㎡/s STANDARD_DEVIATION 0.162	0.847 m㎡/s STANDARD_DEVIATION 0.081	0.811 m㎡/s STANDARD_DEVIATION 0.209
Age, Continuous	58.675 years STANDARD_DEVIATION 10.4479	60.789 years STANDARD_DEVIATION 9.376	56.762 years STANDARD_DEVIATION 11.096
BI index at admission，Median (IQR)	25 units on a scale	25 units on a scale	25 units on a scale
Coronary heart disease (number, %) With coronary heart disease	8 Participants	5 Participants	3 Participants
Coronary heart disease (number, %) Without coronary heart disease	72 Participants	33 Participants	39 Participants
Diabetes (number, %) Diabetes	28 Participants	13 Participants	15 Participants
Diabetes (number, %) Without diabetes	52 Participants	25 Participants	27 Participants
FA value at admission ( Mean±SD)	0.436 units on a scale STANDARD_DEVIATION 0.484	0.427 units on a scale STANDARD_DEVIATION 0.044	0.441 units on a scale STANDARD_DEVIATION 0.055
Hyperhomocysteinemia (number, %) Hyperhomocysteinemia	32 Participants	14 Participants	18 Participants
Hyperhomocysteinemia (number, %) without hyperhomocysteinemia	48 Participants	24 Participants	24 Participants
Hypertension (number, %) Have hypertension	62 Participants	29 Participants	33 Participants
Hypertension (number, %) Without hypertension	18 Participants	9 Participants	9 Participants
Intracranial arterial stenosis ( number, %) Intracranial arterial stenosis	34 Participants	14 Participants	20 Participants
Intracranial arterial stenosis ( number, %) Without intracranial arterial stenosis	46 Participants	24 Participants	22 Participants
MBP Median (IQR) (pg/ml)	0.56 pg/ml	0.64 pg/ml	0.42 pg/ml
Muscle strength at admission，Median (IQR)	2 units on a scale	2 units on a scale	2 units on a scale
NIHSS score at admission ( Mean±SD)	8.66 units on a scale STANDARD_DEVIATION 3.261	8.05 units on a scale STANDARD_DEVIATION 3.196	9.21 units on a scale STANDARD_DEVIATION 3.258
Previous history of cerebral infarction (number, %) Previous history of cerebral infarction	14 Participants	7 Participants	7 Participants
Previous history of cerebral infarction (number, %) Without the history of cerebral infarction	66 Participants	31 Participants	35 Participants
Race and Ethnicity Not Collected	0 Participants	—	—
Sex: Female, Male Female	28 Participants	16 Participants	12 Participants
Sex: Female, Male Male	52 Participants	22 Participants	30 Participants
Smoking and drink (number, %) No history of smoking or drinking	39 Participants	22 Participants	17 Participants
Smoking and drink (number, %) Smoking and drink	41 Participants	16 Participants	25 Participants
The grade of the severity of corticospinal tract injury ( number, %) Grade 1	12 Participants	6 Participants	6 Participants
The grade of the severity of corticospinal tract injury ( number, %) Grade 2	29 Participants	9 Participants	20 Participants
The grade of the severity of corticospinal tract injury ( number, %) Grade 3	29 Participants	16 Participants	13 Participants
The grade of the severity of corticospinal tract injury ( number, %) Grade 4	10 Participants	7 Participants	3 Participants
VEGF Median (IQR) (pg/ml)	22.46 pg/ml	22.56 pg/ml	22.43 pg/ml

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 42	0 / 38
other Total, other adverse events	0 / 42	0 / 38
serious Total, serious adverse events	0 / 42	0 / 38

Outcome results

Primary

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

Arm	Measure	Value (MEDIAN)
Kallikrein+Standard Treatment Group	Change of Apparent Diffusion Coefficient Value Decline Rate‡（ADC Decline Rate‡）	-0.02 percentage of decline rate
Standard Treatment Group	Change of Apparent Diffusion Coefficient Value Decline Rate‡（ADC Decline Rate‡）	0.03 percentage of decline rate

Primary

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

Arm	Measure	Value (MEDIAN)
Kallikrein+Standard Treatment Group	Change of Fractional Anisotropy Valuev Decline Rate† (FA Decline Rate†)	0.036 percentage of decline rate
Standard Treatment Group	Change of Fractional Anisotropy Valuev Decline Rate† (FA Decline Rate†)	0.09 percentage of decline rate

Primary

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.