Study on the Effect of Tongyuan Acupuncture on Consciousness Disorder After Stroke
Phase: NA
Conditions: Stroke
Sponsor: Nanfang Hospital, Southern Medical University

 
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Clinical study protocol 
 
project name：  Tongyuan acupuncture on consciousness disorder after stroke                 
version number/date：           V2.0/2023-10-8                                      
major investigators                                                     
applicant：            Nanfang Hospital, Southern Medical University                      
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Summary of research scheme 
scheme name 
Study on the effect of Tongyuan acupuncture on consciousness 
disorder after stroke 
applicant 
Nanfang Hospital, Southern Medical University 
major 
investigators 
 
research center 
Department of Rehabilitation, Nanfang Hospital, Southern Medical 
University 
research object 
Stroke patients with conscious disturbance 
purpose of 
research 
Objective: To investigate whether Tongyuan acupuncture can 
improve the consciousness disorder after stroke 
Secondary objective: To investigate the possible mechanism of 
action 
Research 
grouping 
Trial group: Tong Yuan acupuncture, once a day, 5 days a week 
for 4 consecutive weeks.Twenty days in total. 
Control group: pseudoacupoint method, once a day, 5 days a week 
for 4 consecutive weeks.Twenty days in total. 
study design 
This study was a randomized, placebo-controlled, single-blind 
study.Patients with post-stroke consciousness disorder hospitalized in 
the rehabilitation Department of Southern Hospital were randomly 
included into the experimental group and the control group, and the 
experimental group was treated with Tongyuan acupuncture on the 
basis of routine rehabilitation treatment and drug treatment.The 
control group was treated with 1cm acupuncture at the same depth 
beside the selected points of the experimental group. Before 
intervention, treatment for 1 week, treatment for 2 weeks, treatment 
for 3 weeks, and treatment for 4 weeks (after completion), 
follow-up:GCS score, CRS-R scale (Modified Coma Recovery 
Scale) were performed 4 weeks after discharge to assess the 
conscious state of the patients, and EEG, brainstem evoked potential 
and brain fluctuation map were examined before intervention and 4 
weeks after treatment.The baseline data of the experimental group 
and the control group showed no statistical difference through 
statistical analysis. Conventional rehabilitation treatment and drug 
treatment were adopted by the current guidelines, and the distribution 
of cases in the two groups was also random. 
Study duration 
2023.1.1-2025.12.31 
sample size 
174 
inclusion 
criteria 
(1) It met the diagnostic criteria of Chinese and Western medicine for 
stroke, and the Glasgow coma score was between 3 and 9 points (the 
score was scored by the rehabilitation physician, and the patient had 
not used sedatives and anesthetics on the day of the score);
 
 

 
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(2) The patient's condition is stable, the vital signs are stable, and the 
onset time of consciousness disorder caused by stroke is confirmed 
not more than 6 months; 
(3) Clinical and auxiliary examination confirmed that cerebral 
infarction or cerebral hemorrhage is the only factor leading to 
consciousness disorders, excluding other diseases caused by 
consciousness disorders;
 
 
(4) Aged between 18 and 85;
 
 
(5) Family members or authorized clients are informed and sign 
informed consent; 
(6) Did not enter other clinical studies at the same time. 
exclusion 
criteria 
(1) People with consciousness impairment mainly due to changes in 
consciousness content or special types;
 
 
(2) Those confirmed by examination to have carbon monoxide 
poisoning, brain tumor, brain trauma, brain parasitic disease, 
metabolic disorders;
 
 
(3) Patients with severe primary diseases such as liver, kidney, blood 
system and endocrine system and other diseases with poor prognosis 
and mental illness;
 
 
(4) Patients with severe complications such as upper gastrointestinal 
bleeding and secondary epilepsy; 
(5) Those who have venous thrombosis and are currently on 
anticoagulant therapy. 
efficiency 
analysis 
Main outcome measure: GCS score 
Secondary outcome measures: CRS-R Scale 
security analysis 
In this experiment, acupuncture treatment was used to exclude 
patients with serious primary diseases of liver, kidney, blood system 
and endocrine system, and other diseases with poor prognosis and 
mental illness;If the patient's condition deteriorates during treatment 
and dangerous events may occur, the clinical observation of the case 
shall be terminated to ensure the safety of the patient. 
statistic analysis 
 Analysis set 
Statistical analysis was carried out using full analysis set, 
coincidence scheme set and security analysis set. 
Full analysis set (FAS) : Included all randomised participants who 
had received at least one study intervention and had a measurable 
baseline stroke. 
Per Protocol Set (PPS) : In the FAS population, participants with at 
least one post-intervention awareness scale assessment, good 
adherence, and no significant violations or deviations from the trial 
protocol. 
Safety Set (SS) : defined as subjects who received at least one 
intervention and were subsequently evaluated for safety. 
Sample size determination: The sample size is estimated according to 

 
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the group design of two sample rates compared sample size 
estimation formula 
 
 
Where, Uα is the first type of error probability U value, Uβ is the second 
type of error probability, when bilateral α=0.05, unilateral β=0.1, Uα=1.96, uβ 
=1.28, P1 is the effective rate of the treatment group, P2 is the effective rate of 
the control group, and P is the rate of the two combinations.According to 
previous research literature [1], P1 and P2 are estimated to be 79.4% and 
54.8%, resulting in n≈76, and the minimum sample size of each group is 
about 76 cases.As shedding cases were not excluded during the study, the 
shedding rate was 15%. For the successful completion of the experiment, 87 
cases were assigned to each group based on various factors, and 174 cases 
were required to be included in the two groups. 
Statistical analysis: All data in the experiment were tested and analyzed for 
normality, and sPSS 25.0 statistical software was used for analysis and 
processing. 
follow-up 
Telephone and video follow-up 
statistical 
method 
Baseline data were analyzed by Chi-square test.Measurement data 
are expressed as mean SD.Univariate analysis of variance was used 
to compare the difference between groups at the same time point, the 
difference at different time points in the group, and the difference 
before and after between the two groups.P < 0.05 was considered 
statistically significant, and multiple comparisons were performed by 
Dunnett-t test. 
Expected 
progress 
Clinical cases will be collected from 2023.1.1 to 2024.12.30, and 
insufficient cases due to shedding will be added from 2025.1.1 to 
2025.12.30. 
 

