Atopic dermatitis (AD) is a chronic inflammatory skin disease with persistent itching, which impairs quality of life (QoL). Although various conventional treatments for AD exist, patients with AD often seek complementary and alternative therapies when conventional therapy has failed to relieve their AD symptoms or has had adverse effects. Acupuncture treatment may relieve AD symptoms, but controlled trials are needed to confirm this. Following our pilot study, which found that acupuncture treatment improves AD symptoms in mild-to-moderate AD patients, we will assess the effect of acupuncture treatment for symptom relief of AD using a trial with a complemented protocol. This is a two-arm, randomized, participant- and assessor-blinded, sham-controlled trial. A total of 36 mild-to-moderate AD patients will be randomly assigned in a 1:1 ratio to receive eight sessions twice weekly of either verum acupuncture (VA) or nonpenetrating sham acupuncture (SA) over four weeks. The primary outcome measured will be the change in the total Scoring Atopic Dermatitis (SCORAD) score. Secondary outcomes will be (1) changes in AD symptoms, QoL, dyspepsia symptoms, and electroencephalography (EEG) between baseline and week 4 and (2) changes in AD symptoms and QoL at baseline and at weeks 2, 4, and 8. This study will assess acupuncture treatment for the alleviation of AD symptoms in patients with mild-to-moderate AD. This clinical trial gas been registered in Korean Clinical Trial Registry (registration number:
Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by intense itching, skin dryness, erythema, exudate, crust, and lichenification [
Initial treatments for AD are emollients, topical corticosteroids, and topical calcineurin inhibitors [
AD has been effectively treated with acupuncture, which has been shown to lack side effects when used with conventional therapies [
In this pilot study [
Taken together, this recent evidence suggests the need for a randomized controlled trial assessing the efficacy of acupuncture in reducing the symptoms of AD. This study protocol describes the first such study. We designed a two-arm, randomized, participant- and assessor-blind, sham-controlled trial based on our pilot study and the above recent studies. The trial aims to assess the effect of twice-weekly acupuncture treatment on the symptoms of mild-to-moderate AD in adults, including changes in quality of life (QoL), GI symptoms, and EEG.
The main study objective is to determine whether or not twice-weekly acupuncture treatment improves symptoms and quality of life (QoL) in adults with mild-to-moderate AD.
Other objectives are (1) to investigate the relationship between severity of AD symptoms and GI symptoms and (2) to determine the effect of acupuncture on the CNS of AD patients using EEG.
This is a randomized, participant- and outcome assessor-blind, sham-controlled trial with a parallel group design. It will be conducted at the Kyung Hee University Korean Medicine Hospital. The flow chart of the study is presented in Figure
Flow of participants through the proposed trial. VA: verum acupuncture; SA: sham acupuncture.
Inclusion/exclusion criteria are as follows.
(A) 19 to 65-year-old men and women able to read and write the Korean language
(B) AD diagnosed according to the Hanifin and Rajka criteria [
(C) Scores from 30 to 80 points on a 100 mm Visual Analog Scale (VAS) for pruritus (0, no symptom at all; 10, worst symptom ever) [
(D) Scores from 10 to 40 points on the objective Scoring Atopic Dermatitis (SCORAD) scale [
(E) Abstinence from prescribed medications for AD for the preceding month
(F) Agreement with a study protocol and willingness to sign written informed consent
(G) No participation in other clinical studies for the preceding month
(A) Severely fluctuating AD symptoms
(B) Treatments (e.g., oral steroids) that may affect the symptoms of AD or that the study KMD deems inappropriate
(C) Secondary infection of AD lesions
(D) Severe mental problems
(E) Pregnancy, breastfeeding, or plans to have a baby during the study period
(F) Medical history that the study KMD considers to be inadequate
Based on our pilot study [
Participants who meet the inclusion criteria and have signed the written informed consent will be randomly assigned to either the VA or the SA group in a 1:1 ratio. An independent statistician will generate a random number table using SAS 9.2 (PROC PLAN, SAS Institute Inc., Cary, NC, USA) and send it to the administrative staff at the Acupuncture and Meridian Science Research Center (AMSRC) at Kyung Hee University. The administrative staff, who are also independent of our research team, will put each random number in a sealed, sequentially numbered, opaque envelope. Once a participant passes screening, the investigator will call the AMSRC staff, who will immediately send the investigator a document containing that participant’s unique random number and group allocation, which will be kept in the trial master file.
