Efficacy of acupuncture in improving the quality of life of patient’s with moderate or severe acne vulgaris: protocol for a randomized controlled trial

Background Acne vulgaris (AV) is a common chronic dermatologic disease that tends to impair the quality of life of patients. None of the previous clinical trials of acupuncture therapy for AV used the quality of life as a primary outcome or employed a sham acupuncture control arm. Methods/design Participants with AV will be randomly assigned to acupuncture or sham acupuncture groups (1:1 allocation). All participants will receive 4-week treatment comprising of a total of 12 sessions (3 sessions per week). The primary outcome will be change from baseline in the Skindex-16 scale total score at treatment completion. The secondary outcomes will be Skindex-16 subscale scores, the Dermatology Life Quality Index scale total score, the total lesion count and inflammatory lesion count, itch and pain assessment using the visual analogue scale score, patient expectations of acupuncture, patient satisfaction with treatment, and the blinding of the effect of sham acupuncture. Follow-up evaluation will be performed at weeks 16 and 28. All outcome analyses will be performed in the intention-to-treat population. Discussion This is the first randomized controlled trial which will compare the effect of acupuncture versus sham acupuncture in improving the quality of life of patients with moderate or severe acne vulgaris (AV). The limitation of the design of this trial is that the sample size of a single center trial, which may lead to potential overestimation of the effect of acupuncture. Meanwhile, blinded


Abstract
Background Acne vulgaris (AV) is a common chronic dermatologic disease that tends to impair the quality of life of patients. None of the previous clinical trials of acupuncture therapy for AV used the quality of life as a primary outcome or employed a sham acupuncture control arm. Methods/design Participants with AV will be randomly assigned to acupuncture or sham acupuncture groups (1:1 allocation). All participants will receive 4-week treatment comprising of a total of 12 sessions (3 sessions per week). The primary outcome will be change from baseline in the Skindex-16 scale total score at treatment completion. The secondary outcomes will be Skindex-16 subscale scores, the Dermatology Life Quality Index scale total score, the total lesion count and inflammatory lesion count, itch and pain assessment using the visual analogue scale score, patient expectations of acupuncture, patient satisfaction with treatment, and the blinding of the effect of sham acupuncture. Follow-up evaluation will be performed at weeks 16 and 28. All outcome analyses will be performed in the intention-to-treat population. Discussion This is the first randomized controlled trial which will compare the effect of acupuncture versus sham acupuncture in improving the quality of life of patients with moderate or severe acne vulgaris (AV). The limitation of the design of this trial is that the sample size of a single center trial, which may lead to potential overestimation of the effect of acupuncture.
Meanwhile, due to the characteristics of acupuncture, the acupuncturists will not be blinded and the use of non-acupoints and minimal acupuncture without any manipulation, which may introduce an element of bias and cause some biological effect.

Background
Acne vulgaris (AV) is a common chronic dermatologic disease involving the pilosebaceous units [1,2] . The symptoms of AV include skin lesions such as comedones, erythematous 3 papules, pustules, nodules, deep pustules, and scarring. The lesions typically affect the face, chest and back [1,3] . An estimated 79-95% of the adolescent population is affected by AV. In Western populations, 40-54% of individuals affected by AV are older than 25 years [4] . As lesions of AV predominantly occur on face, the disease may induce psychosocial symptoms such as anxiety and lowered self-esteem [5,6] . Consequently, AV may lead to a decline in the quality of life of the afflicted individual [5][6][7][8] .
The American Society of Dermatology recommends topical benzoyl peroxide or combination of erythromycin, clindamycin, topical retinoids, or systemic antibiotic therapy as the first-line treatment for mild to severe AV [1][2][3] . However, these treatments may cause side effects such as drying, peeling, erythema, and skin irritation. In addition, longterm treatment may induce drug resistance and is associated with relatively high recurrence rate [9] .
Owing to the side effects of conventional drugs, there is an increasing interest in the use of natural and safer treatment options; these include complementary and alternative treatment remedies, such as herbal medicine and acupuncture [9,10] . Several trials have indicated that acupuncture may alleviate the skin lesions and improve the quality of life of patients with AV [11][12][13][14][15] ; however, these trials were of low quality and the level of evidence was low. In our pilot trial (unpublished) conducted from April 2017 to March 2018, 42 patients with moderate or severe AV were randomized into acupuncture group (n = 21) and sham acupuncture (n = 21) groups. After 4-week treatment, the reduction in the lesions of skin was -6.62 ± 15.42 and -15.10 ± 20.13 after treatment for the acupuncture and the sham acupuncture groups, respectively. And we found no significant betweengroup difference with respect to the the lesions of skin (P = 0.137), which contradicts the 4 results of previous trials [11][12][13][14] . However, After 4 weeks, the reduction in the the Skindex-16 scale total score was -12.50 ± 19.09 (32.39 ± 21.36 at baseline and 19.89 ± 15.40 after treatment) and 0.40 ± 21.12 (30.03 ± 20.78 at baseline and 30.43 ± 19.39 after treatment) after treatment for the acupuncture and the sham acupuncture groups, respectively. There was a significant between-group difference with respect to the Skindex-16 scale total score (P = 0.044), which suggests that acupuncture may afford symptom relief and improve the quality of life of patients with moderate or severe AV. Therefore, the primary objective of the present study was to evaluate the effect of acupuncture on the quality of life of patients with moderate or severe AV. The secondary objective was to evaluate the safety and efficacy of acupuncture in improving the symptoms of AV.