 
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List of abbreviations and term definitions                      
abbreviation 
definition 
CRS-R 
Coma Recovery Scale-Revised 
GCS 
glasgow coma scale 
NIHSS 
National Institutes of Health Stroke 
Scale 
FOUR 
Full Outline of Unresponsiveness Scale 
 

 
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Test flow chart 
item 
Screening period 
Duration of treatment (weeks) 
Four 
weeks 
after 
discharg
e 
Quit 
4week
s~-2da
ys 
base 
line 
/-1day 
1 
2 
3 
4 
Phone 
or video 
follow-u
p 
 
Informed 
consent  
X 
 
 
 
 
 
 
 
Demograph
y  
X 
 
 
 
 
 
 
 
Inclusion/e
xclusion 
criteria  
X 
 
 
 
 
 
 
 
Medical 
history 
X 
 
 
 
 
 
 
 
CRS-R 
scale  
 
X 
X 
X 
X 
X 
X 
 
GCS score 
 
X 
X 
X 
X 
X 
X 
 
NIHSS 
score  
 
X 
X 
X 
X 
X 
X 
 
FOUR 
score  
 
X 
X 
X 
X 
X 
X 
 
Electroence
phalogram  
 
X 
 
 
 
X 
 
 
brainstem 
auditory 
evoked 
potentials 
 
X 
 
 
 
X 
 
 
encephalofl
uctuograph 
 
X 
 
 
 
X 
 
 
 
 

 
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1.research background 
1.1 Post-stroke disturbance of consciousness 
The development of emergency medicine and neuroscience has enabled more 
and more patients to survive after stroke, but a considerable number of severe 
patients remain with impaired consciousness. 
1.1.1 The 
definition 
and 
classification 
of 
consciousness 
disorder: 
consciousness, including the level of consciousness and the content of 
consciousness. The normal level of consciousness is different from hyper alertness, 
wakefulness, sleepiness, light sleep, deep sleep, and dream. Awakening state refers 
to a physiological process of the human brain, which is a periodic alternating 
waking state with sleep, and depends on the integrity of the so-called "switch" 
system-the brain stem network structure ascending activation system. The content 
of consciousness, the so-called higher neural function activities, refers to the 
psychological processes (mental activities) such as human perception, thinking, 
memory, emotion and volitional activity, as well as the alertness of maintaining 
contact with the external environment through speech, hearing, vision, skilled 
movements and complex reactions. It is a function of the cerebral cortex, which 
depends on the integrity of the higher neural activities of the cerebral cortex .When 
the brain stem reticular structure ascending activation system is inhibited or the 
bilateral cerebral cortex is extensively damaged, the awakening state is weakened, 
the content of consciousness is reduced or changed, and the ability of the central 
nervous system to respond to internal and external environmental stimuli is reduced 
or disappeared, which can produce different degrees of consciousness disorders. 
At present, the level of consciousness disorder is generally divided into: 
lethargy, lethargy and coma. According to the state of awakening, the content of 
consciousness and the evolution of the course of the loss of physical movement and 
the degree and breadth of brain function impairment, coma is usually divided into 
four stages: shallow coma: also called semi-coma, moderate coma, deep coma, 
excessive coma: also called irreversible coma or brain death. The common 
disorders of conscious content are: hazy state, hazy consciousness, delirium state, 

 
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waking coma. The common clinical types of waking coma are: de-cortical state, 
inactive silence, persistent vegetative state. 
Although some patients have spontaneity or eye opening after stimulation, 
they lack perception and understanding of internal and external environment and 
cannot communicate effectively with the outside world, which is called vegetative 
state (VS) [1]. In recent years, some scholars believe that when patients with 
vegetative state present fluctuating consciousness, but it is insufficient for reliable 
communication, it is called minimally conscious state (MCS)[2]. 
1.1.2 The pathogenesis of disorders of consciousness: 
Research on the pathogenesis of consciousness disorders in modern medicine: 
Intracranial lesions can directly or indirectly damage the cerebral cortex and the 
ascending activation system of reticular structure, such as widespread acute 
inflammation of the brain, supratentorial space occupying lesions resulting in  
uncal herniation pressing on the brain stem and brain stem hemorrhage, which can 
cause serious consciousness disorders. Extracranial diseases affect consciousness 
primarily by affecting neurotransmitters and energy metabolism in the brain. At 
present, the main causes of consciousness disorders are several categories: ① 
cerebrovascular accident;② Toxic metabolic encephalopathy: such as diabetic 
coma, carbon monoxide poisoning coma, hepatic encephalopathy coma, etc.; 
Meningitis, encephalitis;④ Brain trauma;⑤ Brain tumor, epilepsy, schizophrenia, 
etc. Among them, cerebrovascular accident is the cause of the highest incidence of 
consciousness disorders. 
1.1.3 Assessment of disturbance of consciousness: 
The commonly used consciousness assessment methods include behavioral 
scale assessment, neuroelectrophysiology assessment, neuroimaging assessment 
and serum marker assessment. 
1.1.3.1 Behavioral scale assessment: For patients with consciousness disorders, 
the most commonly used clinical scales mainly include Glasgow Coma Scale (GCS) 
and 
Full 
Outline 
of 
Unresponsiveness 
scale 
(Full 
Outline 
of 
Unresponsiveness).FOUR) and revised Coma Recovery Scale-R (CRS-R).GCS 

 
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scale is the best choice for consciousness assessment of patients with acute brain 
injury. CRS-R scale is divided into 6 parts, including auditory (0-4 points), visual 
(0-5 points), motor (0-6 points), speech (0-3 points), communication (0-2 points) 
and arousal (0-3 points) assessment, with a total score of 0-23 points, is currently an 
internationally recognized measurement tool for identifying vegetative state (VS) 
and minimal state of consciousness (MCS).When patients communication =2 points 
or movement =6 points, that is, emergence from minimally conscious state (EMCS) 
[3].MCS was assessed on the following criteria: visual > 1 or auditory > 2 or verbal 
response > 2 or motor > 2 or communication > 0 or arousal > 2;The evaluation 
criteria of VS were: vision ≤1 score, hearing ≤2 score, speech response ≤2 
score, movement ≤2 score, communication = 0 score and arousal ≤2 score; 
Clarity of mind was assessed on a scale of exercise = 6 points or communication = 
2 points [4-5].However, it is not sensitive to the identification of MCS patients, and 
it cannot accurately assess patients with closed eye disorder caused by other reasons 
such as eye trauma [6].FOUR patients with locked-in syndrome can be identified by 
removing speech ability from GCS [7].The revised Coma Recovery Scale can be 
used to distinguish subtle differences in the level of consciousness and to monitor 
the return of consciousness [8].The scale consists of 6 subscales covering auditory, 
verbal, visual, communication, motor, and arousal levels, and includes 23 
hierarchical grading scales. CRS-R and its operation manual are available in 
Chinese and have been verified for reliability and validity. 
1.1.3.2 Neuroelectrophysiological assessment: The most commonly used 
neuroelectrophysiological evaluation methods are: Electroencephalo Graphic (EEG), 
Evoked Potential (EP) and transcranial magnetic stimulation combined with 
electroencephalographic (TMS-EEG).Conventional EEG is widely used to evaluate 
the prognosis of coma patients by analyzing the frequency, amplitude and 
waveform of brain waves [9] to evaluate brain function. When the brain tissue is 
damaged, the rhythm of the brain will change correspondingly, the brain activity 
slows down, and is proportional to the severity of the injury, mostly from the 
normal rhythm of α waves into the slower frequency of δ waves and θ waves. EP 

