bmj open...rehabilitation program and prevention of recurrence for young stroke. our previous two...

For peer review only

Acupuncture treatment for stroke in young adults: protocol of a randomized, sham-controlled clinical trial

Journal: BMJ Open

Manuscript ID bmjopen-2015-010073

Article Type: Protocol

Date Submitted by the Author: 22-Sep-2015

Complete List of Authors: Chen, Lifang; The Third Affiliated Hospital of Zhejiang Chinese Medical University, Department of Acupuncture and Moxibustion Fang, Jianqiao; The Third Affiliated Hospital of Zhejiang Chinese Medical University, Department of Acupuncture and Moxibustion Jin, Xiaoming; Indiana University School of Medicine, Department of Anatomy and Cell Biology & Department of Neurosurgery Keeler, Crystal; The Third Affiliated Hospital of Zhejiang Chinese Medical University, Department of Acupuncture and Moxibustion

Gao, Hong; The Third Affiliated Hospital of Zhejiang Chinese Medical University, Department of Acupuncture and Moxibustion Fang, Zhen; The Third Affiliated Hospital of Zhejiang Chinese Medical University, Department of Rehabilitation Chen, Qin; The Third Affiliated Hospital of Zhejiang Chinese Medical University, Department of Acupuncture and Moxibustion

<b>Primary Subject Heading</b>:

Complementary medicine

Secondary Subject Heading: Complementary medicine, Rehabilitation medicine, Neurology

Keywords: Rehabilitation medicine < INTERNAL MEDICINE, Stroke < NEUROLOGY, COMPLEMENTARY MEDICINE

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Acupuncture treatment for stroke in young adults: protocol of a randomized,

sham-controlled clinical trial

Lifang Chen1

M.D. Ph.D.

Jianqiao Fang1, 2*

M.D. Ph.D.

Xiaoming Jin3*

M.D. Ph.D.

Crystal Lynn Keeler2 DAOM.

Hong Gao1

M.D.

Zhen Fang4

M.D.

Qin Chen1

M.D. Ph.D.

Corresponding author: Jianqiao Fang*, E-mail: [email protected]

Co-corresponding author: Xiaoming Jin*, E-mail: [email protected].

Itemized list of tables and figures:

Figure 1. Route diagram of study design

Table 1. Trial schedule

Table 2. Locations and manipulations of real and sham acupuncture

Supplementary materials

1. The Ethical Approval Document

2. Funding documents

3. SPIRIT checklist

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ABSTRACT

Introduction: Stroke in young adults is not uncommon. Although the overall

incidence of stroke is declining in recent years, the incidence of stroke in young adults

is unfortunately increasing. Traditional vascular risk factors are the main cause of

young ischemic stroke. Acupuncture has been shown to benefit stroke rehabilitation

and ameliorate the risk factors for stroke. The aims of this study were to determine

whether acupuncture treatment will be effective in improving the activities of daily

living (ADL), motor function, and quality of life (QOL) in patients of young ischemic

stroke, and in preventing stroke recurrence by controlling blood pressure, lipids and

body weight.

Methods and analysis: In this randomized, sham-controlled, subject and assessor

blinded clinical trial, 120 patients aged 18-45 years old with a recent (within one

month) ischemic stroke will be randomized to 8-week acupuncture or sham

acupuncture treatment. The primary outcome is Barthel Index for ADL. The

secondary outcomes include: Fugl-Meyer assessment for motor function;

WHOQOL-BREF for QOL; and risk factors measured by ambulatory blood pressure,

the fasting serum lipid, body mass index, and waist circumference (WC). Incidence of

adverse events and long-term mortality and recurrence rate in 10-year and 30-year

follow-up increments will also be investigated.

Ethics and dissemination: Ethical approval was obtained from ethics committee of

the Third Affiliated Hospital of Zhejiang Chinese Medical University. The results will

be disseminated in a peer-reviewed journal and presented at international congresses.

The results will also be disseminated to patients by telephone, during follow-up calls

inquiring on patient’s post-study health status.

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Trial registration number: Chinese Clinical Trial Register: No. ChiCTR-TRC-

13003317, http://www.chictr.org.cn/showprojen.aspx?proj=6242

Key words: stroke, young, randomized controlled trial, acupuncture

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INTRODUCTION

Stroke is one of the most frequent causes of death and chronic disability in China.1

Although the overall incidence of stroke is declining in recent years, the incidence of

stroke in young adults is unfortunately increasing. Approximately 10% to 14% of

ischemic strokes occur in adults aged 18 to 45 years.2, 3

While a specific definition of

“young stroke” is lacking, the vast majority of authors consider “young stroke” as

pertaining to strokes in individuals under 45 years of age.4 For the purposes of this

research, we defined “young stroke” as adults aged 18 through 45 years and designed

a randomized clinical trial to address the particular needs and differences of this

younger age group.

The causes of young stroke are heterogeneous. However, traditional vascular risk

factors, such as hypertension, hyperlipidemia, obesity, smoking, alcohol drinking, and

diabetes mellitus are suggested to be the main risks.5 This finding challenges the

traditional view that young stroke is often caused by “rare” causes.6 Stroke in the

younger age groups may have a dramatic impact on the quality of life for survivors,

given their longer life expectancy and life stage. Not only does this age group have a

longer life expectancy than older adults suffering from stroke, but also these adults are

likely to be wage-earning caregivers for either children and/or aging parents.

Disability from young stroke may create an additional economic burden on the family

along with a societal impact. Because of the potentially greater impact of disability

adjusted life years for this age group, more attention should be paid to the

rehabilitation program and prevention of recurrence for young stroke.

Our previous two separate clinical trials, one for subacute stroke and one for

acute stroke, have been investigating the impact of acupuncture on stroke outcomes

overall.7, 8

During this investigation, we found young adults with stroke may obtain

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“De Qi” easier and recover better than older patients (“De Qi” is an acupuncture term

for a sensation of qi arriving on the needle). Literature searches on “acupuncture for

young stroke” do not yield any results, and intervention outcomes may have a

different impact on young stroke. To date most of the literature focused on young

stroke is observational studies, only very few intervention studies are published.

Randomized clinical trials investigating the impact of acupuncture on young stroke

are currently scarce. Therefore, the authors felt the area of acupuncture on young

stroke deserved further study.

Acupuncture originated more than 3,000 years ago in China and has gained

popularity in the United States since the late 1970s.9 Over its 2500 years of

development, a wealth of experience has accumulated in the practice of acupuncture

for stroke treatment and prevention. According to a report by the WHO in 2002,

“strokes and their sequelae are another major indication for acupuncture”. 10

The

recent reviews showed positive but limited effectiveness of acupuncture as an adjunct

treatment to the conventional care of stroke.11-13

Acupuncture also has been reported

to have benefits for treating risk factors for stroke, including hypertension,

hyperlipidemia, and obesity.14-16

This intervention modality has a long history of

safety and efficacy. As long as acupuncture is performed by trained practitioners

using clean needle techniques, it is a generally safe procedure.17

However, some of the

studies were at risk of bias. Future studies should focus on the appropriate modality of

acupuncture intervention, sham-controls, the appropriate length of treatment, and the

development of more precise tools to assess outcomes.

This clinical trial focuses on young ischemic stroke. The study will test the

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hypotheses that acupuncture (compared to a sham control group), will be effective in

improving several outcome measures after a first-time young stroke, as well as

improving risk factors associated with recurrent stroke. The outcome measures

include: independence in activities of daily living (ADL), motor function, and quality

of life (QOL). Risk factors examined include: blood pressure, lipids and body weight.

METHODS

Study design

This is a 20-week, single center, randomized, sham-controlled, subject and assessor

blinded, exploratory clinical trial. The study patient flow outline is shown in Fig.1; the

trial schedule is shown in Table 1. Protocol modifications are not expected. The

eligibility criteria are fairly well-established. However, if a trial modification were

necessary, any change in criteria or methodology would be communicated to the

entire research team in a conference. All changes will be included in the final write-up

for journal submission.

Study setting, recruitment, and ethics

This trial was registered at Chictr.org (number ChiCTR-TRC-13003317) and will be

conducted in accordance with the Declaration of Helsinki. The ethics committee of

the Third Affiliated Hospital of Zhejiang Chinese Medical University approved the

study. We will recruit participants by advertising in local newspapers, health-related

TV programs, Internet, and WeChat in Hangzhou city. All patients will give written

informed consent. The research coordinator will arrange an in-person meeting with

potential participants, to discuss the study in detail (the study purpose, procedures and

time commitment, the potential risks and benefits associated with participation in the

study), and to obtain informed written consent. The confidentiality of participant

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records will be protected. At the time of enrolment, each patient is assigned a unique

study identification number; this is the only direct identifier included in all study

paper forms and the electronic database. During and after the trial, all records are to

remain secure, either in a locked filing cabinet in a secure area, or as

password-protected computer files. Compensation for trial participants for

trial-related harms are provided by the Third Affiliated Hospital of Zhejiang Chinese

Medical University and will be made on a case-by-case basis. All hospital and

medical care related to any possible harm from the trial will be provided free of

charge to the patient.

Patient population

Patients aged 18-45 years old with a recent (within one month) ischemic stroke are

eligible for this study. Patients included as eligible subjects should display clear

consciousness and stable vital signs, and have no aphasia or cognitive dysfunction.

Exclusion criteria include: patients with intracranial lesions or cerebrovascular

disease history causing sequelae such as movement disorders, mood disorders,

cognitive dysfunction or speech problems; pregnant or breast-feeding women.

Patients with serious diseases related to the heart, liver, kidney, or hematopoietic

system will not be allowed to participate. Patients who are not interested in this study

or are participating in other clinical trials will also be excluded. In order to increase

the credibility of the sham-control, patients with prior experience of acupuncture will

be excluded from our final protocol. Since many people in China have previously

received acupuncture, this exclusion criterion may prolong the study period by

excluding otherwise eligible participants. However, we believe this exclusion

category will improve the quality of the research by providing a more effective sham

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control. Changes affecting trial participants directly would be explained in person by

their coordinators.

Randomization and blinding

Randomization will be computer-generated by independent research staff using SAS

9.3 software (Order Number: 99TKBM). The generated list of random numbers will

be placed into sequentially numbered, opaque, sealed envelopes. Consecutive patients

will be randomly assigned to acupuncture group (AG) or sham acupuncture group

(SG) in a 1:1 ratio. Two acupuncture doctors will be designated to do acupuncture

treatment for AG or SG separately. The study coordinator, not involved in treatment

or assessment, will inform the subjects that they will receive either a “traditional

Chinese acupuncture” (verum) or a “less-painful acupuncture developed especially for

this study” (sham). All of the rehabilitation therapists, outcome assessors, and data

analysts will be blinded to group assignments.

