Clinical trial NCT04102956
Conditions: Stroke, Acute
Sponsor: The Second Hospital of Hebei Medical University
Start date: 2017-07-01; Completion date: 2019-08-25
Enrollment: 80 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: 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. arm 2: 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.
Interventions: intervention 1: Kallikrein
Intervention descriptions: intervention 1: 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.

Protocol documents:
ICF_001.pdf: 
Human Urinary Kallidinogenase Improve Short Term Motor
Functional Outcome By Reducing The Corticospinal Tract
Damage In Acute Ischemia Stroke Patients
Central Contact Person:Peifang Li
Telephone:
+8615203216570
Department ：Department of Neurology Neurology
Responsible institution：The Second Hospital of Hebei Medical
University
Date：2019.07.15


1
Human Urinary Kallidinogenase Improve Short Term Motor
Functional Outcome By Reducing The Corticospinal Tract
Damage In Acute Ischemia Stroke Patients
Informed Consent
1. Project introduction

Project name: Human urinary kallidinogenase improve short term motor
functional outcome by reducing the corticospinal tract damage in acute ischemia
stroke patients

Human urinary kallidinogenase is a new class of drugs in China. It has a certain
neuroprotective effect, inhibits neuronal apoptosis and acts as nerve repair, which
can promote nerve fiber regeneration and improve prognosis.

Objective: To evaluate of the effect of human urinary kallikrein on corticospinal
tract injury in ischemia stroke patients.

Inclusion Criteria: (1) 18 years old ≤age <80 years old; (2) within 72 hours
of onset; (3) diagnosed as acute cerebral infarction, and confirmed by magnetic
resonance imaging as an acute infarct in the unilateral corticospinal tract; (4) The
patient's onset muscle strength grade <4; (5) no history of cerebral infarction or
residual physical activity disorder; (6) no other intracranial lesions; (7) patients or
their legal representatives voluntarily Sign the informed consent form.

Exclusion Criteria:(1) intracranial hemorrhagic disease: cerebral hemorrhage,
subarachnoid hemorrhage, etc.; (2) transient ischemic attack; (3) intravenous
thrombolysis and interventional thrombectomy; (4) serious physical illness
affects limb movement before enrollment; (5) Apply other drugs with nutritional
nerves and regeneration during the study period; (6) Unstable vital signs, severe
liver and kidney diseases or malignant tumors; (7) Incomprehensible or incapable
of obeying the research procedure or being unable to follow up due to mental
illness, cognitive or emotional disorders;

Study process: This study is expected to last for 2 years. At the time of
admission and after 14±5 days of treatment, the diffusion tensor imaging(DTI) is
performed to evaluate the nerve fiber damage and about 5 ml blood samples will


2
be collected each time, which will be conduct related proteomics tests at the
Second Hospital of Hebei Medical University, and you will get relevant results
after the study. The cost of testing is borne by the project funds.We will keep an
eye on your physical recovery and your health throughout the study.

If you are willing to participate in this study, you will have an equal opportunity
(50%) to be assigned to the experimental or control group. The basic treatment of
both groups is based on the 2016 edition of the Guidelines and Consensus for the
Diagnosis and Treatment of Chinese Cerebrovascular Diseases. If you are in the
thrombolysis time window, you can choose to have intravenous thrombolysis.
2.
Research units and personnel
Department of Neurology, Second Hospital of Hebei Medical University;
Xiaoyun Liu, Chief Physician, Department of Neurology, Second Hospital of Hebei
Medical University;
Peifang Li, Master of Neurology, Second Hospital of Hebei Medical University;
Kun Zhang, Ph.D., Department of Neurology, Second Hospital of Hebei Medical
University;
Xiaoman Shi, Master of Neurology, Second Hospital of Hebei Medical University;
Jing Tian, Master of Neurology, Second Hospital of Hebei Medical University;
Tong Li, Master of Neurology, Second Hospital of Hebei Medical University;
3.
Research benefits:
1. The research doctor will systematically pay close attention to your changes in the
condition, and give the subjects detailed individual medication and exercise guidance
to promote limb recovery; 2. During the visit, the research doctor assists the patient to
make an appointment check, and accepts the patient's consultation free of charge,
facilitating the patient's review and exempting the registration fee.
4.
The study may present discomfort and risk to the subject:
The main risk of subjects participating in the study was the use of research drugs
for adverse reactions such as vomiting, facial flushing and facial fever, headache,
diarrhea, conjunctival hyperemia, palpitation, chest tightness, and itching at the
injection site, but generally lighter, no special treatment is required.There may be
individual patients who may be particularly sensitive to kallikrein and have a blood