 
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has strong objectivity and can avoid the disturbance caused by sleep. Clinically, 
Brainstem Auditory Evoked Potentials (BAEP) and Somatosensory Evoked 
Potentials, SEP) and Event Related Potential (ERP) are the most commonly used 
evoked potentials and can be used to evaluate the prognosis of patients with 
DOC.BAEP stimulates the ear through sound and induces electrical activity of 
nerve cells through electrode conduction, which is not affected by physiological 
changes or drug factors of patients, and can directly reflect the function of the brain 
stem, but cannot show the function of the cerebral cortex. However, a few coma 
patients have no brain stem damage and their auditory function can still work 
normally, and BEAP may be normal at this time. However, in patients with 
prolonged latency and reduced wave amplitude, or disappearance of wave V, about 
90% of these patients will have a severe poor prognosis or death, or a long-term VS 
state. 
1.1.4 Treatment of consciousness disorders: 
1.1.4.1 Drug treatment: Naloxone, an opioid receptor antagonist, is a common 
sedative drug in clinical practice. By inhibiting the production of anti-B-endorphins 
in the central nervous system, naloxone can quickly release the inhibitory effect of 
anti-B-endorphins on brain cells, reverse brain cell damage and neurological 
dysfunction, improve cerebral blood perfusion, and alleviate the hypoxia of edema 
brain cells.The use of calcium channel antagonists, exogenous gangliosides and free 
radical scavengers in acute stage of brain injury may help alleviate secondary brain 
damage, protect brain function, promote disease recovery and improve prognosis, 
but all of them are grade III clinical evidence. 
1.1.4.2 physical agents therapy  
1.1.4.2.1 ：Median nerve stimulation is also used to treat disorders of 
consciousness, but treatment must be started early and for long enough.Some 
studies have shown that deep brain stimulation can produce repeatable and 
sustained improvement in consciousness in MCS patients, and only patients with 
good 
brain 
network 
preservation 
through 
neuroimaging 
and 
neuroelectrophysiological examination can be selected for treatment. 

 
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1.1.4.2.2：In recent years, neuroregulatory therapy technology is often used in 
clinical treatment of coma, in which repetitive transcranial magnetic stimulation is a 
new biological technology that generates local function and electrical activity of 
neurons at the site of magnetic stimulation under the action of induction magnetic 
field caused by induction current. It is widely used in the treatment of nervous 
system diseases because of its advantages of easy operation, non-destructive, 
painless and high safety. Repetitive transcranial magnetic stimulation mainly 
applies pulsed magnetic field to scalp, induces induced current in the brain tissue of 
patients, and induces neuronal depolarization through neuronal stimulation, thus 
generating evoked potential. Other methods include transcranial electrical 
stimulation, high cervical posterior cord electrical stimulation, and acupuncture, 
which have only been studied in small or clinical studies with limited evidence. 
Although hyperbaric oxygen is widely used, there is a lack of grade I clinical 
evidence, and there is no study that clearly applies to the pressure, duration and 
other indicators required for patients with consciousness disorders. 
1.1.4.3：Neurosurgical treatment: persistent vegetative state (PVS) surgical 
rehabilitation and awakening, mainly including spinal cord stimulation (SCS) and 
deep brain stimulation (DBS)[10]. 
SCS and DBS are invasive electrical stimulation with high cost and need 
surgical intervention, so it is difficult to promote them in basic hospitals. Other 
complications may occur, such as electrode displacement, electrode fracture, 
superficial infection, and epidural abscess. 
At present, the clinical treatment of patients with consciousness disorder is still 
mainly comprehensive rehabilitation, including somatotherapy strategies and 
treatment measures to promote consciousness improvement. 
1.2. Application status of acupuncture in the treatment of consciousness 
disorders: 
Acupuncture has been used to treat the sequelae of stroke in China for more 
than 2000 years. Some modern Chinese medicine home acupuncture treatment of 
brain injury after consciousness disorder, found to have a certain effect.  

 
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Bao Yingcun et al. [11] randomly divided 100 patients with vegetative state of 
traumatic brain injury into observation group and control group. Both groups were 
given routine clinical treatment. The control group was given rehabilitation and 
hyperbaric oxygen therapy. Observation group was given "Xingnaokaiqiao" 
acupuncture method on the basis of control group, and the points were Neiguan, 
Shuigou, Sanyin Jiao, Qize, Weizhong, Hegu and Taichong. All patients were 
treated once a day for 5 days and rested for 2 days a week for 30 days. The scores 
of Glasgow Coma Scale (GCS) and Modified International Coma Recovery Scale 
(CRS-R) were observed before treatment and at 10, 20 and 30 days after treatment, 
and the wakefulness rate of the two groups was compared after treatment. Results 
After 10, 20 and 30 days of treatment, GCS score and CRS-R score of 2 groups 
were increased compared with before treatment (P < 0.01), and observation group 
was higher than control group (P < 0.01).After treatment, the wakefulness rate of 
the observation group was 16.7% (8/48), which was higher than that of the control 
group (12.0% (6/50, P < 0.01). 
Ma Liang et al. [12] took 60 patients with consciousness disorder after 
craniocerebral injury as research objects. The control group was treated with routine 
awakening promotion method, and the observation group was treated with Tongdu 
Xingnao acupuncture method on the basis of the control group. It was found that 
the total effective rate of the observation group was significantly higher than that of 
the control group (P < 0.05).The waking time, feeding time, getting out of bed time 
and discharge time of observation group were shorter than those of control group (P 
< 0.05).After treatment, the scores of the revised Coma Recovery Scale (CRS-R) 
and Total non-responsiveness Scale (FOUR) in the observation group were higher 
than those in the control group (P < 0.05).After treatment, the levels of 
neuron-specific enolase (NSE) and astroglia-derived protein (S100β) in observation 
group were lower than those in control group, and the levels of brain-derived 
neurotrophic factor (BDNF) and nerve growth factor (NGF) in observation group 
were higher than those in control group (P < 0.05). 
Ma Qian et al. [13] included 91 cases of acute stroke patients with 