Interventions and comparison

Both groups will receive conventional stroke rehabilitation treatment and care during

the whole 20-week study period. Two certified acupuncturists with more than five

years of clinical experience will separately do acupuncture or sham acupuncture for

assigned patients. The thirty-minute acupuncture or sham treatment will be conducted

bedside in supine position, three times per week (on Monday, Wednesday, and Friday)

for eight weeks. For improving and monitoring adherence, every treatment form and

evaluation form will be filled out and signed by participants’ and researchers’. Those

who have completed all treatments and evaluations will get some financial

compensation.

Acupuncture group

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For scalp acupuncture, filiform stainless steel needles (size 0.25 mm × 40 mm,

Huatuo brand, manufactured by Suzhou Medical Appliance in Suzhou, Jiangsu

Province China) will be inserted through the motor area and the sensory area of the

lesion side. The intervention will include ipsilateral body acupuncture points for the

affected side, LI15 (Jianyu), LI11 (Quchi), LI10 (Shousanli), SJ6 (Zhigou), and LI4

(Hegu) for upper extremities; bilateral points for the lower limbs, ST31(Biguan),

GB34 (Yanglingquan), SP10 (Xuehai), ST36 (Zusanli), ST40 (Fenglong), SP6

(Sanyinjiao), and LR3 (Taichong); and abdominal points, CV12 (Zhongwan), CV10

(Xiawan), CV6 (Qihai), CV4 (Guanyuan), ST25 (Tianshu) and ST15 (Daheng).

Sham acupuncture group

Sham acupuncture in this trial is defined as acupuncture with superficial needle

insertion and minimal stimulation at non-acupoint and non-meridian areas. All

needles for the sham group will be inserted superficially (1～3mm) and without

stimulation, so as to avoid “De Qi”.18

The number of needles inserted, needle

retention time, and the frequency of treatment are all the same as AG. The locations

and manipulations of real acupuncture and sham acupuncture are detailed in Table 2.

Outcome measures

The primary outcome

The primary outcome will be the Barthel Index (BI) for independence in activities of

daily living (ADL). As there are several scoring guidelines for the BI, we adopted the

version of Mahoney.19

Secondary outcomes

Secondary outcomes will include the Fugl-Meyer Assessment (FMA) motor scale, the

World Health Organization Quality of Life BREF (WHOQOL-BREF), ambulatory

blood pressure (BP), fasting serum lipid, body mass index (BMI), and waist

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circumference (WC). The FMA motor scale is recommended highly as a clinical and

research tool for evaluating changes in motor impairment following stroke.20

The

WHOQOL-BREF is a 26-item version of the WHOQOL-100 assessment developed in

the context of four domains of QOL, and is a sound, cross-culturally valid assessment

of QOL.21

We will use the official Chinese version of WHOQOL-BREF, which has

been approved by the WHOQOL Group.22

BP, lipid, BMI, and WC are risk factors for

recurrent stroke, representing relevant secondary outcome measurements. Patients

will receive ambulatory blood pressure measurements, and the average systolic and

diastolic blood pressure levels will be compared. The fasting serum lipid test will

include total cholesterol (TC), low-density lipoprotein cholesterol (LDLC),

high-density lipoprotein cholesterol (HDLC), and triglycerides (TG). The BMI will be

derived from the mass (weight) and height of an individual with the value universally

being expressed in units of kg/m2. The waist circumference will be measured by

starting from the top of the hipbone, bringing the tape all the way around (straight but

not too tight), level with the belly button. All of the primary and secondary outcomes

will be measured at week 0, week 8, and week 20. To observe the long-term

preventive effect and prognosis, we will follow up with all participants annually

through telephone contacts, home-visits, or clinic-visits to collect data on mortality,

recurrence rate of stroke and QOL in 10-year and 30-year increments after stroke.

Incidence of adverse events

All participants will be requested to voluntarily report information about adverse

events (AEs) at each visit. AEs happening during the trial will be recorded and

assessed by the investigators. The acupuncture related AEs may include local bleeding,

hematoma, pallor, sweating or dizziness, fainting during the acupuncture treatment,

unbearable prickling, retained needle after treatment.

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Data collection, management, and monitoring

The Case Report Form (CRF), Treatment Form and Adverse Events Form will be first

completed on paper copies, then double entered into the EDC system electronically by

two independent investigators to act as the first level of control to ensure the accuracy

of the data. The second level of data integrity will include data monitoring and

validation that will be carried out on a regular basis throughout the study. Original

CRFs, all forms (includes consent forms) will be archived securely at The Third

Affiliated Hospital of Zhejiang Chinese Medical University for 5 years following

publication of the last paper or report from the study.

The safety of the study will be monitored by a data and safety monitoring board

(DSMB) of the Clinical Evaluation Center of Zhejiang Provincial Hospital of TCM,

which consists of independent clinical experts and statisticians with access to

unblinded data. The DSMB is independent from the sponsor, the competing interests,

and the investigational site, and will review the performance and safety of the trial

monthly.

The criteria for discontinuing allocated interventions for a given trial participant

include: having recurrent stroke, having serious complications of stroke, or

experiencing serious acupuncture related AEs (if any). Adverse events are described

above. The DSMB will have access to these interim results and make the final

decision to terminate the trial.

The final trial dataset will be under the custody of the Third Affiliated Hospital of

Zhejiang Chinese Medical University. The data manager from Clinical Evaluation

Center of Zhejiang Provincial Hospital of TCM will have access to the complete,

anonymous final dataset. Access to the final dataset or identifiable data by others will

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require written requests to be approved by DSMB of the Clinical Evaluation Center of

Zhejiang Provincial Hospital of TCM, the Third Affiliated Hospital of Zhejiang

Chinese Medical University, and all study investigators.

Sample size estimates

Sample size was calculated based on the results of our previous clinical trial.23

We

expected the primary efficacy parameter (BI) of AG was 10 values higher than that of

SG, and the standard deviation was about 18. A two-sided 5% significance level and

80% power were considered, and the following equation was used:

Based on the calculation, approximately 51 participants in each group would be

required to have a sufficient sample size. With an estimated dropout rate of 15%, each

group required 60 initial participants.

Statistical analysis

Analysis will be conducted at the Clinical Research Institute of Zhejiang Provincial

Hospital of Traditional Chinese Medicine by blinded biostatisticians. SAS software,

version 9.3 will be used for all analysis and two-sided p<0.05 will be considered

statistically significant for all analysis. The full analysis set (FAS) and the per

protocol set (PPS) will both be conducted. Efficacy and safety analysis will be based

on the intention-to-treat (ITT) principle. Missing values will be handled by the mixed

model for repeated measurements (MMRM). Continuous variables with normal

distribution will be expressed as means with standard deviations and compared by

independent sample t-test. For abnormally distributed variables, the data will be

expressed as medians with ranges and non-parametric tests will be used. Categorical

variables will be expressed as number (%) and analyzed by χ2 test or Fisher’s exact

2

2

2

22

az z

nβ σ +

=∆

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test.

Descriptive statistics will be used to detail baseline characteristics of patients

such as gender, type of stroke, and risk factors, and will be compared between two

groups by independent sample t-test or χ2 test. Repeated measures analysis of

variance (ANOVA) will be used to analyze value changes of BI, FMA,

WHOQOL-BREF, blood pressure, blood lipid, BMI, and WC across three testing time

points (week 0, week 8, week 20). To detail all of the outcomes, independent sample

t-test will be used to compare between two groups the final value changes (week

20-week 0) of all above variables. The mortality and occurrence of stroke (including

ischemic stroke and cerebral hemorrhage) in 10-year and 30-year follow-up will be

analyzed with the use of χ2 tests and log-rank test with Kaplan-Meier survival curve

analysis. Differences between the groups in causes of deaths will also be compared by

χ2 test. Safety analysis will be compared with the incidence of adverse events in two

groups by χ2 test.

DISCUSSION

Most of the young adults with stroke have a financial need to return to work and a

desire to enjoy an active social life. To improve fine motor control post-stroke and

obtain more independence in activities of daily living will require a higher level of

recovery. Therefore, any treatments contributing to functional rehabilitation should

not be ignored, including traditional acupuncture. Despite the controversy in recent

years about whether acupuncture should be used as a routine treatment for stroke,

acupuncture may help to improve the neurologic deficits without important side

effects, 24-26

and is well-accepted as part of comprehensive rehabilitation strategies in

China.1 Prevention of ischemic stroke recurrence in young patients also remains an

important clinical problem. Acupuncture may not only be helpful in the treatment of

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post-stroke rehabilitation without significant side effects, but also may have the

effect of regulating blood pressure and lipid counts, and facilitate losing weight at the

same time.12, 13

The acupuncture points used in this trial were designed for treating

both stroke and risk factors, which were selected in compliance with traditional

Chinese medical principles and confirmed by many modern research findings.27

Moreover, because acupuncture reactions and “De Qi” are much easier to achieve in

young adults, acupuncture treatment in these patients is expected to achieve better

therapeutic effects.28

This trial focuses on ADL as the primary outcome, because the ultimate goal of

stroke rehabilitation is to improve the ADL of patients toward greater independence.

Motor dysfunction is the most important sequela after stroke and has a significant

impact on ADL measurements. Because young adults have a longer expected life span

ahead, the quality of life should also be considered. As a result, FMA and WHO-QOL

were chosen as two secondary outcomes of treatment efficacy. Young patients have a

much longer exposure to risk of a recurrent vascular event than older patients, based

on their age alone. Therefore, the study also examines risk-factor-related outcomes

and prevention of recurrent stroke, employing acupuncture for controlling

hypertension, hyperlipidemia, overweight, and abdominal obesity. In addition, AEs

and long-term outcomes with respect to recurrent events and mortality will be

observed. In summary, the comprehensive rehabilitation and efficient secondary

prevention of stroke for young individuals may greatly increase the number of

productive years with good quality of life. To the best of our knowledge, this will be

the first trial of a rigorous, randomized, sham-controlled trial of acupuncture designed

specifically for treating and preventing young stroke.

CONCLUSION

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Stroke in young adults requires a higher level of recovery and effective prevention of

recurrence. This study will be the first rigorous, randomized, sham-controlled trial

focusing on using acupuncture for treating and preventing young ischemic stroke.

Author affiliations

1 Department of Acupuncture and Moxibustion，The Third Affiliated Hospital of

Zhejiang Chinese Medical University, 219 Moganshan Road, Xihu District, Hangzhou

City, Zhejiang Province 310005, China.

2 Zhejiang Chinese Medical University, 548 Binwen Road, Binjiang District,

Hangzhou City, Zhejiang Province 310053, China

3 Department of Anatomy and Cell Biology & Department of Neurosurgery, Indiana

University School of Medicine, 320 West 15th Street, NB Building, Room 500C,

Indianapolis IN 46202, the United States of America

4 Department of Rehabilitation，The Third Affiliated Hospital of Zhejiang Chinese

Medical University, 219 Moganshan Road, Xihu District, Hangzhou City, Zhejiang

Province 310005, China.