Study design
The proposed study is a prospective, randomized, sham acupuncture controlled trial with two parallel arms using a 1:1 allocation ratio. The trial will be conducted at the Guang' anmen Hospital, China Academy of Chinese Medical Sciences. The study protocol conforms to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) [16] and the Standards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA) [17] .
Participants will be recruited between Augest 2019 to March 2020 at the Guang' anmen Hospital, China Academy of Chinese Medical Sciences. Participation will be solicited through advertisement using posters, Wechat social media application, hospital websites, and networks. A dermatologist will be responsible for diagnosis. The randomized scheme has been prepared by the National Clinical Drug testing Institute at the Guang' anmen Hospital. Block randomization using the closed envelope method will be used. Participants 5 will be randomly assigned by the SAS software to receive acupuncture or sham acupuncture in a 1:1 ratio. The numbers of randomization and the group allocation will be sealed in an impermeable envelope, and the numbers based on the order of inclusion will be marked on the cover of the envelope. Randomization envelopes and their distribution will be handled by a researcher who is not involved in the treatment or evaluation.
Additionally, all participants will undergo a baseline assessment (-1 week to 0 week) prior to randomization. The participants, effect evaluator, and data manager will be blinded to group allocation. However, because of the characteristics of acupuncture, acupuncturists will not be blinded in this trial. A schematic illustration of the study design is shown in Figure 1.

Ethical approval
This clinical trial will adhere to the principles of the Declaration of Helsinki of World medical conference. This trial has been approved by the Ethics Committee of the Guang'anmen Hospital (2018-137-KY-01) (See Additional file 1).
Participants 96 participants with AV will be recruited in the trial.

Exclusion criteria
Participants who qualify any of the following criteria will be excluded: Individuals who have acupuncture experience in the past 3 months.

Intervention
All participants will receive treatment for 4 weeks with 3 sessions per week (ideally every other day). Therefore, all participants will undergo a total of 12 sessions. Acupuncturists (academic background: above undergraduate degree) with over 1 year clinical experience at the Guang'anmen Hospital will be responsible for treatment. Two acupuncturists (respectively) will administer treatment in the two groups. Efforts will be made to avoid communication among the participants during the trial period.

Acupuncture group
The locations of acupoints is described as per 'the Nomenclature and Location of  [21] . The selections of acupoints will be decided with reference to the 'Guidelines for AV treatment in China' (revised version 2014) [22] . Participants in the acupuncture group will receive acupuncture at Dazhui (CV14), bilateral Quchi (LI11), bilateral Hegu (LI4), bilateral Zusanli (ST36), and bilateral Neiting (ST44) with disposable acupuncture needles (0.30×40 mm, Huatuo Brand, Suzhou Medical Appliance, China). After routine sterile measures, CV14 will be inserted to a depth of 30-40 mm at an angle of 15°-30° in an inferomedial direction; bilateral LI11, bilateral LI4, bilateral ST36, and bilateral ST44 will be vertically inserted to a depth of 25-30 mm for 3 times (once every 10 minutes) with slight lifting, thrusting, and twisting manipulations to produce a sensation of de-qi.
Each session of acupuncture will last for 30 minutes.

Sham acupuncture group
Participants in the sham acupuncture group will receive sham acupuncture at sham CV14 Participants will not be allowed use of other treatments for AV throughout the trial.
Detailed information pertaining to use of other treatments will be recorded in the case report form.

Outcome measures
The primary outcome will be the change from baseline in the Skindex-16 scale total score at the end of 4-week treatment. The Skindex-16 scale is used to measure the effects of skin disease on the quality of life of patients. The scale includes a total of 16 items categorized into three domains: the symptoms of participants with AV, the emotions of participants with AV, and function of participants with AV [23,24] . The Skindex-16 scale score ranges from 0 (best) to 100 (worst); the minimal clinically important difference (MCID) is 10 [23,24] .
Secondary outcomes will be included:

6.
The change from baseline in the itch assessment with visual analogue scale (IVAS) [27] total score at weeks 4, 16 and 28;

7.
The change from baseline in the pain assessment with visual analogue scale (PVAS) [27] total score at weeks 4, 16 and 28; 8. The participants' expectations of acupuncture will be assessed at baseline using the following 2 questions: "Do you think acupuncture will be effective for treating the illness?" and "Do you think acupuncture will be effective for relieving the related symptoms of AV?" The response options will be "Yes," "No," or "Unclear.".