Participants and outcome assessors will be kept ignorant of treatment group allocations. It is not possible to blind the acupuncturist, so the KMD who applies the acupuncture treatment will not participate in assessment of trial outcomes or in collecting and analyzing the data. During acupuncture treatment, all participants in both groups will be shielded by a screen so that they cannot see the procedures. All participants in both groups will be treated with a Park sham device to ensure ignorance of whether the acupuncture needles penetrate the skin or not. If severe side effects occur or immediate acupuncture cessation is required, the blinding code will be broken.
Acupuncture treatment details are presented in Table
Acupuncture treatment details based on the checklist for STRICTA 2010. STRICTA: Standards for Reporting Interventions in Clinical Trials of Acupuncture; MA: Manual Acupuncture; IA: Intradermal Acupuncture; PTN: Press Tack Needle; AD: Atopic Dermatitis; VA: Verum Acupuncture; SA: Sham Acupuncture; KMD: Korean Medicine Doctor.
Item | Detail |
---|---|
(1) Acupuncture Rationale | (1a) Style of acupuncture |
(i) MA and IA using PTN based on traditional meridian theory | |
(1b) Reasoning for treatment provided, based on historical context, literature sources, and/or consensus methods, with references where appropriate | |
(i) Partially individualized MA treatment and IA treatments based on the traditional meridian theory, clinical experience, and consensus by the experts in acupuncture and AD | |
(1c) Extent to which treatment was varied | |
MA: Partially individualized, that is, 6 fixed points plus optional points according to individual symptoms | |
IA: Fixed treatment | |
| |
(2) Details of Needling | (2a) Number of needle insertions per subject per session (mean and range where relevant) |
(i) fixed points: PC6, LI11, ST36 bilaterally | |
(ii) optional points: ST43, GB11, LI2, TE3, TE6, SI2, SI3, BL66, LR3, SP3 contralaterally (GB41, TE3, SI3 can be applied bilaterally according to the signs or symptoms of the patient) | |
IA: LI11 bilaterally and auricular shenmen contralaterally | |
(2c) Depth of insertion, based on a specified unit of measurement or on a particular tissue level | |
| |
(3) Treatment Regimen | (3a) Number of treatment sessions |
(i) 8 sessions | |
(3b) Frequency and duration of treatment sessions | |
(i) Twice a week for 4 weeks, 15 minutes for each session | |
| |
(4) Other Components of Treatment | (4a) Details of other interventions administered to the acupuncture group (e.g. moxibustion, cupping, herbs, exercises, lifestyle advice) |
(i) Lifestyle advice will be given to all participants | |
(ii) Any other interventions will be prohibited during study period | |
(4b) Settings and context of treatment, including instructions to practitioner and information and explanations to patients | |
(i) Participants will be informed about acupuncture treatment in the study as follows: “In this study, you will be randomly allocated to VA group or SA group. Acupoints will be selected based on traditional Korean medicine textbook and AD-related reports. Also, additional acupoints can be used according to individual conditions, if needed.” | |
| |
(5) Practitioner Background | (5) Description of participating acupuncturists (qualification or professional affiliation, years in acupuncture practice, other relevant experience) |
(i) KMD who has clinical experience in Korean Medicine dermatology more than 2 years. The practitioner KMD will have undergone more than 10 hours of training and simulation workshop to ensure that he is able to provide identical acupuncture treatment in accordance with a predefined protocol. | |
| |
(6) Control and Comparator Interventions | (6a) Rationale for the control or comparator in the context of the research question, with sources that justify this choice |
(i) A control group (SA) will be treated with sham acupuncture using Park sham acupuncture needles and nonpenetrating sham PTNs | |
(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 | |
MA: Park sham acupuncture needles and devices will be used in same environment as in the VA group. However, fixed acupoints will be different: a point 1 to 2 cm proximal and 1 cm medial to LI7, a point 1 cm proximal and 1 cm medial to LI11, and a point 1 cm proximal and 1 cm lateral to ST36, each bilaterally | |
IA: Nonpenetrating sham PTNs, which were designed and validated for blinding for our study, will be used as a control in same environment as in the VA group. The same sized stainless steel rings without needles will be attached to three control points: a point 1 cm proximal and 1 cm medial to LI11, bilaterally, and finger point in the ear contralaterally. |