Acknowledgements We express our profound appreciation to all coordinators,

therapists and evaluators for their diligence. We thank all of the stroke survivors and

their caregivers who participated in this study.

Funding This work was supported by the program of the National Key Discipline of

Traditional Chinese Medicine-Acupuncture (NO.[2009]30), and partly funded by the

International Exchange Program of Clinical Technology from Health and Family

Planning Commission of Zhejiang Province (NO.[2014]48) and the Provincial

Administration of Traditional Chinese Medicine of Zhejiang (No. 2011ZGG003). The

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sponsor will have no role in the design and conduct of the study. The trial sponsor is

The Third Affiliated Hospital of Zhejiang Chinese Medical University (219

Moganshan Road, Xihu District, Hangzhou City, Zhejiang Province 310005, China,

86-571-88393534).

Authors’ contributions Lifang Chen, Jianqiao Fang, and Xiaoming Jin designed or

conceptualized the trial, drafted and revised the manuscript. Crystal Lynn Keeler,

Hong Gao, Zhen Fang, and Qin Chen designed and conducted the trial. All authors

have read revised, and approved this version of the article.

Competing interests None declared.

Patient consent Obtained.

Ethics approval The ethics committee of the Third Affiliated Hospital of Zhejiang

Chinese Medical University approved the study.

Provenance and peer review Not commissioned; peer reviewed for ethical and

funding approval prior to submission.

Data sharing statement The results of our original research will be disseminated in a

peer-reviewed journal and presented at international congresses.

Trial status The trial is currently enrolling participants; the first subject was included

on December 1st, 2013. Estimated completion date for this trial is March 31th, 2016.

Open Access This is an Open Access article distributed in accordance with the terms

of the Creative Commons Attribution (CC BY 4.0) license, which permits others to

distribute, remix, adapt and build upon this work, for commercial use, provided the

original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

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8. Chen L, Fang J, Ma R, et al. Acupuncture for acute stroke: study protocol for a

multicentre, randomised, controlled trial. Trials 2014;15:214.

9. Ernst E. Acupuncture-a critical analysis. J Intern Med 2006;259:125-37.

10. World Health Organization. Acupuncture: Review and analysis of reports on

controlled clinical trials. Geneva, Switzerland, 2002.

11. Vados L, Ferreira A, Zhao SF, et al. Effectiveness of acupuncture combined with

rehabilitation for treatment of acute or subacute stroke: a systematic review. Acupunct

Med 2015: acupmed-2014-010705.

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12. Lee SJ, Shin BC, Lee MS, et al. Scalp acupuncture for stroke recovery: A systematic

review and meta-analysis of randomized controlled trials. Eur J Integr Med 2013;2:

87-99.

13. Zhang J, Wang D, Liu M. Overview of systematic reviews and meta-analyses of

acupuncture for stroke. Neuroepidemiology 2014; 42(1): 50-58.

14. Flachskampf FA, Gallasch J, Gefeller O, et al. Randomized trial of acupuncture to

lower blood pressure. Circulation 2007;115:3121-129.

15. Sui Y, Zhao HL, Wong VC, et al. A systematic review on use of Chinese medicine

and acupuncture for treatment of obesity. Obes Rev 2012;13:409-30.

16. Tuǧrul Cabıoǧlu M, Ergene N. Electroacupuncture therapy for weight loss reduces

serum total cholesterol, triglycerides, and LDL cholesterol levels in obese women. Am

J Chin Med 2005;33:525-33.

17. Lao L, Hamilton GR, Fu J, Berman BM. Is acupuncture safe? A systematic review of

case reports. Altern Ther Health Med 2003;1:72-83.

18. MacPherson H, Asghar A. Acupuncture needle sensations associated with De Qi: a

classification based on experts' ratings. J Altern Complement Med 2006;12: 633-37.

19. Mahoney FI, Barthel DW. Functional evaluation: the Barthel index. Md State Medi J

1965;14:61-5.

20. Gladstone DJ, Danells CJ, Black SE. The Fugl-Meyer assessment of motor recovery

after stroke: a critical review of its measurement properties. Neurorehabil Neural

Repair 2002;16:232-40.

21. Skevington SM, Lotfy M, O'Connell KA, et al. The World Health Organization's

WHOQOL-BREF quality of life assessment: psychometric properties and results of

the international field trial. A report from the WHOQOL group. Qual Life Res

2004;13:299-310.

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22. Wang X, Gao L, Zhang H, et al. Post-earthquake quality of life and psychological

well-being: longitudinal evaluation in a rural community sample in northern China.

Psychiatry Clin Neurosci 2000;54:427-33.

23. Chen LF, Fang JQ, Wu YY, et al. Acupuncture for Motor Dysfunction after Subacute

Stroke: A Multi-center Randomized Controlled Trial. Chinese Acupuncture &

Moxibustion 2014;4:313-18.

24. Wu P, Mills E, Moher D, et al. Acupuncture in poststroke rehabilitation: a systematic

review and meta-analysis of randomized trials. Stroke 2010;41:e171-79.

25. Wong AM, Su TY, Tang FT, et al. Clinical Trial of Electrical Acupuncture on

Hemiplegic Stroke Patients. Am J Phys Med Rehabil 1999;78:117-122.

26. Uchida S, Hotta H. Acupuncture affects regional blood flow in various organs. Evid

Based Complement Altern Med 2008;5:145–151.

27. Naeser MA, Alexander MP, Stiassny-Eder D, et al. Real versus sham acupuncture in

the treatment of paralysis in acute stroke patients: a CT scan lesion site study.

Neurorehabil Neural Repair1992;6:163-74.

28. Park SU, Ko CN, Bae HS, et al. Short-term reactions to acupuncture treatment and

adverse events following acupuncture: a cross-sectional survey of patient reports in

Korea. J Altern Complement Med 2009;15:1275-283.

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Figure 1.Route diagram of study design

AG (n=60) real acupuncture &

rehabilitation (week 1-week 8)

SG (n=60) sham acupuncture &

rehabilitation (week 1-week 8)

Ineligible (n= )

reason recorded

Randomization (n=120)

Recruitment and Screening

Baseline information (week 0)

Evaluation

primary & secondary outcomes

(week 9)

Enrollment

Allocation

Follow-up

Mortality, recurrence rate, QOL

(10 years and 30 years after stroke )

Evaluation

primary & secondary outcomes

(week 20)

Informed consent

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Assessment Screening

Baseline

Week 0

After-treatment

Week 8

Follow-up

Week 20

Follow-up

Year 10

Follow-up

Year 30

Informed consent ○ ○

Demographics ○ ○

Stroke type ○ ○

History of stroke ○ ○ ○ ○

History of disease △ ○ ○ ○

Concomitant

medication

△ ○ ○ ○ ○ ○

Blood pressure △ ○ ○ ○ △ △

Blood lab ○ ○ ○ △ △

Body mass index △ ○ ○ ○ △ △

Waist circumference △ ○ ○ ○ △ △

Barthel Index ○ ○ ○ △ △

FMA motor scale ○ ○ ○ △ △

WHOQOL-BREF ○ ○ ○ ○ ○

Adverse events ○ ○

Mortality ○ ○

Recurrence of stroke ○ ○

Treatment method ○ ○

○, required; △, optional.

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Points

Real acupuncture a

location

Sham acupuncture b

location

LI15

(Jian yu)

In the depression distal and anterior to the

acromion, between the clavicular and acromial

portions of the deltoid muscle.

1cm lateral away

from the actual

points of body

acupuncture

LI11

(Qu chi)

With the elbow flexed, on the lateral end of the

elbow crease, in a depression between the end

of the crease and the lateral epicondyle of the

humerus, on the extensor carpi radialis longus

muscle.

LI10

(Shou san li)

2 cun distal to LI11, on the extensor carpi

radialis longus muscle.

SJ6

(Zhi gou)

3 cun proximal to the dorsal wrist joint space

(‘dorsal wrist

crease’), in a depression between the radius and

the ulna, radial to the tendon of the extensor

digitorum communis muscle.

LI4

(He gu)

On the radial aspect of the hand, between the

1st and 2nd

metacarpal bones, closer to the 2nd metacarpal

bone and

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approximately at its midpoint.

ST31

(Bi guan)

Inferior to the anterior superior iliac spine and

lateral to the sartorius muscle, at the level of

the lower border of the pubic symphysis.

1cm lateral away

from the actual

points of body

acupuncture

GB34

(Yang ling quan)

In the depression anterior and inferior to the

head of the fibula, between the peroneus longus

and extensor digitorum longus muscles.

SP10

(Xue hai)

With the knee flexed, 2 cun proximal and

slightly medial to the medial superior border of

the patella, in a depression on the vastus

medialis muscle.

ST36

(Zu san li)

3 cun distal to ST-35 (‘lateral eye of the knee’)

and 1 finger-breadth lateral to the anterior crest

of the tibia, on the tibialis anterior muscle.

ST40

(Feng long)

At the midpoint of the line joining ST-35 and

ST-41, 2 fingerbreadths lateral to the anterior

crest of the tibia.

SP6

(San yin jiao)

3 cun proximal to the highest prominence of

the medial malleolus, on the posterior border of

the medial crest of the tibia.

LR3

(Tai chong)

On the dorsum of the foot, between the 1st and

2nd metatarsal bones, in the depression

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proximal to the metatarsophalangeal joints and

the proximal angle between the two bones.

CV12

(Zhong wan)

On the anterior midline, 4 cun superior to the

umbilicus.

1cm lateral away

from the actual

points of body

acupuncture

CV10

(Xia wan)


centre of the umbilicus.

CV6

(Qi hai)

On the anterior midline, 1.5 cun inferior to the

umbilicus.

CV4

(Guan yuan)

On the anterior midline, 3 cun inferior to the

umbilicus.

ST25

(Tian shu)

2 cun lateral to the umbilicus.

ST15

(Da heng)

4 cun lateral to the centre of the umbilicus, on

the mamillary line.

The motor area 0.5cms posterior to the midpoint of the

anterior-posterior line defines the upper limit of

the motor area. The lower limit intersects the

eyebrow-occiput line at the anterior border of

the natural hairline on the temple.

1 cm anterior away

from the motor area

and the sensory area

of the lesion side of

scalp acupuncture

The sensory area A line parallel to the motor area and 1.5cms

behind it.

