Heart Rate Variability Assessment in Dialysis Patients by Acupuncture
Phase: NA
Conditions: RLS
Sponsor: China Medical University, Taiwan

Research Protocol 
 
 
 
The effect of acupuncture on hemodialysis patients with restless legs  
syndrome(RLS) 
 
Version 8-23-2019 
 
 
 
 
 
Principal Investigator: 
Principal Investigator(s): Jia-Ming Chen 
Institution: CHANGHUA CHRISTIAN HOSPITAL,TAIWAN 
Protocol No. : Y_105_0300 / CCH IRB No. : 170217 
Date of Approval: Aug 23, 2019 
Address: 135 Nanxiao St., Changhua City, Changhua County 500, Taiwan (R.O.C.) 
Tel: 886-4-723-8595 
 
 

The effect of acupuncture on hemodialysis patients with restless legs 
syndrome(RLS) study protocol for a randomized crossover trial 
 
I. Study Objectives 
 
To our knowledge, there have been no studies on the impact of acupuncture  therapy 
on RLS in patients undergoing hemodialysis. Therefore, the present study was 
conducted to determine the effect of acupuncture on the severity of RLS in 
hemodialysis patients. The study is a randomized crossover trial. 
 
II. Background and Rationale 
 
Restless legs syndrome (RLS), a common sensorimotor movement disorder first 
described in detail by Ekbom, ranges in severity from merely causing annoyance in the 
patient to affecting sleep and quality of life severely enough to warrant medical 
treatment. Remarkable differences in prevalence rates of RLS can be observed across 
countries and geographic regions. Epidemiological research demonstrates that the 
prevalence of RLS in adults (18 years or more) ranges from less than 1%  in Singapore 
to approximately 10% in Europe and the United States. In 1995, a uniform diagnosis of 
RLS was made possible worldwide, based on the criteria proposed by the International 
RLS Study Group (IRLSSG). According to the most recently revised diagnostic criteria, 
the four clinical manifestations mandatory for the diagnosis are: 
(1) an urge to move the legs, accompanied or caused by uncomfortable and unpleasant 
sensations in the legs; 
(2) the urge to move or the unpleasant sensations begin or worsen during periods of rest 
or inactivity; 
(3) the urge to move or the unpleasant sensations are partially or totally relieved by 
movement; 
(4) the urge to move or the unpleasant sensations are worse in the evening or night or 
only occur in the evening or night. 
Acupuncture, an ancient Chinesemedical therapy used in the prevention and treatment 
of disease, is another useful method for treating RLS. It involves inserting needles 
into specific points (acupoints or Xue Wei) on the human body to bring about its 
therapeutic effects. Conventional science suggests that acupuncture works by 
neurological, neurohormonal as well as psychological mechanisms, and it is thought 
to confer an analgesic effect. Several kinds of acupuncture methods, such as body 
acupuncture, auricular acupuncture, scalp acupuncture, electro-acupuncture, laser 
acupuncture, acupressure, acupoint injection therapy (injection of drugs into acupoints) 

or a combination of the approaches mentioned above, are used in the treatment of 
RLS. 
 
The mechanism of acupuncture treatment for RLS is still ill-defined. According to our 
preliminary research, the current practice of acupuncture forRLS ismainly based on 
principles ofTraditional Chinese Medicine (TCM) rather than conventional science. 
The traditional explanation, based on TCM theory, is that acupuncture restores the 
balance between Yin and Yang and regulates Qi (the essence) and blood so that 
integral unity can be maintained and miscellaneous diseases cured. 
 
The development of this disorder in hemodialysis patients is progressive, affecting 
various physical and psychological dimensions over time. The symptoms of this 
syndrome are greatly intensified at rest, and are relieved by moving the extremities, 
especially the legs.  In hemodialysis patients, the symptoms mainly occur during 
dialysis when the patient is at rest and cause discomfort. Evidence suggests that RLS 
in hemodialysis patients is associated with a risk of cardiovascular disease, 
osteoporosis, musculoskeletal pain, and increased mortality. In the general population 
and in patients with end-stage renal disease (ESRD), the potential causes of RLS 
include anemia, pregnancy, iron deficiency, the dysfunction of dopamine within the 
central nervous system, a family history of RLS, and peripheral neuropathy. In 
patients with ESRD, iron deficiency, anemia, and dialysis are predisposing factors 
that can lead to RLS. 
 