3
pressure drop. When the above situation occurs, relevant treatment or withdrawal will
be given in time.
5.
About the cost of participating in the trial:
You are not required to pay an additional fee in addition to the regular related
medical expenses for the illness of the subject.The costs of the drugs and laboratory
tests not related to this study need to be paid normally. If the subjects need to combine
the treatment and examinations required for other diseases, and the cost of switching
to other treatments due to ineffective treatment, normal payment is also required.
6.
If I do not participate in this study, do I have other treatment options?
Participation in this study may improve or not improve the health of the subject. If
the subject does not participate in the study, you may still receive standard treatment
based on the stroke guidelines.
7.
Confidentiality of the study:
The subject's records will be kept in a safe and confidential manner, and the
relevant clinical data and various test results of the subjects will be applied to
anonymous paper presentations and conference exchanges. Subject information may
be subject to surveillance by the relevant authorities (Ethics Committee, Food and
Drug Administration), but will not disclose the identity of the subject.
8.
Related consultation:
If you have any questions related to this study, contact the doctor: Peifang Li
Contact: 15203216570
9.
Subject's rights:
Participation in the study is completely voluntary, the subject can refuse to
participate in the study, or withdraw from the study at any time without any reason,
and the withdrawal from the trial will not have a loss of equity or any punishment.
And the decision does not affect the doctor's treatment of the subject.
The trial protocol was approved by the ethics committee and there were any
violations of the study protocol during the trial. Subjects could complain directly to
the hospital ethics committee. Contact telephone 0311-66002812.
I have read the informed consent form of this clinical trial in detail. My doctor has


4
given me a detailed description of the protocol. I fully understand the purpose, nature,
methods and my rights and risks of this research. I understand that my personal
information is confidential and my privacy can be protected.
I volunteered to participate in this study and agreed to follow the research method
and cooperate with the doctor to complete the study.
This informed consent is 3 pages in total and I will get a copy of the signed
informed consent form.
Subject signature:
Signature of the legal representative of the subject (if necessary):
Date:
I have fully explained to the subject the purpose of the clinical trial, the course of
operation, and the potential risks and benefits that the subject may have in the trial,
and satisfactorily answered all relevant questions of the subject.
Signature of the principal investigator or his designated researcher (informer to the
subject):
Date:

Prot_002.pdf: 
Human Urinary Kallidinogenase Improve Short Term Motor
Functional Outcome By Reducing The Corticospinal Tract
Damage In Acute Ischemia Stroke Patients
Central Contact Person:Peifang Li
Telephone:
+8615203216570
Department ：Department of Neurology
Responsible institution：The Second Hospital of Hebei Medical
University
Date：2019.07.15


1
Study Protocol

Project name: Human urinary kallidinogenase improve short term motor
functional outcome by reducing the corticospinal tract damage in acute ischemia
stroke patients

Background and Purpose: 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 the treatment of AIS has not been
systematically investigated. This study aimed to assess the effect of HUK on
motor functional outcome and relative corticospinal tract damage recovery in the
patients with AIS.

The research participants：The AIS patients in the Neurology Department of the
Second Hospital of Hebei Medical University, North China, from July 2017 to
March 2019 were eligible for inclusion according to the inclusion criteria below,
The acute ischemic stroke diagnosis conformed to "Guidelines for the Diagnosis
and Treatment of Acute Ischemic Stroke in China 2014". This study was
approved by the Ethics Committee of the Second Hospital of Hebei Medical
University (2018-P023).
Inclusion and exclusion criteria
Inclusion Criteria: (1) The enrollment age was between 18 and 80 years old; (2)
Within 72 hours of onset; (3) Diagnosed as acute ischemic stroke, and confirmed
by MRI as an acute infarct with the unilateral corticospinal tract damage; (4) The
patients’ muscle strength of paralyzed side at the admission was below or equal
to grade 4; (5) No history of cerebral infarction, or with cerebral infarction
history but without residual physical activity disorder; (6) No other intracranial


2
lesions; (7) The patients or their surrogates voluntarily sign the informed
consent.
Exclusion Criteria:
(1) Intracranial hemorrhagic disease include cerebral
hemorrhage, subarachnoid hemorrhage, etc; (2) Transient ischemic attack; (3)
Intravenous thrombolysis and interventional thrombectomy; (4) Serious physical
illness affects limb movement before enrollment; (5) Apply other neurotrophic
and promote nerve regeneration drugs through the trial; (6) Unstable vital signs,
severe liver and kidney diseases or malignant tumors; (7) Inability to understand
and/or comply with the study procedures and/or follow-up due to mental
disorders or emotional disorders.