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a Manipulations of real acupuncture. For scalp acupuncture, the needle is swiftly

inserted into the subcutaneous tissue of the scalp in a horizontal direction. When the

tip of needle reaches the subgaleal layer and the practitioner feels low insertion

resistance, the needle is further inserted to a depth of 30mm～40mm by twirling

method. Three needles are used for each area. For body acupuncture, the needle is

inserted into the points to a depth of between 30 mm to 40 mm according to different

regions. Manual stimulation will be applied to the needles until the patients

experience the needling sensation (called “Deqi” in Chinese acupuncture). For

electroacupuncture of CV12 (Zhong wan) and CV10 (Xia wan), ST25 (Tianshu, two

sides) points, SDZ-ⅡB Nerve and Muscle Stimulator (Suzhou Medical Appliance

Factory, Suzhou, China) will be used to give continuous high-frequency (50 Hz)

stimulus. The intensity is adjusted to a level that is tolerable to the patient (usually

about 3～5 grade, with a possible scope of 1～65 gradients of intensity).

b Manipulations of sham acupuncture. The same stainless needles (0.25mm×40mm,

described above) will be used. For body acupuncture, 20 needles will be inserted 1cm

lateral away from the actual acupoints; and the same electro-acupuncture instrument

will be used, but only with 1 grade of intensity. For scalp acupuncture, needles will be

inserted 1 cm anterior away from the motor area and the sensory area of the lesion

side.

c Manipulations of two groups. The acupuncturists of two groups will inserted needles

in about 5-7 minutes, during which minimal interaction with the patients will be

made. Then the patients are left alone to rest for 30 minutes (the needle retention

period for body acupuncture is 30 minutes, that for scalp acupuncture is four hours).

At the end of each treatment, the needles will be removed quickly within 3-5 minutes,

and minimal social interaction is made. Patients receive no additional attention,

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training, or interaction as a result of the acupuncture session, thereby standardizing

the treatment and control groups.

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1

SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents*

Section/item Item No

Description Addressed on page number

Administrative information

Title 1 Descriptive title identifying the study design, population, interventions, and, if applicable, trial

acronym

_______1_____

Trial registration 2a Trial identifier and registry name. If not yet registered, name of intended registry ____ 3 _______

2b All items from the World Health Organization Trial Registration Data Set _____ 3______

Protocol version 3 Date and version identifier See The Ethical Approval

Document

Funding 4 Sources and types of financial, material, and other support _____15_____

Roles and

responsibilities

5a Names, affiliations, and roles of protocol contributors _____15,16___

5b Name and contact information for the trial sponsor ______16_____

5c Role of study sponsor and funders, if any, in study design; collection, management, analysis, and

interpretation of data; writing of the report; and the decision to submit the report for publication,

including whether they will have ultimate authority over any of these activities

______15,16 __

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2

5d Composition, roles, and responsibilities of the coordinating centre, steering committee, endpoint

adjudication committee, data management team, and other individuals or groups overseeing the

trial, if applicable (see Item 21a for data monitoring committee)

_____11,16____

Introduction

Background and

rationale

6a Description of research question and justification for undertaking the trial, including summary of

relevant studies (published and unpublished) examining benefits and harms for each intervention

____4,5______

6b Explanation for choice of comparators ____5,6______

Objectives 7 Specific objectives or hypotheses _____5,6_____

Trial design 8 Description of trial design including type of trial (eg, parallel group, crossover, factorial, single

group), allocation ratio, and framework (eg, superiority, equivalence, noninferiority, exploratory)

______6______

Methods: Participants, interventions, and outcomes

Study setting 9 Description of study settings (eg, community clinic, academic hospital) and list of countries where

data will be collected. Reference to where list of study sites can be obtained

______6____

Eligibility criteria 10 Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for study centres and

individuals who will perform the interventions (eg, surgeons, psychotherapists)

______7______

Interventions 11a Interventions for each group with sufficient detail to allow replication, including how and when they

will be administered

__8,9,Table 2___

11b Criteria for discontinuing or modifying allocated interventions for a given trial participant (eg, drug

dose change in response to harms, participant request, or improving/worsening disease)

______11______

11c Strategies to improve adherence to intervention protocols, and any procedures for monitoring

adherence (eg, drug tablet return, laboratory tests)

_______8_____

11d Relevant concomitant care and interventions that are permitted or prohibited during the trial _______11_____

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3

Outcomes 12 Primary, secondary, and other outcomes, including the specific measurement variable (eg, systolic

blood pressure), analysis metric (eg, change from baseline, final value, time to event), method of

aggregation (eg, median, proportion), and time point for each outcome. Explanation of the clinical

relevance of chosen efficacy and harm outcomes is strongly recommended

_______9,10____

Participant timeline 13 Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and

visits for participants. A schematic diagram is highly recommended (see Figure)

_10, Table 1___

Sample size 14 Estimated number of participants needed to achieve study objectives and how it was determined,

including clinical and statistical assumptions supporting any sample size calculations

______12______

Recruitment 15 Strategies for achieving adequate participant enrolment to reach target sample size ______6______

Methods: Assignment of interventions (for controlled trials)

Allocation:

Sequence

generation

16a Method of generating the allocation sequence (eg, computer-generated random numbers), and list

of any factors for stratification. To reduce predictability of a random sequence, details of any

planned restriction (eg, blocking) should be provided in a separate document that is unavailable to

those who enrol participants or assign interventions

______8______

Allocation

concealment

mechanism

16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially

numbered, opaque, sealed envelopes), describing any steps to conceal the sequence until

interventions are assigned

_____8 ______

Implementation 16c Who will generate the allocation sequence, who will enrol participants, and who will assign

participants to interventions

______8_______

Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers,

outcome assessors, data analysts), and how

_______8______

17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a

participant’s allocated intervention during the trial

______8_______

Methods: Data collection, management, and analysis

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4

Data collection

methods

18a Plans for assessment and collection of outcome, baseline, and other trial data, including any

related processes to promote data quality (eg, duplicate measurements, training of assessors) and

a description of study instruments (eg, questionnaires, laboratory tests) along with their reliability

and validity, if known. Reference to where data collection forms can be found, if not in the protocol

_____11____

18b Plans to promote participant retention and complete follow-up, including list of any outcome data to

be collected for participants who discontinue or deviate from intervention protocols

____8,10_____

Data management 19 Plans for data entry, coding, security, and storage, including any related processes to promote

data quality (eg, double data entry; range checks for data values). Reference to where details of

data management procedures can be found, if not in the protocol

_____11____

Statistical methods 20a Statistical methods for analysing primary and secondary outcomes. Reference to where other

details of the statistical analysis plan can be found, if not in the protocol

____12,13_____

20b Methods for any additional analyses (eg, subgroup and adjusted analyses) ____13_____

20c Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis),

and any statistical methods to handle missing data (eg, multiple imputation)

_____12____

Methods: Monitoring

Data monitoring 21a Composition of data monitoring committee (DMC); summary of its role and reporting structure;

statement of whether it is independent from the sponsor and competing interests; and reference to

where further details about its charter can be found, if not in the protocol. Alternatively, an

explanation of why a DMC is not needed

______11_____

21b Description of any interim analyses and stopping guidelines, including who will have access to

these interim results and make the final decision to terminate the trial

______11_____

Harms 22 Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported

adverse events and other unintended effects of trial interventions or trial conduct

_______11____

Auditing 23 Frequency and procedures for auditing trial conduct, if any, and whether the process will be

independent from investigators and the sponsor

______11_____

Ethics and dissemination

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5

Research ethics

approval

24 Plans for seeking research ethics committee/institutional review board (REC/IRB) approval _____6________

Protocol

amendments

25 Plans for communicating important protocol modifications (eg, changes to eligibility criteria,

outcomes, analyses) to relevant parties (eg, investigators, REC/IRBs, trial participants, trial

registries, journals, regulators)

_____6________

Consent or assent 26a Who will obtain informed consent or assent from potential trial participants or authorised

surrogates, and how (see Item 32)

______6_______

26b Additional consent provisions for collection and use of participant data and biological specimens in

ancillary studies, if applicable

______No_______

Confidentiality 27 How personal information about potential and enrolled participants will be collected, shared, and

maintained in order to protect confidentiality before, during, and after the trial

______6,7_______

Declaration of

interests

28 Financial and other competing interests for principal investigators for the overall trial and each

study site

_______16______

Access to data 29 Statement of who will have access to the final trial dataset, and disclosure of contractual

agreements that limit such access for investigators

______11_______

Ancillary and post-

trial care

30 Provisions, if any, for ancillary and post-trial care, and for compensation to those who suffer harm

from trial participation

_____7________

Dissemination policy 31a Plans for investigators and sponsor to communicate trial results to participants, healthcare

professionals, the public, and other relevant groups (eg, via publication, reporting in results

databases, or other data sharing arrangements), including any publication restrictions

______2_______

31b Authorship eligibility guidelines and any intended use of professional writers _____16________

31c Plans, if any, for granting public access to the full protocol, participant-level dataset, and statistical

code

_____16________

Appendices

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6

Informed consent

materials

32 Model consent form and other related documentation given to participants and authorised

surrogates

See The Ethical Approval

Document

Biological

specimens

33 Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or

molecular analysis in the current trial and for future use in ancillary studies, if applicable

_____No________

*It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013 Explanation & Elaboration for important clarification on the items.

Amendments to the protocol should be tracked and dated. The SPIRIT checklist is copyrighted by the SPIRIT Group under the Creative Commons

“Attribution-NonCommercial-NoDerivs 3.0 Unported” license.

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Acupuncture treatment for ischemic stroke in young adults: protocol for a randomized, sham-controlled clinical trial

Journal: BMJ Open

Manuscript ID bmjopen-2015-010073.R1

Article Type: Protocol

Date Submitted by the Author: 18-Nov-2015

Complete List of Authors: Chen, Lifang; The Third Affiliated Hospital of Zhejiang Chinese Medical University, Department of Acupuncture and Moxibustion Fang, Jianqiao; The Third Affiliated Hospital of Zhejiang Chinese Medical University, Department of Acupuncture and Moxibustion Jin, Xiaoming; Indiana University School of Medicine, Department of Anatomy and Cell Biology & Department of Neurosurgery Keeler, Crystal; The Third Affiliated Hospital of Zhejiang Chinese Medical University, Department of Acupuncture and Moxibustion

Gao, Hong; The Third Affiliated Hospital of Zhejiang Chinese Medical University, Department of Acupuncture and Moxibustion Fang, Zhen; The Third Affiliated Hospital of Zhejiang Chinese Medical University, Department of Rehabilitation Chen, Qin; The Third Affiliated Hospital of Zhejiang Chinese Medical University, Department of Acupuncture and Moxibustion

<b>Primary Subject Heading</b>:

Complementary medicine

Secondary Subject Heading: Complementary medicine, Rehabilitation medicine, Neurology

Keywords: Stroke < NEUROLOGY, young, acupuncture, randomized, sham-controlled


BMJ Open on M

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J Open: first published as 10.1136/bm

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1

Acupuncture treatment for ischemic stroke in young adults: protocol for a

randomized, sham-controlled clinical trial

Lifang Chen1

M.D. Ph.D.

Jianqiao Fang1, 2*

M.D. Ph.D.

Xiaoming Jin3*

M.D. Ph.D.

Crystal Lynn Keeler2 DAOM.

Hong Gao1

M.D.

Zhen Fang4

M.D.