Participants in the VA group will receive eight acupuncture treatments twice a week for a total of four weeks. All VA group patients will receive acupuncture needling at six fixed acupoints. Up to 10 additional acupoints will be used, depending on each participant’s daily general conditions. The six fixed acupoints are LI11, ST36, and PC6 bilaterally. Additional acupoints include ST43, GB41, LI2, TE3, SI3, TE6, SI2, BL66, LR3, SP3, ST43, and GB41 for gastric stuffiness or dyspepsia; LI2 and GB41 for tenderness around ST25, diarrhea, or constipation; TE3 and SI3 for fullness in the chest and hypochondrium; TE3 and TE6 for lower abdominal pain and tenderness on CV17; SI3 and GB41 for lower abdominal pain and dry skin; SI2 and BL66 for lower abdominal pain and heat in the upper body and cold in the lower body; and LR3 and SP3 for pain in the hypogastric region with darkness of the sublingual collateral vessels. Disposable sterile stainless needles (0.25 x 40 mm; Dongbang Acupuncture Inc., Bundang, Seongnam, Korea) will be used. Acupuncture needles will be inserted to depths of 5 to 30 mm, depending on the acupoint, and will remain in place for 15 minutes.
After removal of acupuncture needles, three acupoints will be treated with IA using 1.5 mm press tack needles (Haeng Lim Seo Won Medical Co., Korea). These are bilateral LI11 and auricular-Shenmen contralaterally to the side with more severe symptoms. Participants will be instructed by the study KMD to press LI11 for more than three minutes when they experience severe itching.
Participants in the SA group will receive sham acupuncture treatment eight times twice a week for four weeks. Unlike the VA group, SA group patients will receive sham acupuncture treatment at only six fixed control points. These bilateral acupoints are as follows: 1 to 2 cm proximal and 1 cm medial to LI7, 1 cm proximal and 1 cm medial to LI11, and 1 cm proximal and 1 cm lateral to ST36. To maintain participant blinding, a nonpenetrating sham device (Park sham acupuncture needles, AcuPrime Co., Ltd., Exeter, UK) will be used and left in place for 15 minutes.
After removal of sham acupuncture needles, the IA procedure used in the VA group will be replaced with application of needle-free, stainless steel rings that do not penetrate the skin. These will be attached to three control points: 1 cm proximal and 1 cm medial to LI11 bilaterally and finger point in the ear contra-laterally to the side with more severe symptoms. Unlike the VA group, SA group patients will not be instructed to press the control point.
Two weeks after the eighth visit for the final acupuncture treatment, a telephone interview will be conducted to assess the severity of AD and dyspepsia symptoms, side effects after acupuncture treatment, and whether or not other treatments were used during the trial. During a final visit, four weeks after the eighth visit, the participant will complete a final evaluation. No other treatments will be allowed during the study period.
Frequent hospital visits may be a burden to the participant, resulting in withdrawal from the study. Based on the results of our pilot study [
A researcher who is independent of this study will evaluate the outcomes. The schedule is shown in Table
Treatment and measure | Baseline | Treatment period | Follow-up period | ||||||
---|---|---|---|---|---|---|---|---|---|
1 week | 2 weeks | 3 weeks | 4 weeks | 5 weeks | 6 weeks | 7 weeks | 8 weeks | ||
Demographics | ● | ||||||||
| |||||||||
Physical Examination | ● | ||||||||
| |||||||||
Medical history | ● | ||||||||
| |||||||||
VAS for itch | ● | ● | ● | ● | ● | | ● | ||
| |||||||||
VAS for sleep loss | ● | ● | ● | ● | ● | | ● | ||
| |||||||||
VAS for dyspepsia | ● | ● | ● | ● | ● | | ● | ||
| |||||||||
SCORAD assessment | ● | ● | ● | ● | ● | ● | |||
| |||||||||
EASI assessment | ● | ● | ● | ● | ● | ||||
| |||||||||
POEM assessment | ● | ● | ● | ● | ● | ||||
| |||||||||
DLQI assessment | ● | ● | ● | ● | ● | ||||
| |||||||||
PPT evaluation | ● | ● | ● | ||||||
| |||||||||
NDI-K assessment | ● | ● | ● | ||||||
| |||||||||
AR assessment | ● | ● | | ● | |||||
| |||||||||
Credibility test | ● | ● | |||||||
| |||||||||
Blinding test | ● | ||||||||
| |||||||||
EEG assessment | ● | ● | |||||||
| |||||||||
Acupuncture Treatment | ● | ● | ● | ● | |||||
| |||||||||
Adverse Events | ● | ● | ● | ● | | ● |
SCORAD was developed in 1993 by the European Task Force on Atopic Dermatitis as a useful scoring system that assesses the severity of AD by its extent, intensity, and subjective symptoms [