 
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consciousness disorder for study, and the acupuncture group was given the 
treatment of wakefulness and resuscitation acupuncture. There was significant 
difference in Glasgow scores between the acupuncture group and the control group 
at 10 and 20 days of treatment. 
Xu Junfeng et al. [14] applied head electroacupuncture across the Central Line, 
used high-intensity stimulation combined with amplitude modulation, frequency 
conversion, instantaneous stimulation and continuous stimulation, and combined 
with integrated rehabilitation programs of traditional Chinese and Western medicine, 
Western medicine, exercise therapy, sensory stimulation and other traditional 
Chinese and western medicine, and achieved certain effects on the awakening of 
patients with persistent vegetative state. 
1.3. Point selection and application of Tongyuan needle method: 
Tongyuan acupuncture method was created by Professor Lai Xinsheng in more 
than 40 years of clinical practice. It has the characteristics of regulating Yin and 
Yang, regulating yuan and treating God, unique acupoint group, wide indication and 
remarkable curative effect. Tongyuan needle method is short for the dichotomy of 
Tongduyangshen and qi qi. According to different diseases or symptoms, the 
dichotomy can be used in combination or alone, or combined with syndrome 
differentiation and disease differentiation, or combined with acupuncture and 
medicine. It breaks through the limitations of the limbs meridian points used in the 
past, integrates the various forms of acupoint compatibility such as Shu Mu 
matching, upper and lower matching, left and right matching, and takes the two 
veins of Ren Du as the focus of meridian point selection, giving full play to the 
meridians' therapeutic effect of guiding the brain through the channel and regulating 
the yuan God and Ren pulse connecting the kidney as the return of qi. It is a new 
acupuncture and moxibustion prescription system of "Fuzhengdispelling evil" and 
"treating disease must seek the original". 
The acupuncture method of Tongyuan includes two parts: Tongdu, qi and 
yuan.The main points of the head Baihui, the front top, the back top, the seal hall, 
the middle, the Dazhui, the back of the five viscera are selected; The qi Guiyuan is 

 
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mainly composed of Tianshu, Qi Hai, Hui Hui, Guanyuan, Shanzhong, Zhongwan 
abdominal Ren pulse and Mu points. The two can be used separately and combined, 
and most of the matching points are five transfusion points below the elbow and 
knee. Acupuncture and acupoint prescription composed under the guidance of this 
principle is suitable for many internal injury diseases and difficult diseases, such as 
female infertility, male infertility and other urogenital diseases, stroke and related 
encephalopathy, spinal limbs and neuromotor function diseases, dementia, 
depression, headache, insomnia, intellectual disability, epilepsy and other 
psychiatric diseases. Chronic cough, bronchial asthma, urticaria, hepatitis, colitis, 
gastritis, chronic prostatitis, polycystic ovary syndrome and so on have obtained 
satisfactory curative effect. Some scholars have found that Tongyuan acupuncture 
can significantly improve the cough reflex ability of patients with tracheotomy after 
stroke, control lung infection, improve swallowing function, and thus improve the 
success rate of clinical extubation. 
It has been confirmed that scalp acupuncture based on Baihui can improve the 
volume and area of cerebral infarction [15]. 
1.4 Research status of acupuncture comfort control design 
The design of acupuncture placebo control in clinical trials has always been a 
difficult point. The ideal acupuncture placebo control should have the following 
characteristics: first, it has no or very little physiological therapeutic effect; The 
second is that it is no different or as similar as possible to the trial intervention in 
every other respect, so that its psychological impact on the patient is minimal, and it 
is not easy to destroy the blind method. Acupuncture consolation control generally 
adopts false acupuncture point method or false acupuncture method. The depth of 
acupuncture can be divided into three degrees: shallow acupuncture, the same depth 
and non-transdermal. The general requirements of shallow needling are to Pierce 
the needle body only into the superficial surface of the body about 3~5mm, do not 
twist and other techniques to avoid qi; The same depth means that the acupuncture 
body of the comfort acupuncture group and the treatment group have the same 
depth into the human body; Transdermal is the use of a certain method or needle, 

 
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giving people the illusion that the needle body into the human body but does not 
actually Pierce the skin. The selection of acupuncture sites can be divided into three 
categories: non-meridian point, different meridian point and the same point. 
Non-meridian point is no name, no function, no positioning point, including the 
selection of fixed non-acupoints or false acupoints near the original meridian point 
(the original acupoint is opened outward by 5~20mm);Different meridian points 
mean that although they are clear acupoints, they have no therapeutic effect on the 
disease under study. The same point means that the selected acupoints are consistent 
with the treatment group [16-17].From the perspective of practical clinical 
operability and the implementation of the blind method, the control group of this 
experiment selected the original acupuncture point to open outwards by 1cm, with 
the same depth of acupuncture. 
As for the study on the physiological effects of fake acupuncture points, some 
scholars collected clinical trial literature that used functional magnetic resonance 
imaging (fMRI) as the observation index to compare the changes in brain activity 
after true point acupuncture and fake point acupuncture, and used SDM-PSI 
software to conduct a meta-analysis of voxel-based whole brain fMRI imaging. It 
was found that acupuncture at the true point had more significant effects on brain 
connection, higher nervous function and motor regulation than that at the false point 
[18]. 
1.5 Current research status of encephalofluctuograph: 
Encephalofluctuograph 
(EFG) 
is 
a 
non-invasive 
electrophysiological 
technology used to detect the function of brain neurotransmitters. It collects 10 min 
brain waves and extracts ultra-slow waves for analysis (frequency range: 1~255 
mHz). A large number of experiments have proved that dominant ultra-slow waves 
are related to the activity of neurotransmitters in brain. Each neurotransmitter has a 
one-to-one correspondence (cryptographic relationship) with ultra-slow waves of a 
particular frequency. Through experiments, the code of several common 
neurotransmitters has been deciphered, which are acetylcholine, norepinephrine, 
gamma-aminobutyric acid, glutamic acid, 5-hydroxytryptamine and dopamine 

 
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[19-20].At present, many domestic scholars have used brain fluctuation graph to 
study the changes of neurotransmitter power in different nervous system diseases, 
especially in the study of neurodegenerative diseases, cerebrovascular diseases, 
emotional disorders and other diseases, and have obtained similar results in 
different research groups. 
He Renhong et al. [21] included 39 patients with brain injury, and then 
collected the neurotransmitters in the brain during EEG assessment (detected by 
brain fluctuation map). The detection indexes included the transmitter power, 
relative power and index analysis of γ-aminobutyric acid, 5-hydroxytryptamine, 
norepinephrine, dopamine and other transmitters. The results showed that the brain 
transmitter power of the poor outcome group was significantly lower than that of 
the good group. Logistic regression analysis showed that gamma-aminobutyric acid 
and serotonin were the factors that could significantly affect the outcome. The 
authors suggest that in the clinical rehabilitation of brain injury, therapeutic 
methods that can improve the efficacy of gamma-aminobutyric acid and serotonin 
transmitters should be considered. 
At present, the study on the effect of acupuncture on awakening has been 
developed from behavior to molecular mechanism. 
2.purpose of research 
2.1 Main Objective: To confirm the effect of Tongyuan acupuncture on 
consciousness disorder after stroke; 
2.2 Secondary objective: To explore the mechanism of acupuncture intervention 
in post-stroke consciousness disorder. 
3.study endpoint 
3.1 Primary endpoint: GCS score. 
3.2 Secondary endpoints: CRS-R Scale (Coma Recovery Scale–Revised), 
EEG(electroencephalograph), BAEP (Brainstem Auditory Evoked Potential)，and 
EFG (Encephalofluctuography). 
4.experiment design 
This clinical study was a randomized (1:1), single-blind, single-center, parallel 