Qin Chen1

M.D. Ph.D.

Corresponding author: Jianqiao Fang*, E-mail: [email protected]

Co-corresponding author: Xiaoming Jin*, E-mail: [email protected].

Itemized list of tables and figures:

Figure 1. Route diagram of study design



Supplementary materials

1. Ethics Approval document

2. Funding documents

3. SPIRIT checklist

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2

ABSTRACT

Introduction: Stroke in young adults is not uncommon. Although the overall

incidence of stroke has been recently declining, the incidence of stroke in young

adults is increasing. Traditional vascular risk factors are the main cause of young

ischemic stroke. Acupuncture has been shown to benefit stroke rehabilitation and

ameliorate the risk factors for stroke. The aims of this study were to determine

whether acupuncture treatment will be effective in improving the activities of daily

living (ADL), motor function, and quality of life (QOL) in patients of young ischemic

stroke, and in preventing stroke recurrence by controlling blood pressure, lipids and

body weight.

Methods and analysis: In this randomized, sham-controlled, subject and assessor

blinded clinical trial, 120 patients between 18-45 years of age with a recent (within

one month) ischemic stroke will be randomized for an 8-week acupuncture or sham

acupuncture treatment. The primary outcome will be the Barthel Index for ADL. The

secondary outcomes will include the Fugl-Meyer assessment for motor function; the

WHOQOL-BREF for QOL; and risk factors that are measured by ambulatory blood

pressure, the fasting serum lipid, body mass index, and waist circumference (WC).

Incidence of adverse events and long-term mortality and recurrence rate during a

10-year and 30-year follow-up will also be investigated.

Ethics and dissemination: Ethics approval was obtained from the ethics committee

of the Third Affiliated Hospital of Zhejiang Chinese Medical University. Protocol V.

3 was approved in June 2013. The results will be disseminated in a peer-reviewed

journal and presented at international congresses. The results will also be

disseminated to patients by telephone, during follow-up calls inquiring on patient’s

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3

post-study health status.

Trial registration number: Chinese Clinical Trial Register: No. ChiCTR-TRC-

13003317, http://www.chictr.org.cn/showprojen.aspx?proj=6242

Key words: stroke, young, randomized, sham-controlled, acupuncture

Strengths and limitations of this study

� This will be the first study protocol concerning the effect of acupuncture

for treating and preventing stroke specifically in young adults.

� Methodological strengths included: Rigorous randomized,

sham-controlled, subjects and assessors blinded, and lengthy follow-ups.

� Limitations: The sham acupuncture (superficial needle insertion and

minimal stimulation at non-acupoint and non-meridian areas) may be

associated with larger effects than pharmacological and other physical

placebos, and produce some physiological activity.

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INTRODUCTION

Stroke is one of the most frequent causes of death and chronic disability in China.1

Although the overall incidence of stroke has been recently declining, the incidence of

stroke in young adults is increasing. Approximately 10% to 14% of ischemic strokes

occur in adults between 18 to 45 years of age.2, 3

While a specific definition of “young

stroke” does not exist, the vast majority of authors consider “young stroke” as strokes

that occur in individuals under 45 years of age.4 For the purposes of this research, we

defined “young stroke” as strokes occurring in adults between 18 and 45 years of age

and designed a randomized clinical trial to address the particular needs and

differences of this younger age group.

The causes of young stroke are heterogeneous; however, traditional vascular risk

factors, such as hypertension, hyperlipidemia, obesity, smoking, alcohol drinking, and

diabetes mellitus are suggested to be the main risk factors.5 This finding challenges

the traditional view that young stroke is often caused by “rare” events.6 Stroke in the

younger age group may have a dramatic impact on the quality of life for survivors,

given their longer life expectancy and life stage. Not only does this age group have a

longer life expectancy than do older adults who suffer from strokes, but also these

adults are likely to be wage-earning caregivers for either children and/or aging parents.

Disability from young stroke may create an additional economic burden on the family

along with a societal impact. Because of the potentially greater impact of disability

adjusted life years for this age group, more attention should be paid to the

rehabilitation program and prevention of recurrence for young stroke.

Our previous two separate clinical trials, one for subacute stroke and one for

acute stroke, have been investigating the impact of acupuncture on stroke outcomes

overall.7, 8

During this investigation, we have found that young adults with stroke may

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obtain “De Qi” easier and recover better than do older patients (“De Qi” is an

acupuncture term for the sensation of “qi” arriving on the needle, also known as

“obtaining qi”, causing the acupuncture needle to elicit the patient’s feeling of

soreness, numbness, distention, heaviness, or electric shock around the point together

with the practitioner’s feeling of tenseness around the needle). A literature search for

“acupuncture for young stroke” did not yield any results, while intervention outcomes

may have a different impact on young stroke. To date, most of the literature that is

focused on young stroke is observational studies and few intervention studies have

been published. Randomized clinical trials that investigate the impact of acupuncture

on young stroke are currently scarce. Therefore, the role of acupuncture in young

stroke treatment deserved further study.

Acupuncture originated more than 3,000 years ago in China and has gained

popularity in the United States since the late 1970s.9 Over its 2500 years of

development, a wealth of experience has accumulated in the practice of acupuncture

for stroke treatment and prevention. According to a report by the WHO in 2002,

“strokes and their sequelae are another major indication for acupuncture.”10

Furthermore, recent reviews have shown positive, but limited, effectiveness of

acupuncture as an adjunct treatment to the conventional care of stroke.11-13

Acupuncture also has been reported to have benefits for treating risk factors for stroke,

including hypertension, hyperlipidemia, and obesity.14-16

This intervention modality

has a long history of safety and efficacy. As long as trained practitioners perform

acupuncture using clean needle techniques, it is a generally safe procedure17

; however,

some studies were at risk of bias. Future studies should focus on the appropriate

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modality of acupuncture intervention, sham-controls, the appropriate length of

treatment, and the development of more precise tools to assess outcomes.

This clinical trial focuses on young ischemic stroke. The study will test the

hypotheses that acupuncture (when compared to a sham control group), will be

effective in improving several outcome measures after a first-time young stroke, as

well as improving risk factors that are associated with recurrent stroke. The outcome

measures will include independence in activities of daily living (ADL), motor

function, and quality of life (QOL). The risk factors that will be examined include

blood pressure, lipids and body weight.

METHODS

Study design

This is a 20-week, single center, randomized, sham-controlled, subject and assessor

blinded, exploratory clinical trial. The study patient flow outline is shown in Fig. 1

and the trial schedule is shown in Table 1. Protocol modifications are not expected.

The eligibility criteria are fairly well established; however, if a trial modification is

necessary, any change in the criteria or methodology will be communicated to the

entire research team in a conference. All changes will be included in the final write-up

for a journal submission.

Study setting, recruitment, and ethics

This trial is registered at Chictr.org (number ChiCTR-TRC-13003317) and will be

conducted in accordance with the Declaration of Helsinki. The ethics committee of

the Third Affiliated Hospital of Zhejiang Chinese Medical University approved the

study (No. ZSLL-KY-2013-016). We will recruit participants by advertising in local

newspapers, health-related TV programs, Internet, and WeChat in Hangzhou city. We

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Assessment Screening

Baseline

Week 0

After-treatment

Week 8

Follow-up

Week 20

Follow-up

Year 10

Follow-up

Year 30

Informed consent ○ ○

Demographics ○ ○

Stroke type ○ ○

History of stroke ○ ○ ○ ○

History of disease △ ○ ○ ○

Concomitant

medication

△ ○ ○ ○ ○ ○

Blood pressure △ ○ ○ ○ △ △

Blood lab ○ ○ ○ △ △

Body mass index △ ○ ○ ○ △ △

Waist circumference △ ○ ○ ○ △ △

Barthel Index ○ ○ ○ ○ ○

FMA motor scale ○ ○ ○ △ △

WHOQOL-BREF ○ ○ ○ ○ ○

Adverse events ○ ○

Mortality ○ ○

Recurrence of stroke ○ ○

Treatment method ○ ○

○, required; △, optional; FMA: the Fugl-Meyer Assessment; WHOQOL-BREF: the World Health

Organization Quality of Life BREF.

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will conduct this trial in the acupuncture and rehabilitation departments of a teaching

hospital that is located at the center of Hangzhou city. There are fifty beds in the

inpatient clinic and eighty beds in the outpatient clinic of the acupuncture department,

and sixty beds in the rehabilitation department. All patients will provide written

informed consent. The research coordinator will arrange an in-person meeting with

potential participants to discuss the study in detail (i.e., the study purpose, procedures

and time commitment, as well as the potential risks and benefits associated with

participation in the study) and to obtain written informed consent. The confidentiality

of participant records will be protected. At the time of enrollment, each patient will be

assigned a unique study identification number, which is the only direct identifier

included on all study paper forms and in the electronic database. During and after the

trial, all records will remain secure, either in a locked filing cabinet in a secure area or

on a password-protected computer files. Compensation for trial participants for

trial-related harms will be provided by the Third Affiliated Hospital of Zhejiang

Chinese Medical University and will be made on a case-by-case basis. All hospital

and medical care related to any possible harm from the trial will be provided free of

charge to the patient.

Patient population

Patients between the 18-45 years of age with a recent (within one month) ischemic

stroke are eligible for this study. Patients who will be included as eligible subjects

should display clear consciousness and stable vital signs, with modified Rankin score

(mRS) 2-4, and have no aphasia or cognitive dysfunction.

The exclusion criteria will include patients with intracranial lesions or

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cerebrovascular disease history that have caused sequelae, such as movement

disorders, mood disorders, cognitive dysfunction or speech problems; or individuals

who are pregnant or breast-feeding. Patients with serious diseases that are related to

the heart, liver, kidney, or hematopoietic system will not be allowed to participate.

Patients who are not interested in this study or are participating in other clinical trials

will also be excluded. To increase the credibility of the sham-control, patients with

prior experience of acupuncture will be excluded from our final protocol. Because

many people in China have previously received acupuncture, this exclusion criterion

may prolong the study period by excluding otherwise eligible participants.

Nevertheless, we believe this exclusion category will improve the quality of the

research by providing a more effective sham control. Changes that affect trial

participants directly will be explained in person by their coordinators.

Randomization and blinding

Randomization will be computer-generated by independent research staff using SAS

9.3 software (Order Number: 99TKBM). The generated list of random numbers will

be placed into sequentially numbered, opaque, sealed envelopes. Consecutive patients

will be randomly assigned to an acupuncture group (AG) or a sham acupuncture

group (SG) in a 1:1 ratio according to the information they received from the

envelopes. Two acupuncture doctors will be designated to perform the acupuncture

treatment for the AG or SG separately. The study coordinator, who will not be

involved in treatment or assessment, will inform the subjects that they will receive

either a “traditional Chinese acupuncture” (verum) or a “less-painful acupuncture

developed especially for this study” (sham). All rehabilitation therapists, outcome

assessors, and data analysts will be blinded to group assignments.