EASI is a tool for evaluating the severity of AD symptoms. Like the SCORAD index, it is known as a useful evaluation tool [
POEM is a simple, easily understood, and well-validated tool for evaluating the severity of AD symptoms in the preceding week. It is known to be appropriate for use in outpatient clinic or clinical trial settings [
DLQI is a well-validated clinical research tool that is widely used to assess the QoL of patients with dermatologic symptoms. It evaluates the effect of skin disease on QoL during the preceding week and consists of 10 questions [
In Korean Medicine, KMDs use abdominal examination for diagnosis, choice of treatment methods, and/or evaluation of prognosis [
NDI is a reliable scale for functional dyspepsia which evaluates dyspepsia symptoms and related QoL. NDI consists of period, severity, and degree of distress of 15 dyspepsia-related symptoms [
AR assesses improvement in overall functional dyspepsia symptoms [
Using 100 mm VAS (0 mm for no discomfort to 100 mm for the worst discomfort), we will measure a degree of overall dyspeptic symptoms.
In order to evaluate the credibility of the study participants’ acupuncture treatment, a questionnaire-type credibility test will be conducted at the first and eighth treatment visits and the follow-up visit [
Subjective feelings of itchiness in AD may be induced or enhanced by watching someone scratch himself or herself. Brain signals associated with somatosensory perception may be changed by contagious itch [
All patients will be asked to evaluate how much itchiness they feel after watching video clips of a person either scratching or performing a control movement. Their evaluation will use a visual analog scale ranging from 0 to 10. Continuous EEG will be recorded using Brain Products EEG amplifiers with a 32-channel ActiCAP system according to the international 10-20 system. Event-related spectral perturbation (ERSP) methods will be applied to EEG data, while patients are watching the video clips. Through time-frequency analysis, the suppression of mu activity will be measured over central-parietal regions. Mu rhythm represents frequencies in the range of 8-13 Hz, and the suppression of mu activity can be observed over the primary sensorimotor cortex when an action is performed, observed, or imagined [
Sample size calculation was carried out using G
Statistical analyses will be performed by an independent statistician who is unaware of group assignments, using IBM SPSS for Windows (Version 21.0). Continuous variables will be presented as mean ± 1 standard deviation, and bivariate variables will be presented as numbers (%). The effect of the intervention will be assessed as the change in outcome measures between baseline and four weeks (after treatment sessions end) and through eight weeks (after follow-up period ends), using a repeated-measures analysis of variance (ANOVA) and
ITT (intention-to-treat) analysis will be used for all participants who have undergone at least one acupuncture treatment. For missing values, the last observation carried forward (LOCF) method will be applied. PP (per protocol) analysis will be used for only the participants who have completed the entire course of the test exactly as specified in the trial plan. Primary evaluation of the intervention effect will be based on the results of the ITT analysis.
During the informed consent procedures, study participants will be informed of potential adverse events such as local bleeding, subcutaneous hematoma, or pain associated with acupuncture treatment. Adverse events that occur after acupuncture treatment will be assessed at each visit and after treatment is concluded and will be recorded in the case report form (CRF). Appropriate actions will be taken to minimize adverse events. If a serious adverse event occurs, the blinding code will be broken and the case immediately reported to the clinical trial director and the Institutional Review Board (IRB) at Kyung Hee University Korean Medicine Hospital. If necessary, part or all of the trial will be suspended until further instructions are available. Should a participant experience adverse events from trial participation, she/he will be treated at the research institute’s expense until recovery.
After enrollment, all records that identify the research participants will be kept confidential and can only be viewed by researchers. All documents related to the study will be identified by unique codes rather than participants’ names to protect confidentiality. All data and records related to the trial will be securely locked under the curation of the administration for three years after publication of the trial results and then destroyed.
