bmj open...rehabilitation program and prevention of recurrence for young stroke. our previous two...
TRANSCRIPT
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
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open on M
ay 7, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2015-010073 on 6 January 2016. Dow
nloaded from
For peer review only
1
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
Page 1 of 32
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
2
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.
Page 2 of 32
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
3
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
Page 3 of 32
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
4
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
Page 4 of 32
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
5
“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
Page 5 of 32
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
6
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
Page 6 of 32
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
7
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
Page 7 of 32
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
8
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
Page 8 of 32
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
9
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
Page 9 of 32
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
10
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.
Page 10 of 32
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
11
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
Page 11 of 32
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
12
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 +
=∆
Page 12 of 32
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
13
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
Page 13 of 32
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
14
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
Page 14 of 32
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
15
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
Page 15 of 32
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
16
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/
Page 16 of 32
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
17
REFERENCES
1. Liu M, Wu B, Wang WZ, et al. Stroke in China: epidemiology, prevention, and
management strategies. Lancet Neurol 2007;6: 456-64.
2. JiR, Schwamm LH, Pervez MA, et al. Ischemic stroke and transient ischemic attack
in young adults: risk factors, diagnostic yield, neuroimaging, and thrombolysis. JAMA
Neurol 2013;70:51-7.
3. Kissela BM, Khoury JC, Alwell K, et al. Age at stroke: temporal trends in stroke
incidence in a large, biracial population. Neurology 2012;79:1781-7.
4. Griffiths D, Sturm J. Epidemiology and etiology of young stroke. Stroke Res Treat
2011;2011: ID209370.
5. Bi Q, Wang L, Li X, et al. Risk factors and treatment of stroke in Chinese young
adults. Neurol Res 2010;32:366-70.
6. Ferro JM, Massaro AR, Mas JL. Aetiological diagnosis of ischaemic stroke in young
adults. Lancet Neurol 2010;9:1085-96.
7. Fang J, Chen L, Chen L, et al. Integrative medicine for subacute stroke rehabilitation:
a study protocol for a multicentre, randomised, controlled trial. BMJ open 2014;4:
e007080.
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.
Page 17 of 32
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
18
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.
Page 18 of 32
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
19
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.
Page 19 of 32
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
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
Page 20 of 32
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
Table 1. Trial schedule
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.
Page 21 of 32
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
Table 2. Locations and manipulations of real and sham acupuncture
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
Page 22 of 32
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
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
Page 23 of 32
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
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)
On the anterior midline, 2 cun superior to the
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.
Page 24 of 32
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
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,
Page 25 of 32
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
training, or interaction as a result of the acupuncture session, thereby standardizing
the treatment and control groups.
Page 26 of 32
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
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 __
Page 27 of 32
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. Protected by copyright. http://bmjopen.bmj.com/ BMJ Open: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. Downloaded from
For peer review only
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_____
Page 28 of 32
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. Protected by copyright. http://bmjopen.bmj.com/ BMJ Open: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. Downloaded from
For peer review only
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
Page 29 of 32
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. Protected by copyright. http://bmjopen.bmj.com/ BMJ Open: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. Downloaded from
For peer review only
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
Page 30 of 32
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. Protected by copyright. http://bmjopen.bmj.com/ BMJ Open: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. Downloaded from
For peer review only
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
Page 31 of 32
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. Protected by copyright. http://bmjopen.bmj.com/ BMJ Open: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. Downloaded from
For peer review only
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.
Page 32 of 32
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. Protected by copyright. http://bmjopen.bmj.com/ BMJ Open: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. Downloaded from
For peer review only
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
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open on M
ay 7, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2015-010073 on 6 January 2016. Dow
nloaded from
For peer review only
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
Table 1. Trial schedule
Table 2. Locations and manipulations of real and sham acupuncture
Supplementary materials
1. Ethics Approval document
2. Funding documents
3. SPIRIT checklist
Page 1 of 36
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
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
Page 2 of 36
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
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.
Page 3 of 36
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
4
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
Page 4 of 36
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
5
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
Page 5 of 36
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
6
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
Page 6 of 36
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
7
Table 1. Trial schedule
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.