 
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controlled clinical study. Seventy-two patients were recruited. After signing the 
informed consent, patients meeting the inclusion/exclusion criteria will be randomly 
assigned to the experimental group (Tongyuan acupuncture) and the control group 
(fake acupoint method) in a 1:1 ratio, and a total of 72 patients will be recruited. 
Subjects randomized to the trial group will be treated with regular rehabilitation 
therapy and drug therapy + acupuncture once a day, 5 days a week for 4 weeks. 
Twenty days in total. 
Subjects randomized to the control group will be treated with regular 
rehabilitation and drug therapy + pseudoacupoint method once a day, 5 days a week 
for 4 weeks. Twenty days in total. 
Safety and study compliance were assessed for each subject at 1, 2, and 3 
weeks of initial treatment and at the end of the intervention, and treatment guidance 
was given by the investigator. A safety assessment and survival follow-up were 
conducted 4 weeks after discharge, and the corresponding consciousness scale was 
evaluated. 
4.2 Randomization and blinding 
4.2.1 randomize 
In this study, patients meeting the inclusion criteria will be randomized into the 
trial group and the control group in a 1:1 ratio. 
Random numbers generated by SPSS software were used to include eligible 
subjects. 
4.2.2 Blind state/broken blind 
Because of the particularity of acupuncture treatment, it is impossible to 
implement double blindness, so this study implemented single blindness. The 
realization of single blind conditions: false acupoint method, and Tongyuan 
acupuncture method are adopted acupuncture methods so that patients and family 
members do not know the grouping. Moreover, trial designers, scale evaluators, 
acupuncture operators, and data statisticians do not know the status of treatment 
groups of individual subjects. 
Blindness is crucial to the integrity of this clinical study. However, in the event 

 
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of a medical emergency or pregnancy event in an individual subject, the information 
about the study treatment received by the subject is so important to the subject's 
management that the treating physician will need to de-blind the subject. 
Before blinding a subject's treatment, the investigator should determine that this 
information is necessary, that it will change the subject's immediate treatment. In 
many cases, especially when the subject's emergency condition is clearly unrelated to 
the study protocol, it can be assumed that the subject is being treated with the active 
drug without the need for blind treatment. 
The need for blindness should first be discussed with the responsible medical 
monitor before determining the best response. 
After unblinding, the subjects will withdraw from the study and terminate 
treatment. Safety follow-up and survival follow-up are still required. 
5. Subject population 
The subjects of this study were patients with post-stroke consciousness 
disorder. 
5.1 diagnostic criteria 
(1) Patients diagnosed with cerebral hemorrhage and cerebral infarction 
according to the Chinese Guidelines for the Diagnosis and Treatment of Cerebral 
Hemorrhage 2019 and the Chinese Guidelines for the Diagnosis and Treatment of 
Acute Ischemic Stroke 2018 authored by the Neurology Branch of the Chinese 
Medical Association; 
(2) Disturbance of consciousness dominated by altered degree of arousal: refer to 
the patients diagnosed as disturbance of consciousness in the 8th edition diagnostic 
criteria of Neurology, the textbook of the 13th Five-Year Plan of the National 
Health Commission in 2018.
 
5.2 inclusion criteria: 
(1) sign the informed consent voluntarily; 
(2) met the above diagnostic criteria, and the GCS score was between 3 and 9 
(the score was scored by a rehabilitation physician, and the patient had not used 
sedatives or anesthetics on the day of the score); 

 
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(3) The patient's condition is stable, vital signs are stable, and the onset time of 
consciousness disturbance caused by stroke is confirmed to be less than 6 months; 
(4) Cerebral infarction or cerebral hemorrhage confirmed by clinical and 
auxiliary examination is the only factor causing consciousness disorder, excluding 
other diseases caused consciousness disorder patients; 
(5) those aged between 18 and 85; 
(6) Family members or authorized principals know and sign informed consent; 
(7) did not enter other clinical studies at the same time. 
5.3 exclusion criteria： 
(1) People with consciousness impairment mainly due to changes in 
consciousness content or special types; 
(2) confirmed carbon monoxide poisoning, brain tumor, brain trauma, brain 
parasitic disease, metabolic disorders; 
(3) Patients with severe primary diseases of liver, kidney, blood system, 
endocrine system and other diseases with poor prognosis, mental diseases; 
(4) have upper gastrointestinal hemorrhage, secondary epilepsy and other serious 
complications; 
(5) Those who have venous thrombosis and are currently on anticoagulant 
therapy; 
(6) patients judged by the investigator to be unsuitable for participation in this 
trial. 
5.4 Exit criteria 
Subjects withdrawing from the study for any reason are required to document 
their reasons, including, but not limited to, the following: 
1) The subject withdraws the informed consent; 
2) The sponsor terminates the study; 
3) More serious adverse events affect participants' continued participation in the 
trial; 
4) serious program violations/deviations; 
5) pregnancy; 

 
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6) Poor compliance; 
7) Loss of follow-up; 
8) The investigator and/or sponsor considers that the subject's medical condition 
may endanger the subject's safety or that the continuation of the study will harm the 
subject's health; 
9) Death; 
10) Others. 
5.5 Termination criteria  
Test termination criteria (if any of the following tests are met, the trial is 
terminated) : 
1) Serious safety problems occur during the test; 
2) Major errors in the clinical trial protocol are found in the trial; 
3) The Ethics committee requests the termination of the trial. 
6. Research treatment techniques: 
6.1 Test instrument: Tianxie brand 25mm× (25mm~40mm)  millimeter needle 
produced by Suzhou Medical Supplies Factory Co., LTD. 
6.2 Non-research drugs: common first-line drugs for the treatment of hypertension, 
such as amlodipine, nifedipine, nirendipine, metoprolol, valsartan, etc.; The 
commonly used first-line drugs for the treatment of diabetes such as metformin, 
acarbose, insulin aspartate, insulin glargine, etc. 
6.3 Treatment methods:  
experimental group selected points: Baihui, Zhongwan, Guanyuan, Qihai, 
Tianshu (double);Point selection criteria: the national standard "Name and Location 
of points" (GB/T12346-2006).Intervention time: once a day, 5 days a week for 4 
consecutive weeks. Twenty days in total; 
Point selection of the control group: acupuncture treatment was performed 1cm 
beside the point selection of the experimental group. 
6.4 Intervention discontinuation Indicators: Subjects will withdraw from the 
study if they have the following indications during treatment: 
(1) If the patient's condition deteriorates during treatment and there is a possibility 

 
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of dangerous events, the clinical observation of the case should be terminated 
according to the doctor's judgment;
 
 
(2) In the course of treatment, the patient's family members give up the clinical 
treatment halfway, request the doctor in charge to terminate the treatment, and 
terminate the clinical observation of the case;
 
 
(3) The treatment is effective, but the patient's family uses other treatment methods 
in order to speed up the therapeutic effect, and cannot determine the efficacy of the 
clinical study, and the clinical observation of the case is terminated.
 
