Fu-Sheng Liu,Xiao-Lei Fang, ,Zhi-Rui Cheng,Jin Liu,Zhi Liu,Chen-Chen Sun,Lei Sun,Hui Jin

1 Dongfang Hospital of Beijing University of Chinese Medicine,Beijing,China

2 Beijing University of Chinese Medicine,Beijing,China

3 Dongzhimen Hospital,Beijing University of Chinese Medicine,Beijing,China

Abstract

Key words: traditional Chinese medicine; acute ischemic stroke; Barthel index; vascular endothelial growth factor; stroke initial state decoction; Gastrodin injection and Tanreqing injection; Xingnaojing injection; randomized controlled trial

INTRODUCTION

Research background

Acute ischemic stroke (AIS) is a major cause of adult disability(Catanese et al.,2017; Rabinstein,2017; Sun et al.,2017).Early diagnosis and intervention is considered an important measure in preventing long-term disability after AIS (Ly and Maquet,2018; Yin and Wang,2018).Current standard methods for early treatment of AIS include fibrinolytic therapy (Phan et al.,2016) and antiplatelet therapy (Yin and Wang,2018).However,few patients with AIS receive fibrinolytic therapy within 3-4.5 hours after disease onset (Cheng and Kim,2015;Yan et al.,2015),and there is evidence that antiplatelet therapy does not lower the risk for recurrent stroke,but can instead increase the risk for hemorrhage (Bakheet et al.,2015).

Traditional Chinese medicine is the most widely used method to treat AIS in Chinese and Central Asian Chinese communities (Venketasubramanian et al.,2009,2013; Young et al.,2010; Chen et al.,2013; Wan et al.,2015; Du et al.,2016; Zhang et al.,2016).Given the limitations of standard therapies,researchers are increasingly interested in the use of traditional Chinese medicine to treat this condition (Chang et al.,2016).According to traditional Chinese medicine theory,the syndrome is the overall reaction of the body's pathophysiological state.AIS has been shown to be caused by three pathogens,“wind,” “fire,” and “phlegm” (Song et al.,2009),and the elimination of these pathogenic factors may alleviate the symptoms of stroke.

Although traditional Chinese medicine and western medicine have been widely used for treatment of AIS in clinical settings (Chen et al.,2013; Wan et al.,2015; Du et al.,2016)(Table1),the objective efficacy of traditional Chinese medicine combined with western medicine requires further investigation.

Study objective

This randomized controlled trial will investigate the efficacy and safety of traditional Chinese medicine combined with western medicine in the treatment of AIS during the early phase.

SUBJECTS AND METHODS

Study design

A prospective,single-center,assessor-blinded randomized controlled trial.

Table1: Clinical trial results of traditional Chinese medicine for treatment of acute ischemic stroke

Study setting

Dongfang Hospital,Beijing University of Chinese Medicine,China.

Investigator qualifications

Dongfang Hospital,Beijing University of Chinese Medicine is a grade 3 class-A traditional Chinese medicine hospital,and has previously participated in a number of key traditional Chinese medicine projects funded by the National Population and Family Planning Commission and Ministry of Health of China.Each investigator within the study team is educated to master's degree level or higher,has a professional title of associate chief physician or higher,and has more than 5 years of clinical experience in neurology.

Study population Recruitment

Patients with AIS will receive treatment at the emergency department because of their unstable disease condition.Therefore,the study population will be screened for eligibility and recruited from the Department of Emergency,Dongfang Hospital,Beijing University of Traditional Chinese Medicine.Demographic data for each patient,including sex,age,body mass,body weight,and medical history,will be collected on a case report form upon admission.

Eligibility Inclusion criteria

Patients who are scheduled to receive treatment will be considered for inclusion if they meet the following criteria: a)fulfillment of the diagnostic criteria for AIS as per the 2014 Chinese Guidelines on the Diagnosis and Treatment of Acute Ischemic Stroke (Chinese Society of Neurology and Chinese Society of Neurology Cerebrovascular Disease Section,2015);b) National Institute of Health Stroke Scale (NIHSS) score of 5-20; c) stroke onset time ≤ 72 hours; d) men and women＞ 40 years of age; e) provision of written informed consent from participants,or from the legal guardians of patients who are unconscious.