Page 7 of 36
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
8
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
Page 8 of 36
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
9
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
Page 9 of 36
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
10
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
Page 10 of 36
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
11
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.
Table 2. Locations and manipulations of real and sham acupuncture
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
Page 11 of 36
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
12
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
Page 12 of 36
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
13
(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)
On the anterior midline, 4 cun superior to the
umbilicus. 1cm lateral away
from the actual
points of body
acupuncture
CV10
(Xia wan)
On the anterior midline, 2 cun superior to the
centre of the umbilicus.
CV6
(Qi hai)
On the anterior midline, 1.5 cun inferior to the
umbilicus.
Page 13 of 36
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
14
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).
Page 14 of 36
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
15
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
Page 15 of 36
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
16
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
Page 16 of 36
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
17
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
Page 17 of 36
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
18
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 +
=∆
Page 18 of 36
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
19
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
Page 19 of 36
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
20
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
Page 20 of 36
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
21
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.
Page 21 of 36
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
22
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,
Page 22 of 36
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
23
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
Page 23 of 36
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
24
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/
Page 24 of 36
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
25
REFERENCES
1. Liu M, Wu B, Wang WZ, et al. Stroke in China: epidemiology, prevention, and
management strategies. Lancet Neurol 2007;6: 456-64.
2. JiR, Schwamm LH, Pervez MA, et al. Ischemic stroke and transient ischemic attack
in young adults: risk factors, diagnostic yield, neuroimaging, and thrombolysis. JAMA
Neurol 2013;70:51-7.
3. Kissela BM, Khoury JC, Alwell K, et al. Age at stroke: temporal trends in stroke
incidence in a large, biracial population. Neurology 2012;79:1781-7.
4. Griffiths D, Sturm J. Epidemiology and etiology of young stroke. Stroke Res Treat
2011;2011: ID209370.
5. Bi Q, Wang L, Li X, et al. Risk factors and treatment of stroke in Chinese young
adults. Neurol Res 2010;32:366-70.
6. Ferro JM, Massaro AR, Mas JL. Aetiological diagnosis of ischaemic stroke in young
adults. Lancet Neurol 2010;9:1085-96.
7. Fang J, Chen L, Chen L, et al. Integrative medicine for subacute stroke rehabilitation:
a study protocol for a multicentre, randomised, controlled trial. BMJ open 2014;4:
e007080.
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.
Page 25 of 36
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
26
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):50-8.
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. 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
classification based on experts' ratings. J Altern Complement Med 2006;12: 633-37.
20. Mahoney FI, Barthel DW. Functional evaluation: the Barthel index. Md State Medi J
1965;14:61-5.
21. 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.
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
Page 26 of 36
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
27
the international field trial. A report from the WHOQOL group. Qual Life Res
2004;13:299-310.
23. 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.
24. 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.
25. 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.
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
Page 27 of 36
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
28
Moxibustion 2015;1:1-11.
Page 28 of 36
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
Figure 1.Route diagram of study design 211x287mm (120 x 120 DPI)
Page 29 of 36
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from
For peer review only
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 _____ 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____
Page 30 of 36
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. Protected by copyright. http://bmjopen.bmj.com/ BMJ Open: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. Downloaded from
For peer review only
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___
Page 31 of 36
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. Protected by copyright. http://bmjopen.bmj.com/ BMJ Open: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. Downloaded from
For peer review only
3
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_____
Page 32 of 36
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. Protected by copyright. http://bmjopen.bmj.com/ BMJ Open: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. Downloaded from
For peer review only
4
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________
Page 33 of 36
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. Protected by copyright. http://bmjopen.bmj.com/ BMJ Open: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. Downloaded from
For peer review only
5
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________
Page 34 of 36
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. Protected by copyright. http://bmjopen.bmj.com/ BMJ Open: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. Downloaded from
For peer review only
6
*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.
Page 35 of 36
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. Protected by copyright. http://bmjopen.bmj.com/ BMJ Open: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. Downloaded from
For peer review only
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.
Page 36 of 36
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 7, 2020 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2015-010073 on 6 January 2016. D
ownloaded from