6.5 drug combination：Information on all drug combinations during the study 
period (generic name, purpose of administration, dose, time of administration, etc.) 
must be recorded in detail in the case report form. Treatment with other 
investigational drugs is prohibited during the study period. 
7. Research methods and procedures  
All subjects need to sign informed consent before screening, and successful 
subjects can enter this study. According to the protocol, the experimental group and 
the control group were treated respectively, and the effectiveness and safety were 
evaluated at 1, 2, 3 and 4 weeks. Telephone and video follow-up were conducted 4 
weeks after discharge for statistical analysis. Treatment continued until subjects 
completed the 4-week course or met any of the exit criteria. Participants are evaluated 
comprehensively by the investigator, and if it is determined that the continuation of 
the experimental treatment can bring clinical benefit to the subject, the treatment can 
be continued until the subject's PD, intolerance, or death. 
7.1 screening machine 
All subjects were required to complete relevant examinations during the 
screening period before enrollment, and were screened according to the admission 
criteria. 
(1) Sign informed consent; 
(2) Record demographic data: date of birth, gender, initials; 
(3) Medical history and physical examination (including vital signs, height, weight, 
physical examination of the whole body system; Past and present history of HCC, 

 
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etiology; 
(4) Other laboratory tests, such as blood routine (white blood cells, neutrophils, 
hemoglobin, platelets, etc.), urine routine (urine white blood cells, urine protein, red 
blood cells), stool routine (stool occult blood); 
(5) Liver function (albumin, aminotransferase), kidney function (filtration rate, 
creatinine), neuron-specific enolase, interleukin 6, etc ; 
(6) Consciousness level assessment: GCS score. 
7.2 therapeutic session 
(1) Treatment plan: 
Test group: Subjects will use conventional rehabilitation therapy (exercise training, 
physical factor therapy, etc.) and drug therapy (such as controlling blood pressure, 
blood sugar, promoting microcirculation, nutritional nerve and other supportive 
treatment) + Tongyuan acupuncture method: point selection: Baihui, Zhongwan, 
Guanyuan, Qihai, Tianshu (double);Point selection criteria: the national standard 
"Name and Location of points" (GB/T12346-2006).Intervention time: once a day, 5 
days a week for 4 consecutive weeks. Twenty days in total. 
Control group: Subjects will receive conventional rehabilitation treatment (exercise 
training, physical factor therapy, etc.) and drug treatment (such as symptomatic 
support treatment for controlling blood pressure, blood sugar, promoting 
microcirculation, nutritional nerve, etc.) + pseudacupoint method (acupuncture 
treatment is performed 1cm apart from the selected points of the experimental group), 
once a day, 5 days a week, for 4 consecutive weeks. Twenty days in total. 
(2) Evaluation: 
Consciousness levels were assessed before intervention, at 1, 2, 3, and 4 weeks of 
treatment, and 4 weeks after discharge: GCS score, NIHSS score, CRS-R Scale 
(Modified Coma Recovery Scale), and FOUR scale score . Electroencephalogram, 
brainstem auditory evoked potentials and encephalofluctuograph were examined 
before intervention and at 4 weeks of treatment. 
7.3 follow-up period 
Consciousness level assessment: GCS score, NIHSS score, CRS-R scale, FOUR 

 
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scale score. 
8. evaluation index 
8.1 Evaluation of effectiveness: Before and after the intervention and at 4 weeks of 
treatment: GCS score. 
8.1.1 Glasgow Coma Scale (GCS) : 3 to 15 points 
Open eyes (E) : 1-4 points; Vocalization (V) : 1-5 points; Exercise (M) :1-6 points. 
The consciousness improvement rate of each patient was calculated according to the 
following formula: 
Consciousness improvement rate of each patient = (score after treatment - score 
before treatment)/score before treatment ×100%  
Consciousness improvement rate ≥20% is effective, 15%≤ consciousness 
improvement rate < 20% is effective, good consciousness 
Turnover rate < 15% is invalid 
Efficiency = (obvious + effective)/(obvious + effective + ineffective) ✖100% 
8.1.2 Revised Coma Recovery Scale (CRS-R) : 0-23 points 
The minimum state of consciousness (MCS) was assessed as: visual > 1 or 
auditory > 2 or verbal response > 2 or motor > 2 or communication > 0 or arousal > 2; 
The evaluation criteria of persistent vegetative state (VS) were: vision ≤1 score, 
hearing ≤2 score, speech response ≤2 score, movement ≤2 score, communication 
= 0 score and arousal ≤2 score; 
Clarity of mind was assessed on a scale of exercise = 6 points or communication 
= 2 points. 
A change from below MCS to MCS, or from MCS to VS, or from VS to clear 
consciousness, or an increase of one level or more in the state of consciousness is 
considered valid. 
8.2 Safety evaluation: Events such as needle dizziness, hematoma and unstable vital 
signs were recorded in the case report and reported to the trial designer. After group 
discussion, the case was withdrawn from the study. Follow-up of subjects after 
adverse events: in-hospital monitoring, 1 week after discharge, 4 weeks back to the 
hospital for re-examination. 

 
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9. Safety monitoring, reporting and medical treatment 
9.1 Adverse event (AE) definition 
An adverse event is any adverse medical event that occurs after a patient or subject 
receives a drug that is not necessarily causally related to the treatment. Therefore, an 
adverse event can be any adverse physical sign (including abnormal laboratory 
results), symptom, or disease that has a time correlation with the use of the 
investigational drug, regardless of whether a causal relationship with the 
investigational drug is considered. Adverse events include Serious adverse events 
(SAE) and non-serious adverse events. 
9.2 SAE definition 
SAE refers to the occurrence of medical events during clinical trials that require 
hospitalization or prolonged hospitalization, disability, affect work ability, endanger 
life or death, and lead to congenital malformations. Includes the following medical 
events: 
1) events leading to death; 
2) life-threatening events (defined as subjects in immediate danger of death at the 
time of the event); 
3) Events requiring hospitalization or prolonged hospitalization; 
4) Events that can cause permanent or severe disability/disability/affect the ability to 
work; 
5) Congenital abnormalities or birth defects; 
Other medically important events (defined as events that endanger subjects or 
require intervention to prevent the occurrence of any of the above). 
9.3. Adverse event recording, collection, reporting and handling 
9.3.1 Collection, reporting and handling of AE 
From the signing of the informed consent to the beginning of the test, all AE 
related to the operating procedures specified in the test protocol shall be recorded in 
the eCRF... 
The recording of AE should include: description of the AE and all related 
symptoms, time of occurrence, severity, duration, correlation with the means of the 