9.
The participants' self-satisfaction of acupuncture treatment will be measured at 9 weeks 4, 16 and 28.
The details of the evaluation of outcomes are shown in Table 1.

Safety evaluation and blinding assessment
Adverse events (AE) including AEs related to acupuncture (broken needle, local hematoma, infection, abscess, and others), AEs related to post-acupuncture (nausea, vomiting, palpitations, dizziness, headache, insomnia, or any other symptoms after acupuncture treatment), and AEs unrelated to treatment. For safety assessment, details of all AEs will be recorded in the case report form by a research assistant.
To assess the blinding effect of sham acupuncture, participants will answer the following questions within 5 minutes after any treatment session during period of week 4 treatment: "Do you think you have received traditional acupuncture?" The response options will be "Yes," "No," or "Unclear.".

Sample size and statistical analysis
The sample size of this trial was calculated based on the primary outcome, which is the change from baseline in the Skindex-16 scale score at the end of week 4. In our unpublished pilot trial, the mean (± standard deviation) reduction in the Skindex-16 scale score after 4-week treatment was -12.50 ± 19.09 and 0.40 ± 21.12 after treatment for the acupuncture and the sham acupuncture groups, respectively. Assuming an alpha risk of 5% and a beta risk of 20%, a sample size of 96 (48 participants in each group) was calculated considering a 20% dropout rate.
The data will be analyzed using SPSS software V.20.0 (IBM SPSS Statistics; IBM Corp, Somers, NY) according to intention-to-treat principle. Normally distributed continuous variables will be reported as mean±standard deviation and 95% confidence intervals; nonnormally distributed continuous variables will be reported as median (interquartile range).
Categorical variables will be presented as frequency (%). For data pertaining to drop-outs, multiple imputation will be used for statistical analysis. Between-group differences with respect to normally distributed continuous variables will be assessed using the t-test or Chi-squared test; those with respect to non-normally distributed continuous variables will be assessed using the non-parametric Wilcoxon statistics. Chi-squared test will be used for categorical variables. All P values will be two-tailed; P ≤ 0.05 will be considered indicative of statistical significance.

Quality control
All researchers will undergo a training course before the beginning of this trial. Due measures will be implemented to ensure the traceability and confidentiality of the case report form, informed consent form, and other original data. Double input method will be used for data entry. All AEs will be recorded in detail, properly handled, and tracked. All trial-related procedures and data management will be supervised.

Discussion
Several RCTs suggest that acupuncture may be effective for patients with AV. However, the results of these RCTs are controversial due to lower quality of their design and the possible placebo effects of acupuncture [11][12][13][14][15] . In this trial, we aim to evaluate the therapeutic effect of acupuncture on the quality of life of patients with moderate or severe AV compared with sham acupuncture; in addition, we seek to partially exclude the possible placebo effects of acupuncture.
Generally speaking, there is no ideal placebo acupuncture control; the sham control with use of a non-insertion-type needle on non-acupoints is the best possible choice to reduce its possible biological effects as much as possible [24,25] . However, the non-insertion-type needle leaves no marks or wounds of acupuncture on the skin; moreover, the acupoints chosen in this trial were mostly located in the chest, abdomen, and the forearm.
Therefore, it will be easy for the participants to perceive this sham acupucnture which will compromise the blinding. Therefore, we opted for non-acupoints and minimal acupuncture without any manipulation as the sham acupuncture in this trial. Besides, the nonacupoints are in proximity to the classical acupoints, which will increase the feasibility of blinding.
The Skindex-16 scale and the DLQI scale are two brief, skin-related, quality-of-life scales with satisfactory reliability and validity; these will be used to evaluate the efficacy of acupuncture in improving the quality of life of patients with AV [26,27] . The Skindex-16 scale is a skin-related measure with three domains related to patients with AV (symptoms, emotions, and functioning of patients with AV). We also use TLC, ITC, IVAS, and PVAS as secondary outcomes to assess the lesion counts and main symptoms (itch or pain) related to AV. These would provide a comprehensive evaluation of the overall effectiveness of acupuncture.
Finally, some potential limitations of our study should be acknowledged. This will be a single center study with a relatively small sample size; therefore, the results may not apply to other countries or settings. Moreover, it may lead to overestimation of the effect of acupuncture. The use of non-acupoints and minimal acupuncture without any manipulation may cause some biological effect leading to false-negative results [24,25] .
Above all, the expectant results of our trial will answer whether acupuncture is effective in improving the quality of life of patients with AV in some extent. Meanwhile, all study participants will have right to exit test.

Consent for publication:Not applicable.
Availability of data and material: All of the relevant data will be shared for a period beginning 3 months after publication and ending 5 years after publication.  SPIRIT_checklist.doc