Interventions and comparison

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Both groups will receive conventional stroke rehabilitation treatment and care during

the whole 20-week study period. The program was designed according to Chinese

stroke rehabilitation treatment guidelines and will be consistent across groups, 18

which included two-hours of physical therapy (PT) and one half-hour of occupational

therapy (OT) for five days a week. Western medicine will be permitted for

conventional symptomatic treatment (e.g., antihypertensive drugs and lipid-lowering

drugs). Chinese herbal medicine and Chinese patent drugs will be prohibited during

the trial. The acupuncture intervention and comparison adheres to the Standards for

Reporting Interventions in Controlled Trials of Acupuncture (STRICTA) guidelines.

Two certified acupuncturists with more than five years of clinical experience will

separately perform the Traditional Chinese Medicine acupuncture or sham

acupuncture for assigned patients. The thirty-minute acupuncture or sham treatment

will be manipulated by manual stimulation, and conducted bedside, in the supine

position, three times per week (on Monday, Wednesday, and Friday) for eight weeks,

and with no individual differences. For improving and monitoring adherence, every

treatment form and evaluation form will be completed and signed by participants and

researchers. Those who have completed all treatments and evaluations will receive

some form of financial compensation.

Acupuncture group

For scalp acupuncture, filiform stainless steel needles (size 0.25 mm × 40 mm,

Huatuo brand, manufactured by Suzhou Medical Appliance in Suzhou, Jiangsu

Province China) will be inserted with the whole body of needle through the motor

area and the sensory area of the lesion side. The intervention will include ipsilateral

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body acupuncture points for the affected side, LI15 (Jianyu), LI11 (Quchi), LI10

(Shousanli), SJ6 (Zhigou), and LI4 (Hegu) for upper extremities; bilateral points for

the lower limbs, ST31 (Biguan), GB34 (Yanglingquan), SP10 (Xuehai), ST36

(Zusanli), ST40 (Fenglong), SP6 (Sanyinjiao), and LR3 (Taichong); and abdominal

points, CV12 (Zhongwan), CV10 (Xiawan), CV6 (Qihai), CV4 (Guanyuan), ST25

(Tianshu) and ST15 (Daheng). The depth of insertion varies from 20 mm to 35 mm,

according to different points and the response of the patients to “De Qi”.

Sham acupuncture group

Sham acupuncture in this trial is defined as acupuncture with superficial needle

insertion and minimal stimulation at non-acupoint and non-meridian areas. All

needles for the sham group will be inserted superficially (1～3 mm) and without

stimulation, to avoid “De Qi”.19

The number of needles inserted, needle retention time,

and the frequency of treatment are all of the same as in the AG. The locations and

manipulations of the real acupuncture and sham acupuncture groups are detailed in

Table 2.


Points

Real acupuncture a

location

Sham acupuncture b

location

LI15

(Jian yu)

In the depression distal and anterior to the

acromion, between the clavicular and acromial

portions of the deltoid muscle.

1cm lateral away

from the actual

points of body

acupuncture

LI11

(Qu chi)

With the elbow flexed, on the lateral end of the

elbow crease, in a depression between the end

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of the crease and the lateral epicondyle of the

humerus, on the extensor carpi radialis longus

muscle.

LI10

(Shou san li)

2 cun distal to LI11, on the extensor carpi

radialis longus muscle.

SJ6

(Zhi gou)

3 cun proximal to the dorsal wrist joint space

(‘dorsal wrist

crease’), in a depression between the radius and

the ulna, radial to the tendon of the extensor

digitorum communis muscle.

LI4

(He gu)

On the radial aspect of the hand, between the

1st and 2nd

metacarpal bones, closer to the 2nd metacarpal

bone and

approximately at its midpoint.

ST31

(Bi guan)

Inferior to the anterior superior iliac spine and

lateral to the sartorius muscle, at the level of

the lower border of the pubic symphysis.

1cm lateral away

from the actual

points of body

acupuncture

GB34

(Yang ling quan)

In the depression anterior and inferior to the

head of the fibula, between the peroneus longus

and extensor digitorum longus muscles.

SP10 With the knee flexed, 2 cun proximal and

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(Xue hai) slightly medial to the medial superior border of

the patella, in a depression on the vastus

medialis muscle.

ST36

(Zu san li)

3 cun distal to ST-35 (‘lateral eye of the knee’)

and 1 finger-breadth lateral to the anterior crest

of the tibia, on the tibialis anterior muscle.

ST40

(Feng long)

At the midpoint of the line joining ST-35 and

ST-41, 2 fingerbreadths lateral to the anterior

crest of the tibia.

SP6

(San yin jiao)

3 cun proximal to the highest prominence of

the medial malleolus, on the posterior border of

the medial crest of the tibia.

LR3

(Tai chong)

On the dorsum of the foot, between the 1st and

2nd metatarsal bones, in the depression

proximal to the metatarsophalangeal joints and

the proximal angle between the two bones.

CV12

(Zhong wan)


umbilicus. 1cm lateral away

from the actual

points of body

acupuncture

CV10

(Xia wan)


centre of the umbilicus.

CV6

(Qi hai)

On the anterior midline, 1.5 cun inferior to the

umbilicus.

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CV4

(Guan yuan)

On the anterior midline, 3 cun inferior to the

umbilicus.

ST25

(Tian shu)

2 cun lateral to the umbilicus.

ST15

(Da heng)

4 cun lateral to the centre of the umbilicus, on

the mamillary line.

The motor area 0.5cms posterior to the midpoint of the

anterior-posterior line defines the upper limit of

the motor area. The lower limit intersects the

eyebrow-occiput line at the anterior border of

the natural hairline on the temple.

1 cm anterior away

from the motor area

and the sensory area

of the lesion side of

scalp acupuncture

The sensory area A line parallel to the motor area and 1.5cms

behind it.

a Manipulations of real acupuncture. For scalp acupuncture, the needle is swiftly inserted into the

subcutaneous tissue of the scalp in a horizontal direction. When the tip of needle reaches the subgaleal

layer and the practitioner feels low insertion resistance, the needle is further inserted to a depth of

30mm～40mm by twirling method. Three needles are used for each area. For body acupuncture, the

needle is inserted into the points to a depth of between 30 mm to 40 mm according to different regions.

Manual stimulation will be applied to the needles until the patients experience the needling sensation

(called “Deqi” in Chinese acupuncture). For electroacupuncture of CV12 (Zhong wan) and CV10 (Xia

wan), ST25 (Tianshu, two sides) points, SDZ-ⅡB Nerve and Muscle Stimulator (Suzhou Medical

Appliance Factory, Suzhou, China) will be used to give continuous high-frequency (50 Hz) stimulus.

The intensity is adjusted to a level that is tolerable to the patient (usually about 3～5 grade, with a

possible scope of 1～65 gradients of intensity).

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b Manipulations of sham acupuncture. The same stainless needles (0.25mm×40mm, described above)

will be used. For body acupuncture, 20 needles will be inserted 1cm lateral away from the actual

acupoints; and the same electro-acupuncture instrument will be used, but only with 1 grade of intensity.

For scalp acupuncture, needles will be inserted 1 cm anterior away from the motor area and the sensory

area of the lesion side.

c Manipulations of two groups. The acupuncturists of two groups will inserted needles in about 5-7

minutes, during which minimal interaction with the patients will be made. Then the patients are left

alone to rest for 30 minutes (the needle retention period for body acupuncture is 30 minutes, that for

scalp acupuncture is four hours). At the end of each treatment, the needles will be removed quickly

within 3-5 minutes, and minimal social interaction is made. Patients receive no additional attention,

training, or interaction as a result of the acupuncture session, thereby standardizing the treatment and

control groups.

Outcome measures

The primary outcome

The primary outcome will be the Barthel Index (BI) for independence in ADL. As

there are several scoring guidelines for the BI, we adopted the version of Mahoney.20

Secondary outcomes

Secondary outcomes will include the Fugl-Meyer Assessment (FMA) motor scale, the

World Health Organization Quality of Life BREF (WHOQOL-BREF), ambulatory

blood pressure (BP), fasting serum lipid, body mass index (BMI), and waist

circumference (WC). The FMA motor scale is highly recommended as a clinical and

research tool for evaluating changes in motor impairment following stroke.21

The

WHOQOL-BREF is a 26-item version of the WHOQOL-100 assessment that was

developed in the context of four domains of QOL and is a sound, cross-culturally

valid assessment of QOL.22

We will use the official Chinese version of the

WHOQOL-BREF, which has been approved by the WHOQOL Group.23

BP, lipid,

BMI, and WC are risk factors for recurrent stroke and represent relevant secondary

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outcome measurements. Patients will receive ambulatory blood pressure

measurements, and the average systolic and diastolic blood pressure levels will be

compared. The fasting serum lipid test will include total cholesterol (TC), low-density

lipoprotein cholesterol (LDLC), high-density lipoprotein cholesterol (HDLC), and

triglycerides (TG). The BMI will be derived from the mass (weight) and height of an

individual with the value universally being expressed in units of kg/m2. The waist

circumference will be measured by starting from the top of the hipbone and

measuring around the waist at the level of the umbilicus. All primary and secondary

outcomes will be measured at week 0, 8, and 20. To observe the long-term preventive

effect and prognosis, we will follow up with all participants annually through

telephone contact, home-visits, or clinic visits to collect data on mortality, recurrence

rate of stroke, ADL, and QOL at 10-year and 30-year increments after stroke.

Incidence of adverse events

All participants will be requested to voluntarily report information about adverse

events (AEs) at each visit. AEs that occur during the trial will be recorded and

assessed by the investigators. Acupuncture-related AEs might include local bleeding,

hematoma, pallor, sweating or dizziness, fainting during acupuncture treatment,

unbearable prickling, or retained needle after treatment.

Data collection, management, and monitoring

To promote participant retention and complete follow-up, all interventions and

outcome measurements are free to participants, and financial incentives will be

provided to those who completed all interventions and/or follow-ups. Participants

who discontinue interventions but do not drop out will be invited to enter the

follow-up phase and will receive assessments throughout the remainder of the study

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period.

The Case Report Form (CRF), Treatment Form and Adverse Events Form will be

first completed on paper copies and then double entered into the Electronic Data

Capture System (EDC) electronically by two independent investigators to act as the

first level of control to ensure the accuracy of the data. The second level of data

integrity will include data monitoring and validation that will be conducted on a

regular basis throughout the study. The original CRFs and all other forms (including

the consent forms) will be archived securely at The Third Affiliated Hospital of

Zhejiang Chinese Medical University for five years following publication of the last

paper or report from the study.

The safety of the study will be monitored by a data and safety monitoring board

(DSMB) of the Clinical Evaluation Center of Zhejiang Provincial Hospital of

traditional Chinese medicine (TCM), which consists of independent clinical experts

and statisticians with access to unblinded data. The DSMB is independent from the

sponsor, the competing interests, and the investigational site and will review the

performance and safety of the trial monthly.