Some clinical trials have examined the efficacy of acupuncture in the treatment of 
RLS and demonstrated that it was able to alleviate the clinical symptoms. To our 
knowledge, however, There have been no studies on the impact of acupuncture  
therapy on RLS in patients undergoing hemodialysis. Therefore, the present study 
was conducted to determine the effect of acupuncture on the severity of RLS in 
hemodialysis patients. 
III. Procedures  
A. Research and Design  
Subject Selection/Sample  
Inclusion criteria:  
1) Patients between 18-80 years old diagnosed with RLS in hemodialysis patients 
according to the diagnostic criteria of the International Restless Legs Syndrome Study 
Group (11).  
2) Subjects should have bothersome RLS symptoms, despite best medical therapy  
3) Subjects should be stable on all RLS medication for at least 4 weeks prior to 

enrollment  
4) All subjects must be able to read and write in English in order to be able to complete 
home diary cards and questionnaires.  
5) All women of childbearing age must be using an acceptable form of birth control, 
including abstinence, IUD or intrauterine system in place for at least 3 months prior to 
screening, subject or partner using barrier method (e.g., condom, diaphragm, or cervical 
cap) with spermicide from screening through study completion; partner has a documented 
vasectomy > 6 months prior to Baseline, Stable hormonal contraception (with approved 
oral, transdermal, or depot regimen) for at least 3 months prior to screening.  
 

 
Exclusion criteria:  
1) RLS secondary associated with end stage renal disease, iron deficiency or pregnancy  
2) Does not have sufficient vision to be compliant with study procedures.  
3) Any other condition (other than the primary indications), which in the opinion of the 
investigators might contribute to difficulty complying with the protocol  
 
Study setting  
The trials will be conducted at the Changhua Christian Hospital. This study will adhere to 
the recommendations of the Consolidated Standards of Reporting Trials (CONSORT) [15] 
to allow for greater completeness, transparency and accuracy of reporting. The protocol 
for this study has been registered in the Clinical Trials register (ClinicalTrials.gov 
Identifier: NCT04356794).  
  
Eligibility criteria  
Subjects who voluntarily sign a consent form will undergo the trial according to the study 
design. When a subject is determined to be fit for participation based on inclusion and 
exclusion criteria, the subject will be randomly assigned to 1 of 2 groups in a ratio of 1:1. 
One group is the true EA experimental group and the other is the sham EA control group. 
Each group will receive their treatment 2 times a week for 4 weeks. After 4 weeks of 
treatment and a 2-week washout period, the control group will switch to the experimental 
group while the experimental group will switch to the control group. The subjects then 
undergo the treatment of their new group for another 4 weeks. 
Treatment and assessment will be performed independently and the practitioners will not 
be involved in assessing the outcome of the treatment. The subjects, the outcome 
assessors and the statistician performing the data analyses will be blinded to the treatment 
allocation throughout the study. 
 
Ethics 
This research protocol adheres to the principles of the Declaration of Helsinki and has 
been approved by the institutional review boards of the Changhua Christian Hospital 
(No. : 170217). Informed consent will be obtained from each participant before any 
treatment is given. All subjects will have the right to withdraw from the study at any time. 
 
Inclusion criteria 
The inclusion criteria were as follows:  
1. 
Informed consent to participate in the study; 
2. 
Between the ages of 20 - 80 years;  

3. 
A mean frequency of RLS symptoms during the last 6 months of more than twice 
per week;  
4. 
A score of at least 20 on the International Restless Legs Syndrome Rating 
Scale(corresponding to severe RLS,IRLSRS);  
5. 
A history of chronic renal failure treated with regular and continuous hemodialysis 
for at least 3 months; 
6. 
No acupuncture treatment in the last one month.  
 