 
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test, measures taken, and final results and outcomes. The recording of AE must use 
medical terminology, and if the subject's signs and symptoms can be summarized by a 
common cause, the diagnosis should be recorded as far as possible. In addition to 
indicators related to disease progression, all clinical events and clinically significant 
laboratory adverse events can be treated with reference to the Common Adverse Event 
Evaluation Criteria (CTCAE) version 5.0.Adverse reactions to treatment will be 
recorded by the investigator. 
9.3.2 SAE collection and reporting 
All SAE, regardless of cause or drug correlation, occurring from the time the 
subject signed the informed consent to the completion of the trial intervention within 
4 weeks were to be reported using the SAE Report Form. In case of SAE, the 
researcher should immediately take appropriate treatment measures for the subject, 
ensure the safety of the subject, and report within 24 hours to the applicant for drug 
registration, the State Drug Administration, the provincial Food and Drug 
Administration, the ethics committee of the relevant clinical trial center and the 
medical Department of the Medical Administration Bureau of the Health Commission, 
and timely report to the ethics committee of the group leader. The first report should, 
as far as possible, include the following: source of the report, name of the trial 
intervention, name of the serious adverse event, time of occurrence, severity, duration, 
association with the trial drug, action taken, and outcome. 
9.3.3 gestation 
Pregnant patients were not included in this study. Since the included subjects were 
hospitalized patients with consciousness disorder, the possibility of pregnancy during 
the study period was excluded.  
9.3.4 Criteria for judging the severity of AE 
Researchers will evaluate severity according to the five-level criteria developed by 
the NCI CTCA version 5.0: 
Grade 1, mild; Asymptomatic or with mild signs; For clinical or diagnostic 
observation only, without medical intervention; 
Grade 2, moderate; Age-appropriate limited functions of daily living (such as 

 
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cooking, shopping, making phone calls, etc.); 
Grade 3, serious or medically important but not immediately life-threatening; 
Resulting in hospitalization or prolonged hospitalization; Disability; Limited daily 
self-care activities (daily self-care activities refer to bathing, dressing, undressing, 
eating, toilet use, medication, etc., but not bedridden); 
Level 4, life-threatening, requiring emergency treatment; 
Level 5, AE-related death 
9.3.5 Other investigator responsibilities during  
follow-up of serious adverse events 
Serious adverse events should be examined and treated according to clinical 
judgment, including necessary clinical laboratory examination and physical 
examination. The results of any inspection or other updated SAE-related information 
obtained must be reported in a follow-up report within the same time frame and 
process as the initial report. 
10. Trial termination/suspension criteria 
10.1 Sponsor reserves the right to terminate/suspend this trial. Before 
terminating/suspending a clinical trial, the sponsor must notify the investigator, the 
Ethics Committee and the State Food and Drug Administration and state the reasons. 
After the early termination/suspension of the study, the restart of the study must be 
reviewed and approved by the Ethics Committee; 
10.2 Termination/suspension requested by the Ethics Committee. 
11. Regulations to end clinical trials. 
The trial ends when all subjects meet the following conditions: 
1) All subjects completed at least 6 months of survival follow-up; 
2) or the death, loss of follow-up, or withdrawal of informed consent of all subjects. 
12.data administration 
12.1 data administration 
1) The researcher must ensure that the data is true, complete and accurate; 
2) When any correction is made to the test record, the revised data can only be 
underlined, annotated by the margin, and the reason should be stated. The original 

 
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record should not be erased or overwritten. 
3) Complete laboratory inspection items. 
12.2. Data recording and file preservation 
Subject data on the case report form should be recorded in subject code and 
subject can only be identified by subject code or their initials. 
From data entry to the verification requirements of the source data to the question 
answer of the quality control data, and finally to the operation of data locking and 
export, after confirming that the data is no doubt, all parties sign the database 
locking application form, and the data administrator locks the database. After the 
database is locked, the data administrator exports the analysis database and sends it 
to statisticians for statistical analysis. The locked data cannot be edited again, and 
the problems found after the database is locked can be corrected in the statistical 
analysis program after confirmation. 
13.statistic analysis 
13.1 Sample size determination 
In this study, 1:1 parallel control was used to estimate the sample size according 
to the group design of two sample rates comparison sample content estimation 
formula: 
 
Where, Uα is the first type of error probability U value, Uβ is the second type of 
error probability, when bilateral α=0.05, unilateral β=0.1, Uα=1.96, uβ =1.28, P1 is 
the effective rate of the treatment group, P2 is the effective rate of the control group, 
and P is the rate of the two combinations.According to previous research literature, 
P1 and P2 are estimated to be 79.4% and 54.8%, resulting in n≈76, and the 
minimum sample size of each group is about 76 cases.As shedding cases were not 
excluded during the study, the shedding rate was 15%. For the successful 
completion of the experiment, 87 cases were assigned to each group based on 
various factors, and 174 cases were required to be included in the two groups. 

 
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13.2 Analysis set definition and selection 
A Full Analysis Set (FAS) is a set of participants who have received the 
investigational drug at least once since enrollment and have been evaluated for 
effectiveness at least once. 
Safety Set (SS) : The set of all subjects who received the investigational drug at 
least once after enrollment and were evaluated for safety at least once. 
Per Protocol Set (PPS) : The set of cases in which all patients in the full analysis 
completed protocol treatment and did not seriously violate the protocol. 
13.3 Statistical method 
The analysis included case distribution, demographic data, baseline analysis and 
therapeutic effect analysis. Baseline data included sex, age, stroke type, stroke 
duration, underlying medical history (diabetes, hypertension, heart disease, chronic 
obstructive pulmonary disease), and history of smoking and alcohol use. Baseline 
data were tested by chi-square test. The end point data was the score of the State of 
Consciousness scale, and the measurement data was expressed as mean SD. 
Univariate analysis of variance was used to compare the difference between groups 
at the same time point, the difference at different time points in the group, and the 
difference before and after between the two groups. P < 0.05 was considered 
statistically significant, and multiple comparisons were performed by Dunnett-t test. 
13.4 Statistical software and general requirements: 
1)All statistical analysis was performed using SPSS25.0 statistical software. 
2)Measurement data were described using mean, standard deviation, median, 
maximum and minimum values. 
3)Counting data are described by frequency and percentage. 
4)All data in the experiment were tested for normality. 
5)Baseline data were analyzed using Chi-square test. Measurement data are 
expressed as mean SD. Univariate analysis of variance was used to compare the 
difference between groups at the same time point, the difference at different time 
points in the group, and the difference before and after between the two groups. P < 
0.05 was considered statistically significant, and multiple comparisons were 