The criteria for unblinding and discontinuing allocated interventions for a given

trial participant include having a recurrent stroke, having serious complications of

stroke, or experiencing serious acupuncture related AEs (if any), which have been

described previously. The DSMB will reveal a participant’s allocated intervention,

and make the final decision to terminate the trial.

The final trial dataset will be under the custody of the Third Affiliated Hospital of

Zhejiang Chinese Medical University. The data manager from the Clinical Evaluation

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Center of Zhejiang Provincial Hospital of TCM will have access to the complete,

anonymous final dataset. Access to the final dataset or identifiable data by others will

require written requests to be approved by the DSMB of the Clinical Evaluation

Center of Zhejiang Provincial Hospital of TCM, the Third Affiliated Hospital of

Zhejiang Chinese Medical University, and all study investigators.

Sample size estimates

The sample size was determined using the results of our previous clinical trial.24

We

expected that the primary efficacy parameter (BI) of the AG would be 10 values

higher than that of the SG and that the standard deviation would be approximately 18.

A two-sided 5% significance level and 80% power were considered, and the following

equation was used:

Based upon the calculation, approximately 51 participants in each group would be

required to have a sufficient sample size. With an estimated dropout rate of 15%, each

group required 60 initial participants.

Statistical analysis

Analyses will be conducted at the Clinical Research Institute of Zhejiang Provincial

Hospital of Traditional Chinese Medicine by blinded biostatisticians. SAS software,

version 9.3, will be used for all analysis and a two-sided p<0.05 will be considered

statistically significant for all analyses. The full analysis set (FAS) and per protocol

set (PPS) will both be conducted. Efficacy and safety analyses will be based upon the

intention-to-treat (ITT) principle. Missing values will be handled by the mixed model

for repeated measurements (MMRM). Continuous variables with normal distribution

will be expressed as the means with standard deviations and compared by an

2

2

2

22

az z

nβ σ +

=∆

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independent sample t-test. For abnormally distributed variables, the data will be

expressed as medians with ranges and non-parametric tests will be used. Categorical

variables will be expressed as number (%) and analyzed by χ2 test or Fisher’s exact

test.

Descriptive statistics will be used to detail baseline characteristics of patients,

such as gender, type of stroke, and risk factors and will be compared between two

groups using an independent sample t-test or χ2 test. Repeated measures analysis of

variance (ANOVA) will be used to analyze value changes of BI, FMA,

WHOQOL-BREF, blood pressure, blood lipid, BMI, and WC across three testing time

points (week 0, week 8, week 20). To detail all outcomes, an independent sample

t-test will be used to compare the final value changes (week 20-week 0) between the

two groups of the above variables. The mortality and occurrence of stroke (including

ischemic stroke and cerebral hemorrhage) at the 10-year and 30-year follow-up will

be analyzed using the χ2 tests and log-rank test with the Kaplan-Meier survival curve

analysis. Differences between the groups in causes of deaths will also be compared by

the χ2 test. Safety analyses will be compared with the incidence of adverse events in

two groups using the χ2 test.

DISCUSSION

Most young adults with stroke have a financial need to return to work and a desire to

enjoy an active social life. To improve the fine motor control post-stroke and obtain

more independence in activities of daily living will require a higher level of recovery.

Therefore, any treatments that contribute to functional rehabilitation should not be

ignored, including traditional acupuncture. Despite controversy in recent years

concerning the role of acupuncture as a routine treatment for stroke, acupuncture may

help to improve neurologic deficits without important side effects, 25-27

and is

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well-accepted as part of comprehensive rehabilitation strategies in China.1 Prevention

of ischemic stroke recurrence in young patients also remains an important clinical

problem. Acupuncture may not only be helpful in the treatment of post-stroke

rehabilitation without significant side effects but also may have the effect of

regulating blood pressure and lipid counts as well as facilitate losing weight at the

same time.12, 13

The acupuncture points used in this trial were designed for treating

both stroke and risk factors, which were selected in compliance with traditional

Chinese medical principles and confirmed by modern research studies.28

Moreover

because acupuncture reactions and “De Qi” are much easier to achieve in young

adults, acupuncture treatment in these patients is expected to achieve better

therapeutic effects.29

This trial focuses on ADL as the primary outcome because the ultimate goal of

stroke rehabilitation is to improve the ADL of patients toward greater independence.

Motor dysfunction is the most important sequela after stroke and has a significant

impact on ADL measurements. Because young adults have a longer expected life span

after the incidence of stroke, the quality of life should also be considered. As a result,

FMA and WHO-QOL were chosen as two secondary outcomes of treatment efficacy.

Young patients have a much longer exposure to risk of a recurrent vascular event than

do older patients, based upon their age alone. Therefore, the study also examines

risk-factor-related outcomes and the prevention of recurrent stroke by employing

acupuncture for controlling hypertension, hyperlipidemia, excessive weight, and

abdominal obesity. In addition, AEs and long-term outcomes with respect to recurrent

events and mortality will be observed. In summary, the comprehensive rehabilitation

and efficient secondary prevention of stroke for young individuals may greatly

increase the number of productive years with good quality of life. To the best of our

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knowledge, this will be the first trial of a rigorous, randomized, sham-controlled trial

of acupuncture that was designed specifically for treating and preventing young

stroke.

There is a limitation in our trial that should be acknowledged. Including a third,

“no acupuncture” group will improve the control design in our acupuncture trial. The

possibility of a placebo effect, particularly for those who believe in traditional

medicine, should not be dismissed; however, sham acupuncture interventions might,

on average, be associated with larger effects than pharmacological and other physical

placebos.30

Some of the sham acupuncture methods may also produce physiological

activity.31

The nature of the placebo effect that is associated with sham acupuncture is

an entire field of study unto itself. We consulted several Chinese acupuncture experts,

many of whom believed that the effect of acupuncture for stroke is closely related

with the stimulation of acupoints and meridians and "De Qi," which is in accordance

with the ancient TCM theory that states, “no De Qi, no effects.” These experts believe

that sham-acupuncture that is designed as “superficial needle insertion and minimal

stimulation at non-acupoint and non-meridian areas” in this trial could produce a

placebo effect, but with no additional efficacy (or that a reduced influence by the

sham acupuncture could be ignored when compared with real acupuncture).

Nevertheless, in an acupuncture analgesia clinical trial, a sham-acupuncture (of any

type) could produce additional influence beyond that of a placebo. In our experience,

sham acupuncture may produce different effects in different diseases. This may be

because of the different mechanisms of acupuncture treatment for different diseases.

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For example, stroke is a major and complex disease while acupuncture treatment for

stroke should focus on regulating the whole body and under the guideline of TCM

theory. For painful syndromes, acupuncture treatment is much simpler to perform and

easier to produce effects even if we do not select acupoints and meridians and only

use local points. In this respect, the influence of sham-acupuncture for pain may be

greater than that of stroke. Taking into account that sham-acupuncture may have little

effect on the treatment of stroke, but could eliminate the placebo effect, we reasoned

that sham-acupuncture is an ideal control setting in this trial so long as it is conducted

well. This conclusion is based upon our clinical practice and requires further study.

We will consider the nature of sham acupuncture in future studies to maximize the

avoidance of this limitation.

CONCLUSION

Stroke in young adults requires a higher level of recovery and an effective prevention

of recurrence. This study will be the first rigorous, randomized, sham-controlled trial

that focuses on using acupuncture for treating and preventing young ischemic stroke.

Author affiliations

1 Department of Acupuncture and Moxibustion，The Third Affiliated Hospital of

Zhejiang Chinese Medical University, 219 Moganshan Road, Xihu District, Hangzhou

City, Zhejiang Province 310005, China.

2 Zhejiang Chinese Medical University, 548 Binwen Road, Binjiang District,

Hangzhou City, Zhejiang Province 310053, China

3 Department of Anatomy and Cell Biology & Department of Neurosurgery, Indiana

University School of Medicine, 320 West 15th Street, NB Building, Room 500C,

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Indianapolis IN 46202, the United States of America

4 Department of Rehabilitation，The Third Affiliated Hospital of Zhejiang Chinese

Medical University, 219 Moganshan Road, Xihu District, Hangzhou City, Zhejiang

Province 310005, China.

Acknowledgements We express our profound appreciation to all coordinators,

therapists and evaluators for their diligence. We thank all of the stroke survivors and

their caregivers who participated in this study.

Funding This work was supported by the program of the National Key Discipline of

Traditional Chinese Medicine-Acupuncture (NO.[2009]30), and partly funded by the

International Exchange Program of Clinical Technology from Health and Family

Planning Commission of Zhejiang Province (NO.[2014]48) and the Provincial

Administration of Traditional Chinese Medicine of Zhejiang (No. 2011ZGG003). The

sponsor will have no role in the design and conduct of the study. The trial sponsor is

The Third Affiliated Hospital of Zhejiang Chinese Medical University (219

Moganshan Road, Xihu District, Hangzhou City, Zhejiang Province 310005, China,

86-571-88393534).

Authors’ contributions Lifang Chen, Jianqiao Fang, and Xiaoming Jin designed or

conceptualized the trial, drafted and revised the manuscript. Crystal Lynn Keeler,

Hong Gao, Zhen Fang, and Qin Chen designed and conducted the trial. All authors

have read revised, and approved this version of the article.

Competing interests No, there are no competing interests.

Patient consent Obtained.

Ethics approval The ethics committee of the Third Affiliated Hospital of Zhejiang

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Chinese Medical University approved the study.

Provenance and peer review Not commissioned; peer reviewed for ethical and

funding approval prior to submission.

Data sharing statement The results of our original research will be disseminated in a

peer-reviewed journal and presented at international congresses.

Trial status The trial is currently enrolling participants; the first subject was included

on December 1st, 2013. Estimated completion date for this trial is March 31th, 2016.

Open Access This is an Open Access article distributed in accordance with the terms

of the Creative Commons Attribution (CC BY 4.0) license, which permits others to

distribute, remix, adapt and build upon this work, for commercial use, provided the

original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

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12. Lee SJ, Shin BC, Lee MS, et al. Scalp acupuncture for stroke recovery: A systematic

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case reports. Altern Ther Health Med 2003;1:72-83.

18. Zhang T. Chinese stroke rehabilitation treatment guidelines 2011. Chin J Rehabil

Theory Pract 2012;18:301-318.

19. MacPherson H, Asghar A. Acupuncture needle sensations associated with De Qi: a

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20. Mahoney FI, Barthel DW. Functional evaluation: the Barthel index. Md State Medi J

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22. Skevington SM, Lotfy M, O'Connell KA, et al. The World Health Organization's

WHOQOL-BREF quality of life assessment: psychometric properties and results of

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the international field trial. A report from the WHOQOL group. Qual Life Res

2004;13:299-310.