All study researchers will receive centralized and unified training before the study. This study will be conducted under the periodic monitoring of AMSRC at Kyung Hee University and Korean Medicine Clinical Trial Center at Kyung Hee University Korean Medicine Hospital. This protocol follows Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) (see Additional File
If a protocol modification is required due to a serious adverse event or unanticipated problem, the representatives of Kyung Hee University Korean Medicine Hospital and the AMSRC will discuss the matter fully to take the appropriate steps.
The incidence of AD is increasing in developed countries, and the disorder affects both children and adults [
The relationships between skin, brain, and GI system health [
We will recruit 36 mild-to-moderate AD patients for this study, scoring 30 to 80 points on a 100 mm VAS for pruritus (0, no symptom at all; 10, worst symptom ever) [
In this study, we will use the same acupoints as in the pilot study [
The dose of acupuncture treatment was also determined based on our pilot study [
An appropriate sham control procedure is key to the success of an acupuncture RCT study. We designed the sham control to avoid physiological effects that might be induced by percutaneous needle insertion and to avoid specific acupoints. First, to avoid needle penetration, we will use the Park sham acupuncture device (AcuPrime Co., Ltd., Exeter, UK), which is known to be an adequate sham control for acupuncture [
There is a battery of outcome measures in this study. They can be divided into five categories: (1) measures of the severity of AD symptoms: SCORAD, VAS (Pruritus), VAS (Insomnia), EASI, and POEM, (2) a measure of the QoL affected by AD: DLQI, (3) measures of the severity of dyspepsia symptoms: NDI-K, AR, VAS of dyspepsia, and abdominal PPT, (4) measures of central nervous system responses of AD patients: EEG, and (5) a credibility test, blinding test, and assessment of adverse effects.
In our previous pilot study [
The unique finding of our pilot study [
This study protocol will provide an important and thorough assessment of the effectiveness of twice-weekly acupuncture treatment in improving the symptoms of mild-to-moderate AD in adults. It also aims to explore changes in QoL affected by AD, changes in the degree of GI symptoms, and EEG as secondary outcomes.
Atopic Dermatitis
Acupuncture and Meridian Science Research Center
Adequate Relief of functional dyspepsia pain and discomfort
Dermatology Life Quality Index
Eczema Area and Severity Index
Electroencephalogram
Intradermal Acupuncture
Institutional Review Board
Intention-to-treat analysis
Korean Medicine
Korean Medicine Doctor
Manual Acupuncture
Nepean Dyspepsia Index-Korean version
Patient Oriented Eczema Measure
Per protocol analysis
Pain Pressure Threshold
Press Tack Needle
Sham Acupuncture group
Scoring Atopic Dermatitis
Standards for Reporting Interventions in Clinical Trials of Acupuncture
Quality of Life
Verum Acupuncture group
Visual Analog Scale.
Data and materials are available upon request from the corresponding authors.
This study protocol was approved by the ethics committee at Kyung Hee University Korean Medicine Hospital (KOMCIRB-171117-HR-047, 2018.3.23, ver1.4). It is performed in accordance with the standards of the International Council for Harmonisation of Good Clinical Practice and the revised version of the Declaration of Helsinki.
Before participation in the study, a study KMD would thoroughly inform all potential study participants about the study aims, methods, and the anticipated benefits and potential risks of participation. Patients who meet the inclusion criteria and are willing to participate would be included in the trial only after giving written informed consent. Signed written consent documents would be filed in the trial master file.
This trial was registered via Clinical Research information Service (CRiS) on 13 April 2018 (identifier:
The authors declare that they have no conflicts of interest.
Younbyoung Chae, Hi-Joon Park, Hyangsook Lee, and Kyuseok Kim conceived and designed the trial. Jung Gun Park wrote the first draft. Jung Gun Park, Yu-Kang Kim, Younbyoung Chae, Hi-Joon Park, Hyangsook Lee, and Kyuseok Kim were responsible for critical revision of the draft. All authors read and approved the final manuscript.
The authors thank all subjects participating in the study. This research was supported by the National Research Foundation of Korea funded by the Korean Ministry of Science, ICT and Future Planning (NRF-2015M3A9E052338).
SPIRIT 2013 Checklist: recommended items to address in a clinical trial protocol and related documents*.