 
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performed by Dunnett-t test. 
14.testing management 
14.1 Comply with GCP requirements 
Governing body and implementation of the GCP: 
1) Drug registration applicants and investigators should adopt standard operating 
procedures to implement quality control and quality assurance systems for clinical 
trials; 
2) The original data must meet the GCP requirements of our country; 
3) Laboratory test results must be accurate and reliable; 
4) The observations and findings used should be verified to ensure the reliability of 
the data; 
5) Establish a complete test organization and clarify the responsibilities of 
personnel at all levels; 
6) The main researcher shall be responsible for the overall quality control and carry 
out the responsibilities of personnel at all levels; 
7) The main investigator shall be responsible for the design of the experimental 
protocol and informed consent, and the main investigator shall write the 
experimental summary report after the end of the experiment; 
8) The designated researcher shall be responsible for developing the 
implementation rules and SOP for use in the test; 
9) The study plan for all participants shall be organized by the test group before the 
experiment, and all participants shall undergo GCP training; 
10) The doctors, nurses and therapists participating in the experiment shall strictly 
abide by the protocol and follow the procedure, and shall not change it at will; 
11) Designated statisticians are responsible for the overall statistical processing of 
the data. 
14.2 Protect the subject's privacy 
All the data of the subjects during the experiment will be recorded into the 
computer for confidential storage and analysis. If necessary, the records may be 
reviewed by relevant institutions to confirm the truth, accuracy and completeness of 

 
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the data. The data obtained from the experiment may also be published in academic 
journals, but the names of the subjects will not be published and the privacy of the 
subjects will be kept confidential. 
Extra precautions are taken to ensure confidentiality of documents and to prevent 
identification of subjects through genetic data. However, in exceptional circumstances, 
someone may see a subject's genetic data and personal identification number. For 
example, in the event of a medical emergency, the sponsor, its representative 
physician or investigator is aware of the subject identification number and has access 
to the subject's genetic data. In addition, the relevant regulatory authorities requested 
access to the relevant documents. 
14.3 Problems arising in the test and their treatment measures 
1) Revision of the protocol: After the protocol is approved by the Ethics Committee, 
if the protocol is to be revised, a "Protocol Revision Statement" shall be formulated 
and signed by the principal investigator. The scheme can only be revised with the 
consent of the researcher and the applicant for drug registration through 
consultation; 
2) The revised plan shall be submitted to the Ethics Committee for review and 
approval before implementation; 
3) Any adverse event (AE) or severe adverse event (SAE) that occurs during the test 
will be reported and handled in accordance with the requirements of the protocol 
and SOP. 
14.3 Quality control and quality assurance 
14.3.1 quality assurance： 
The sponsor and the cooperating units entrusted by the sponsor to be responsible 
for all or part of the responsibilities and tasks related to this study (including CRO, 
SMO, statistical unit, clinical center, etc.) shall establish their own quality assurance 
systems, perform their respective duties, strictly follow the clinical trial protocol, 
and adopt the corresponding standard operating procedures. To ensure the 
implementation of clinical trial quality control and quality assurance system. 
14.3.2 Quality assurance of clinical trial process 

 
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Before starting clinical trials, researchers should receive training on the trial 
protocol, so that researchers have a full understanding of the clinical trial protocol 
and the specific connotation of each indicator. Quality control personnel should 
check the basic conditions of clinical trials to ensure that clinical trial conditions 
can meet the requirements of the program. In the course of the trial, the investigator 
shall carefully perform the clinical operation and other work according to the 
institutional SOP and the requirements of the trial protocol, and record it in a true, 
timely, complete and standardized manner. Quality control personnel conduct 
quality verification of the test process and corresponding original records. After the 
end of the test, the research unit sorted out the corresponding project files, which 
were checked by the quality control personnel and archived. The quality assurance 
department of the clinical research unit shall check the feasibility of the trials 
conducted. When non-conforming items are found, timely notify the researcher and 
the head of the unit to correct, and track the correction. 
14.4 The expected schedule and completion date of the clinical trial 
1)2023.1.1~2024.12.30: Clinical cases were collected 
2)2025.1.1~2025.12.30: Cases of deficiency due to supplementary Shedding 
14.5 Sponsor's duties 
The sponsor is responsible for initiating, applying for and organizing this clinical 
trial, and providing trial funds. The sponsor shall submit the application for clinical 
trial to the State Food and Drug Administration in accordance with the provisions of 
China's GCP, drug registration Administration and other regulatory documents, and 
may also entrust a contract research organization (CRO) to perform certain work and 
tasks in the clinical trial. 
The sponsor selects the institution and investigator of the clinical trial and 
recognizes its qualifications and conditions to ensure the completion of the trial. 
In providing experimental drugs to researchers, sponsors shall establish a 
management system and record system for experimental drugs. 
14.5.1 Researcher responsibility 
This clinical study will be conducted in accordance with the moral, ethical and 

 
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scientific principles as well as protocol design and regulations stipulated by the 
Declaration of Helsinki and the Chinese GCP. 
The investigator is responsible for making medical decisions related to the clinical 
trial to ensure that the subject receives timely treatment if AE occurs during the trial. 
Researchers should be aware of the procedures and requirements for reporting SAE, 
and record and report these events as required. 
The researcher shall accurately, completely, timely and legally load the data into 
the eCRF, and accept the supervision or audit of the sponsor or CRO company and the 
inspection and inspection of the drug regulatory department to ensure the quality of 
the clinical trial. 
14.5.2 Sponsor research methods for data publication 
The sponsor has exclusive rights to this research data. Individual contributions 
should not be published until the final report of the multi-centre study has been 
completed, except with the written consent of the sponsor. The Sponsor has the final 
say in respect of the manuscript and publication. 
15. Ethics related to trials 
15.1 Ethics committee 
The investigator shall submit the Investigator Handbook, protocol, informed 
consent, CRF and test drug inspection Report (as submitted), and any other 
information to the subject to the Ethics Committee for approval prior to the 
commencement of the study. Any amendments to the protocol must be approved by 
the Ethics Committee. 
15.2 Informed consent 
In informed consent, a qualified investigator must explain in detail to each subject 
the nature, purpose, procedure, expected time, potential risks and benefits, and any 
discomfort that may arise. Each subject must be aware that participation in the trial is 
voluntary and that he/she may withdraw from the trial and withdraw informed consent 
at any time without affecting his/her subsequent treatment or relationship with the 
treating physician. 
Informed consent should be given in a standard writing format and in 

 
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non-professional language as far as possible. Each informed consent form must 
include all of the above and include a voluntary declaration. Informed consent must 
be submitted to the Ethics Committee for approval. 
After the basics of the trial have been explained and the investigator is satisfied that 
each subject understands the purpose of the trial, each subject should be asked to sign 
and date the informed consent form. Subjects should read and consider their 
statements before signing and dating them, and should obtain an informed consent 
form to keep after signing. Subjects are not allowed to enter the study without 
informed consent. 
15.3 other 
When the subject is unable to participate independently in informed consent, a 
reliable and fair witness/legal representative must be present throughout the informed 
consent process. The selection of fair witnesses/legal representatives shall not violate 
the subject's right to confidentiality. After the subject has given verbal consent, the 
fair witness/legal representative should sign and date the informed consent to certify 
that the information is accurate. 
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