Exclusion criteria  
The exclusion criteria were as follows: 
1. 
An unwillingness to continue to participate in the study;  
2. 
Vascular access in the leg area, such as an arteriovenous shunt;  
3. 
The presence of peripheral neuropathy and vascular problems in the lower 
extremities;  
4. 
Currently taking drugs for RLS, such as dopamine agonists, benzodiazepines, 
opioids, and gabapentin;  
5. 
A history of other motor disorders, such as Parkinson's disease, dyskinesia, and 
dystonia; 
6. 
With an artificial cardiac pacemaker; 
7. 
Pregnancy or breastfeeding. 
 
B. Measurement/Instrumentation  
1) International Restless Legs Severity Scale (12): a 40 point scale measuring severity of 
restless leg symptoms. Patients are asked to answer a series of 10 questions each of which 
have values ranging from 0 to 4 and the points are then added. Higher values are 
associated with more severe symptoms.  
2) Insomnia Severity Index: a series of 7questions assessing quality of sleep, with values 
ranging from 0 to 28. 
3) heart rate variability: HRV is the measure of the inconsistent gaps between each 
heartbeat and is used as an index for different aspects of psychology. HRV is an index of 
the influence of both the parasympathetic nervous system and the sympathetic nervous 
systems. 
Outcome measures will be at baseline and at week 4,10 and 18. Medical history including 
demographic information and information about alcohol, drug and tobacco use will be 
collected at the baseline visit. Medications and vital signs will be recorded at each visit. 
Adverse events will be recorded at week 4,10 and 18 or as reported by the patients. 
Anticipated benefits for the subjects in the treatment arms will be attenuation of RLS 
symptoms and improvement in quality of life and sleep. 

 
 
Statistical Considerations:  
A. Sample Size:  
A total of 112 patients will be accrued to the study with roughly equal allocation to each 
treatment arm. This sample size will achieve over 90% power to detect a 5 point change 
in the International Restless Legs Severity Scale for the main effects of acupuncture 
assuming a standard deviation of 4 within each cohort. Additionally we will have roughly 
80% power to detect a potential interaction effect on acupuncture therapy. Every effort 
will be made to reduce attrition; consent documents will emphasize the importance of 
complete data and encourage patients to return for the follow-up visit.  
B. Randomization:  
Patients will be randomized to one of the two treatment options with equal allocation. In 
an attempt to balance severity across treatment cohorts the randomization scheme will be 
stratified by baseline severity of RLS symptoms as measured by the International Restless 
Legs Severity Scale (severe vs. very severe). The randomization scheme will be generated 
by the study statistician with varying block sizes and uploaded to a web-based 
randomization program. After the patients eligibility has been confirmed and consent 
documents signed the research coordinator will randomize the patient to one of the two 
treatment options via the web-based randomization program. The PI will not randomize 
patients or have access to their treatment assignments.  
C. Analysis plan:  
All demographic and baseline characteristics of interest will be summarized both overall 
and by cohort. Frequencies and percentages will be used to summarize categorical 
variables and means, standard deviations and other appropriate measures of spread for 
continuous variables. ANOVA models will be used for testing and to estimate the effects 
of acupuncture. Sensitivity analyses may be considered to assess the impact of baseline 
severity and other clinically relevant covariates on the outcomes. We will adjust for 
multiplicity for all contrasts. Secondary outcomes will be analyzed using a similar 
approach. Further details will be provided in the Statistical Analysis Plan (SAP).  
For study-related patient data (case report forms) a unique identifier will be used. 
Study-related documents will be kept in a locked cabinet in a locked office. A separate 
list (paper-only) will be made containing the unique identifier and the name of each 
participant. This list will be kept separate from the study related documents. Study 
databases will be stored on a password protected computer network in a locked office and 
kept for 5 years. 
 
 

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