Exclusion criteria

Patients presenting with one or more of the following criteria will be excluded from the study: a) mental disorders; b) severe liver dysfunction (total bilirubin ＞ 2 mg,transaminase levels＞ 10 times the upper reference limit),kidney dysfunction(creatinine clearance ＜ 30 mL/min),cardiac dysfunction (New York Heart Association (NYHA) class III or higher (Raphael et al.,2007)) or severe systemic diseases; c) allergy to gastrodin injection,Tanreqinginjection,Xingnaojinginjection,or Chinese decoction; d) women who are lactating or pregnant;e) participation in other clinical trials within 3 months prior to enrolment

Withdrawal criteria

Patients presenting with one or more of the following criteria will be withdrawn from the study: a) Allergy to the study drug; b) concomitant use of other treatments or drugs that may enhance the efficacy of the investigational products; c)worsening condition,serious complications,or serious adverse events.The detailed reasons for withdrawal will be recorded in the case report forms.

Patients that experience serious adverse events or die following an adverse drug reaction will be financially compensated by an insurance company.Serious adverse events refer to adverse drug reactions that occur during the duration of the clinical trial and result in hospitalization,prolonged hospital stay,disability,or decreased work capacity; are life-threatening;or result in death.

Interventions Grouping

Patients will be randomly divided into one of two groups: a traditional Chinese medicine + western medicine group (combined treatment group) and a control group.Immediately after admission,all patients will receive 3-day early treatment for AIS.

Treatments

Both groups of patients will receive routine western medicine treatment consisting of thrombolysis or thrombectomy,antiplatelet therapy,neuroprotective therapy,blood pressure and glucose control,nutritional supplementation,and rehabilitation.

In addition,the combined treatment group will receive the following traditional Chinese medicine treatments: stroke initial state decoction (SISD,Beijing Tcmages Pharmaceutical Co.,Ltd.,China),orally administered 250 mL 0.9% normal saline and 0.6 g Gastrodin injection (State Medical Permission No.H20013046; KPC Pharmaceuticals,Inc.,Kunming,China),intravenously administered; and 250 mL 0.9% normal saline and 20 mLTanreqinginjection (State Medical Permission No.Z20030054; Shang Hai Kai Bao Pharmaceutical Co.,Ltd.,China),intravenously administered.250 mL 0.9%normal saline and 20 mLXingnaojinginjection (State Medical Permission No.Z32020563; Wuxi Jimin Kexin Shanhe Pharmaceutical Co.,Ltd.,China) will also be administered intravenously.

Outcome measures Primary outcome measures

1.National Institute of Health Stroke Scale (NIHSS) score on days 1,3,7,and 14 after treatment.The NIHSS is used to evaluate neurological deficits,including level of consciousness,cognitive function,sensory function,visual field test,and reflex,and has been widely used for evaluating neurological deficits in patients with AIS (Kwah and Diong,2014).

2.Traditional Chinese medicine stroke scale score on days 1,3,7,and 14 after treatment.This scale is used to evaluate the severity of neurological deficits based on the severity of traditional Chinese medicine syndromes (Gao et al.,2011).

Secondary outcome measures

1.Barthel index on days 1,3,7,and 14 after treatment.Barthel index can reflect the severity of stroke (Quinn et al.,2011).

2.Modified Rankin scale score on days 1,3,7,and 14 after treatment.The Modified Rankin scale is used to reflect the severity of stroke (Bruno et al.,2013).

3.Glasgow coma scale score before treatment and on days 1,3,7,and 14 after treatment.The Glasgow coma scale is used to evaluate patient consciousness (Teasdale and Jennett,1974).

4.Serum matrix metalloproteinase-9 and vascular endothelial growth factor levels before treatment and on day 3 after treatment.Previous studies have shown that these factors are associated with infarct volume and clinical prognosis in patients with AIS (Abdelnaseer et al.,2017; Geiseler and Morland,2018).

Adverse events

To ensure patient safety,routine blood and urine testing,routine stool analysis,liver and kidney function,coagulation function,D-dimer level,and electrocardiogram assessment will be performed after treatment.Key indicators will be monitored throughout the trial.

The onset time,symptoms and signs,duration,severity,treatment measures,treatment efficacy,and causal relationship of any adverse events occurring during the 3-day treatment period and the 2-week follow-up period will be recorded.Serious adverse events will be reported in the case report forms and promptly to the institutional ethics committee.