Therapy：With the random number table method, the patients were consecutively
enrolled and divided into two groups: the HUK group and the control group. All
patients were treated with standard therapy based on the Guideline, besides, the
HUK group were given the HUK (Guangdong tianpu biochemical pharmaceutical
co. LTD, National drug approval no. H20052065) for injection (0.15PNA diluted
in 100ml physiological sodium chloride solution, 1 time/day, intravenous infusion)
within 24 hours after admission. Both groups were treated continuously for 14 ±
5 days.

Data collection：At admission and discharge, 2-3ml venous blood was collected,
blood samples were centrifuged and serum were collected, the concentrations of
VEGF and MBP were tested by ELISA (Wuhan Servicebio Technology Co., Ltd).
At the same time, National Institute of Health Stroke Scale(NIHSS), Barthel


3
Index(BI), muscle strength were also assessed. Both groups underwent a brain
MRI within 72h of onset and 14±5 days after treatment. The sequences included
the axial and sagittal T2WI sequence (TR/TE, 5000/89 ms), the axial T1WI
sequence (TR/TE, 500/8.4 ms), and the axial T2 FLAIR (Fluid-attenuated
Inversion-recovery) sequence (TR/TE/TI, 9000/89ms), axial DWI sequence. The
diffusion tensor imaging (DTI) examination adopted single excitation SE-EPI
sequence, TR/TE: 3138/60 ms. DTI were performed to record the Dffusion
Tensor
Tractography(DTT)
classification,
Fractional
anisotrophy(FA)
and
Apparent Diffusion Coefficient(ADC) parameters were to evaluate the injury
degree of the corticospinal tract; The decline rate (the decline rate = [contralateral
side - ipsilateral side ] / contralateral side) was obtained, ΔFA and ΔADC
represent the decline rate of the second time minus the first time. The severity of
the corticospinal tract injury evaluated by DTT was classified as: Grade 1, with
complete corticospinal tract; Grade 2, the corticospinal tract was slightly injured
with the injury less than 50%. Grade 3, moderate corticospinal tract injury with
the injury between 50%~75%; Grade 4, severe corticospinal tract injury, almost
interrupted more than 75%. Besides, the Magnetic resonance angiography(MRA)
was also performed, for persons with intracranial arteries≥70% were diagnosed
as severe stenosis.
Primary outcome is the short-term motor function prognosis of the AIS patients in
two groups, secondary outcomes are the recovery of corticospinal tract and the
serum MBP and VEGF changes during treatment.

SAP_003.pdf: 
Human Urinary Kallidinogenase Improve Short Term Motor
Functional Outcome By Reducing The Corticospinal Tract
Damage In Acute Ischemia Stroke Patients
Central Contact Person:Peifang Li
Telephone:
+8615203216570
Department ：Department of Neurology
Responsible institution：The Second Hospital of Hebei Medical
University
Date：2019.07.15


1
Statistical Analysis Plan

Project name: Human urinary kallidinogenase improve short term motor
functional outcome by reducing the corticospinal tract damage in acute ischemia
stroke patients

Purpose: This study aimed to assess the effect of Human urinary kallidinogenase
on motor functional outcome and relative corticospinal tract damage recovery in
the patients with AIS.

Statistical analysis：The categorical variables were e܀pressed as freTuencies and
percentages戴and the radios were compared by the Ȥ or )isher e܀act test
continuous variables were e܀pressed as means  standard deviation S' and
were compared by Student¶s t test. 1onQnormally distributed continuous variables
were presented as median interTuartile range and compared between groups
using 0annQ:hitney 8 test for independent samples and :ilco܀on test for
compared samples. 3䇅. was considered to indicate a statistically significant
difference between values. The Spearman bivariate correlation was used to
e܀amine relationships between 1IHSS戴m5S戴%I scores at discharge and initial
9扨᡼)戴0%3 concentrations戴'TT classification戴se܀戴age戴previous stroke戴
intracranial arterial stenosis戴comorbidities戴)A values戴A'᡼values. 9ariables
with 3
.1 were entered into the multivariable linear regression with the
discharge 1IHSS戴m5S戴%I scores as dependent variable and the intercept set to
the origin. The measurement data were analyed by the S3SS 1. statistical
analytical software I%0戴Armonk戴1<戴8SA.