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25. Wu P, Mills E, Moher D, et al. Acupuncture in poststroke rehabilitation: a systematic

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26. Wong AM, Su TY, Tang FT, et al. Clinical Trial of Electrical Acupuncture on

Hemiplegic Stroke Patients. Am J Phys Med Rehabil 1999;78:117-122.

27. Uchida S, Hotta H. Acupuncture affects regional blood flow in various organs. Evid

Based Complement Altern Med 2008;5:145–151.

28. Naeser MA, Alexander MP, Stiassny-Eder D, et al. Real versus sham acupuncture in

the treatment of paralysis in acute stroke patients: a CT scan lesion site study.

Neurorehabil Neural Repair1992;6:163-74.

29. Park SU, Ko CN, Bae HS, et al. Short-term reactions to acupuncture treatment and

adverse events following acupuncture: a cross-sectional survey of patient reports in

Korea. J Altern Complement Med 2009;15:1275-283.

30. Linde K, Niemann K, Meissner K. Are sham acupuncture interventions more effective

than (other) placebos? A re-analysis of data from the Cochrane review on placebo

effects. Forsch Komplementmed 2010;5:259-64.

31. CARNEIRO M, KAWAKITA K. Re-analysis of acupuncture trials with sham

interventions based on data from the Cochrane Review. Japanese Acupuncture and

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Figure 1.Route diagram of study design 211x287mm (120 x 120 DPI)

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SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents*

Section/item Item No

Description Addressed on page number

Administrative information

Title 1 Descriptive title identifying the study design, population, interventions, and, if applicable, trial

acronym

_______1_____

Trial registration 2a Trial identifier and registry name. If not yet registered, name of intended registry ____ 3 _______

2b All items from the World Health Organization Trial Registration Data Set _____ 3______

Protocol version 3 Date and version identifier _____ 2______

Funding 4 Sources and types of financial, material, and other support _____22_____

Roles and

responsibilities

5a Names, affiliations, and roles of protocol contributors _____22___

5b Name and contact information for the trial sponsor ______9_____

5c Role of study sponsor and funders, if any, in study design; collection, management, analysis, and

interpretation of data; writing of the report; and the decision to submit the report for publication,

including whether they will have ultimate authority over any of these activities

______22 __

5d Composition, roles, and responsibilities of the coordinating centre, steering committee, endpoint

adjudication committee, data management team, and other individuals or groups overseeing the

trial, if applicable (see Item 21a for data monitoring committee)

_____16,24____

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2

Introduction

Background and

rationale

6a Description of research question and justification for undertaking the trial, including summary of

relevant studies (published and unpublished) examining benefits and harms for each intervention

____4,5______

6b Explanation for choice of comparators ____5,6______

Objectives 7 Specific objectives or hypotheses _____5,6_____

Trial design 8 Description of trial design including type of trial (eg, parallel group, crossover, factorial, single

group), allocation ratio, and framework (eg, superiority, equivalence, noninferiority, exploratory)

______6______

Methods: Participants, interventions, and outcomes

Study setting 9 Description of study settings (eg, community clinic, academic hospital) and list of countries where

data will be collected. Reference to where list of study sites can be obtained

______6,8____

Eligibility criteria 10 Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for study centres and

individuals who will perform the interventions (eg, surgeons, psychotherapists)

______8______

Interventions 11a Interventions for each group with sufficient detail to allow replication, including how and when they

will be administered

__10,11,Table 2___

11b Criteria for discontinuing or modifying allocated interventions for a given trial participant (eg, drug

dose change in response to harms, participant request, or improving/worsening disease)

______16______

11c Strategies to improve adherence to intervention protocols, and any procedures for monitoring

adherence (eg, drug tablet return, laboratory tests)

_______10_____

11d Relevant concomitant care and interventions that are permitted or prohibited during the trial _______11_____

Outcomes 12 Primary, secondary, and other outcomes, including the specific measurement variable (eg, systolic

blood pressure), analysis metric (eg, change from baseline, final value, time to event), method of

aggregation (eg, median, proportion), and time point for each outcome. Explanation of the clinical

relevance of chosen efficacy and harm outcomes is strongly recommended

_______11,15____

Participant timeline 13 Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and

visits for participants. A schematic diagram is highly recommended (see Figure)

_15, Table 1___

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Sample size 14 Estimated number of participants needed to achieve study objectives and how it was determined,

including clinical and statistical assumptions supporting any sample size calculations

______17______

Recruitment 15 Strategies for achieving adequate participant enrolment to reach target sample size ______6______

Methods: Assignment of interventions (for controlled trials)

Allocation:

Sequence

generation

16a Method of generating the allocation sequence (eg, computer-generated random numbers), and list

of any factors for stratification. To reduce predictability of a random sequence, details of any

planned restriction (eg, blocking) should be provided in a separate document that is unavailable to

those who enrol participants or assign interventions

______9______

Allocation

concealment

mechanism

16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially

numbered, opaque, sealed envelopes), describing any steps to conceal the sequence until

interventions are assigned

_____9 ______

Implementation 16c Who will generate the allocation sequence, who will enrol participants, and who will assign

participants to interventions

______9_______

Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers,

outcome assessors, data analysts), and how

_______9______

17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a

participant’s allocated intervention during the trial

______16,17____

Methods: Data collection, management, and analysis

Data collection

methods

18a Plans for assessment and collection of outcome, baseline, and other trial data, including any

related processes to promote data quality (eg, duplicate measurements, training of assessors) and

a description of study instruments (eg, questionnaires, laboratory tests) along with their reliability

and validity, if known. Reference to where data collection forms can be found, if not in the protocol

_____15____

18b Plans to promote participant retention and complete follow-up, including list of any outcome data to

be collected for participants who discontinue or deviate from intervention protocols

____16_____

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Data management 19 Plans for data entry, coding, security, and storage, including any related processes to promote

data quality (eg, double data entry; range checks for data values). Reference to where details of

data management procedures can be found, if not in the protocol

_____15____

Statistical methods 20a Statistical methods for analysing primary and secondary outcomes. Reference to where other

details of the statistical analysis plan can be found, if not in the protocol

____16,17_____

20b Methods for any additional analyses (eg, subgroup and adjusted analyses) ____17_____

20c Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis),

and any statistical methods to handle missing data (eg, multiple imputation)

_____16____

Methods: Monitoring

Data monitoring 21a Composition of data monitoring committee (DMC); summary of its role and reporting structure;

statement of whether it is independent from the sponsor and competing interests; and reference to

where further details about its charter can be found, if not in the protocol. Alternatively, an

explanation of why a DMC is not needed

______16_____

21b Description of any interim analyses and stopping guidelines, including who will have access to

these interim results and make the final decision to terminate the trial

______16_____

Harms 22 Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported

adverse events and other unintended effects of trial interventions or trial conduct

_______16____

Auditing 23 Frequency and procedures for auditing trial conduct, if any, and whether the process will be

independent from investigators and the sponsor

______16_____

Ethics and dissemination

Research ethics

approval

24 Plans for seeking research ethics committee/institutional review board (REC/IRB) approval _____6,8________

Protocol

amendments

25 Plans for communicating important protocol modifications (eg, changes to eligibility criteria,

outcomes, analyses) to relevant parties (eg, investigators, REC/IRBs, trial participants, trial

registries, journals, regulators)

_____6,8________

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Consent or assent 26a Who will obtain informed consent or assent from potential trial participants or authorised

surrogates, and how (see Item 32)

______8_______

26b Additional consent provisions for collection and use of participant data and biological specimens in

ancillary studies, if applicable

______No_______

Confidentiality 27 How personal information about potential and enrolled participants will be collected, shared, and

maintained in order to protect confidentiality before, during, and after the trial

______6,8_______

Declaration of

interests

28 Financial and other competing interests for principal investigators for the overall trial and each

study site

_______20______

Access to data 29 Statement of who will have access to the final trial dataset, and disclosure of contractual

agreements that limit such access for investigators

______15_______

Ancillary and post-

trial care

30 Provisions, if any, for ancillary and post-trial care, and for compensation to those who suffer harm

from trial participation

_____8________

Dissemination policy 31a Plans for investigators and sponsor to communicate trial results to participants, healthcare

professionals, the public, and other relevant groups (eg, via publication, reporting in results

databases, or other data sharing arrangements), including any publication restrictions

______2_______

31b Authorship eligibility guidelines and any intended use of professional writers _____20________

31c Plans, if any, for granting public access to the full protocol, participant-level dataset, and statistical

code

_____20________

Appendices

Informed consent

materials

32 Model consent form and other related documentation given to participants and authorised

surrogates

See The Ethics Approval

Document

Biological

specimens

33 Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or

molecular analysis in the current trial and for future use in ancillary studies, if applicable

_____No________

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*It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013 Explanation & Elaboration for important clarification on the items.

Amendments to the protocol should be tracked and dated. The SPIRIT checklist is copyrighted by the SPIRIT Group under the Creative Commons

“Attribution-NonCommercial-NoDerivs 3.0 Unported” license.

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Checklist for items in STRICTA 2010

Item Detail Page number

1. Acupuncture rationale (Explanations and examples)

1a) Style of acupuncture (e.g. Traditional Chinese Medicine, Japanese, Korean, Western medical, Five Element, ear acupuncture, etc)

9

1b) Reasoning for treatment provided, based on historical context, literature sources, and/or consensus methods, with references where appropriate

5

1c) Extent to which treatment was varied 9

2. Details of needling (Explanations and examples)

2a) Number of needle insertions per subject per session (mean and range where relevant)

10

2b) Names (or location if no standard name) of points used (uni/bilateral)

10

2c) Depth of insertion, based on a specified unit of measurement, or on a particular tissue level

10

2d) Response sought (e.g. de qi or muscle twitch response)

10

2e) Needle stimulation (e.g. manual, electrical) 9

2f) Needle retention time 9

2g) Needle type (diameter, length, and manufacturer or material)

10

3. Treatment regimen (Explanations and examples)

3a) Number of treatment sessions 9

3b) Frequency and duration of treatment sessions

9

4. Other components of treatment (Explanations and examples)

4a) Details of other interventions administered to the acupuncture group (e.g. moxibustion, cupping, herbs, exercises, lifestyle advice)

No other interventions

4b) Setting and context of treatment, including instructions to practitioners, and information and explanations to patients

9

5. Practitioner background (Explanations and examples)

5) Description of participating acupuncturists (qualification or professional affiliation, years in acupuncture practice, other relevant experience)

9

6. Control or comparator interventions (Explanations and examples)

6a) Rationale for the control or comparator in the context of the research question, with sources that justify this choice

10

6b) Precise description of the control or comparator. If sham acupuncture or any other type of acupuncture-like control is used, provide details as for Items 1 to 3 above.

10

Note: This checklist, which should be read in conjunction with the explanations of the STRICTA items,

is designed to replace CONSORT 2010’s item 5 when reporting an acupuncture trial.

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