Timing of outcome measure evaluation and adverse events is shown in Table2.

Table2: Schedule of outcomes and adverse events

Trial procedure

Trial flow chart is shown in Figure1.

Sample size calculation

With reference to a previous study (Zeng and Zhao,2016),we assumed an NIHSS score for the combined treatment and control groups of 9.49 ± 4.98 and 12.32 ± 4.43 points,respectively.Takingα= 0.05 andβ= 0.1,an effective sample size ofn= 53/group was calculated according to superiority and non-inferiority design formulae.Assuming a withdrawal rate of 10%,a final sample size ofn= 60/group will be used.Therefore,a total of 120 patients (60 patients in each group)will be included in this study.

Figure1: Trial flow chart.

Randomization

Designated researchers will generate a random digital sequence using Excel 2007 software (Microsoft Corporation,Redmond,WA,USA),and sequence numbers will be printed onto digital cards and sealed in opaque envelopes printed with a serial number corresponding to the random digital sequence numbers.Eligible patients who have provided written informed consent will be randomized to the combined treatment group(n= 60) or the control group (n= 60) according to the assigned digital sequence.

Blinding

It is difficult to perform blinding to investigators and participants,so only assessors will be blinded to grouping.

Ethical approval

This study will be performed in accordance with theDeclaration of Helsinkideveloped by the World Medical Association.This study was approved by Hospital Ethics Committee,Dongfang Hospital,Beijing University of Chinese Medicine(approval No.JDF-IRB-2016033602) on November 2,2016(Additional file 1).The whole study process will be supervised by the research committee.Any severe adverse events will be reported to the research committee immediately.Changes to the study design can only be made with the permission of the research committee.

Informed consent

It is the responsibility of the investigators to provide the patient or his or her legal guardian with a complete and comprehensive introduction about the purpose,procedure,and possible benefits and risks of this study.Each patient or his or her legal guardian will sign the informed consent (Additional file 2) and he or she will understand that they have the right to withdraw from the study at any time.The participant's personal privacy and data confidentiality will be protected during the study period.The manuscript was prepared in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statements (Additional file 3).Results will be disseminated through presentations at scientific meetings and/or by publication in a peer-reviewed journal.

Statistical analysis

SPSS 20.0 software (IBM Corp.,Armonk,NY,USA) will be used for data analysis.Continuous variables are expressed as the mean ± SD.Categorical variables are expressed as frequency or percentage.Thet-test (if normally distributed)or nonparametric test (if abnormally distributed) will be used for comparison of continuous variables between groups.The chi-square test or nonparametric test will be used for comparison of categorical variables between groups.A level ofP＜ 0.05 will be considered statistically significant.Efficacy will be analyzed according to the intention-to-treat principle.Missing values will be imputed by the last observation carried forward method.

Data collection

All data will be recorded in case report forms by trained investigators.To ensure data reality,all investigators participating in this trial will receive training regarding how to fill in case report form prior to initiation of this trial.All data will be collected on site and input in real-time using a double data entry strategy with Epi-Data 3.0 data management software.

Data management

After data entry,real-time quality control and online error correction will be performed by investigators responsible for data entry using a two-pass verification method.The missing data or special errors will be detected by the software program and resolved by the investigators.Transparency in the research process should be ensured,the research progress and the existing problems should be managed at any time and rationally solved under the permission of protocol principle.

Quality control

Before the study protocol put into practice,a series of training sessions will be performed to ensure that all the investigators have a full understanding of the study protocol and mastery of the standard operating procedures.The case report forms will be regularly checked by the supervisors,and the investigators will be notified of any problems in a timely manner.The members of research team will meet regularly to discuss problems that they have confronted and share their experience with others.Moreover,a telephone will be established for the participants who have been discharged.Patients enrolled in the clinical trial will be able to receive a certain amount of traditional Chinese medicine for combined treatment group and some related examination subsidies for both groups.

Audits

The clinical monitors will be the persons who come from the department of neurology but do not participate in this study and be responsible for reviewing trial data,extracting medical records,visiting the trial site,and inquiring about relevant personnel once every 6 months during the study period.The clinical monitors will report the progression of the trial to the Medical Ethics Committee.Trial registration will be updated simultaneously.

Confidentiality

All electronic data will be password-protected.

Results dissemination

Results will be available at ResMan Research Manager(http://www.medresman.org/) within 6 months after the completion of the trial without any charge and disseminated by publication through publication in a peer-reviewed journal.

DISCUSSION

Study limitations

This study will not evaluate the long-term efficacy of traditional Chinese medicine combined with western medicine in the treatment of AIS,and the study will be conducted at a one center only.

Treatment applicability

Traditional Chinese medicine has been widely used in China for the treatment of AIS (Zhang et al.,2016),although most studies examining combination treatment with traditional Chinese medicine and western medicine focus only on the effects of the specific drugs (Venketasubramanian et al.,2009,2013;Young et al.,2010; Chen et al.,2013; Venketasubramanian et al.,2013; Wan et al.,2015; Du et al.,2016; Zhang et al.,2016).To date,few studies have reported the efficacy of traditional Chinese medicine combined with western medicine in the early phase of AIS.

This study will be the first to investigate the efficacy and safety of traditional Chinese medicine combined with western medicine for the treatment of AIS based on the primary syndrome elements of traditional Chinese medicine theory.

Interpretation

Traditional Chinese medicine has been widely used for the clinical treatment of acute ischemic stroke in China (Zhang et al.,2016).Gastrodin injection (Yu et al.,2007),Tanreqinginjection (He,2007),andXingnaojinginjection (Peng et al.,2014) are described in the Chinese Pharmacopoeia for the clinical treatment of AISviaan intravenous administration routes.In this study,oral stroke initial state decoction will be administered alongside intravenous Gastrodin injection andTanreqinginjection.This study will investigate the efficacy and safety of 3-day comprehensive intensive therapy by assessing neurological deficits,traditional Chinese medicine stroke scale score,quality of life in patients with acute ischemic stroke.Results of this study will provide evidence for the use of traditional Chinese medicine in combination with western medicine for the treatment of AIS.

TRIAL STATUS

Patient recruiting is ongoing.

Additional files

Additional file 1: Hospital ethics approval (Chinese).

Additional file 2: Informed consent form (Chinese).

Additional file 3: SPIRIT Checklist.

Author contributions

Design of study: XLF,FSL; manuscript writing: FSL,JL; concept and implementation of study: FSL,ZRC,CCS,ZL,LS,HJ; approval of final manuscript for publication: all authors.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Financial support

This work was supported by the National Special Scientific Research Project for the Construction of Traditional Chinese Medicine Clinical Research,No.JDZX2015289; the Central University Basic Scientific Research Foundation of China,No.2016-JYB-JSPY-047.The funders had no role in the study design,data collection,management,analysis,and interpretation; paper writing; or decision to submit the manuscript for publication.

Institutional review board statement

All experimental procedures will be performed in strict accordance with theDeclaration of Helsinkiand relevant ethical requirement of the Dong Fang Hospital,Beijing University of Chinese Medicine,China (approval No.JDF-IRB-2016033602) on November 2,2016.

Declaration of patient consent

The authors certify that they will obtain all appropriate patient consent forms from the patients or their legal guardians.In the forms,the patients or their legal guardians will give their consent for patients'images and other clinical information to be reported in the journal.The patients or their legal guardians understand that the patients'names and initials will not be published and due efforts will be made to conceal the patients' identity.

Reporting statement

This study follows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidance for protocol reporting.

Biostatistics statement

The statistical methods of this study were reviewed by the biostatistician of the Dongfang Hospital,Beijing University of Chinese Medicine,China.

Copyright license agreement

The Copyright License Agreement has been signed by all authors before publication.

Data sharing statement

Individual participant data that underlie the results reported in this manuscript,after deidentification (text,tables,figures,and appendices)will be available indefinitely at ResMan Research Manager (http://www.medresman.org/) within 6 months after the completion of the trial without any charge.Other raw data can be achieved through contact with the corresponding author.Results will be disseminated by publication in a peer-reviewed journal.

Plagiarism check

Checked twice by iThenticate.

Peer review

Externally peer reviewed.

Open access statement

This is an open access journal,and articles are distributed under the terms of the Creative Commons Attribu-tion-NonCommercial-ShareAlike 4.0 License,which allows others to remix,tweak,and build upon the work non-commercially,as long as appropriate credit is given and the new creations are licensed under the identical terms.