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)  and the Standards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA) .
Participants will be recruited between August 2019 and August 2020 at the Guang’ anmen Hospital via advertisements on posters, Wechat, and hospital websites. A dermatologist will be responsible for the screening which will include diagnosis of the type of acne of patients and a series of physical examinations (discrimination between inflammatory and non-inflammatory lesions of AV by the face pictures obtained using a digital camera) according to the diagnostic criteria for AV [22, 23] and the classification of lesions of AV , respectively.
All participants will be asked to read the informed consent form that describes the trial, randomization process for treatments, and the potential benefits and risks of this trial by a research assistant. Participants will be informed that both acupuncture and sham acupuncture may be effective for AV and they will be randomly assigned to the acupuncture group or sham acupuncture group. Participants will be allowed to withdraw from the trial at any time. Written informed consent will be obtained from all subjects prior to their enrolment.
The demographic and clinical characteristics of the participants at baseline will be recorded by a research assistant: age; gender; race; BMI (kg/m2); marital status; educational level (primary education or below, secondary education, and tertiary education); working duration (<8 hours, 8–12 hours, and >12 hours); duration of sports activities (<7 hours; 7–9 hours; and >9 hours); sleep duration (0-3 times/ month, 1-2 times/week, 3-4 times/week, and ≥ 5 times/week); smoking history; history of alcohol intake; AV duration in months; severity of AV as assessed by global acne grading system (GAGS) score [none (0 score), mild (1-18 score), moderate (19-30 score), severe (31-38 score), and markedly severe (> 39 score)] .
Randomization and allocation concealment
The randomization scheme has been prepared by the National Clinical Drug Testing Institute of the Guang’anmen Hospital. Participants will be randomly assigned to receive acupuncture or sham acupuncture treatment in a 1:1 ratio with the fixed block of four. Sealed opaque envelope will be used to ensure randomization concealment. The number of randomization sequence and information of group allocation will be sealed in ordered envelopes. With the inclusion of patients, those envelopes will be opened one by one in sequence. The envelopes will be kept by a researcher assistant who is not involved in the treatment or assessment. Additionally, assistant researchers will perform a baseline assessment of all participants (-1 week to 0 week) prior to randomization.
The participants, outcome assessors, and statisticians will be blinded to the group allocation. However, because of the characteristics of acupuncture, acupuncturists will not be blinded in this trial. To assess the blinding effect of sham acupuncture, participants will be asked to answer the following questions within 5 minutes after any treatment in week 4: “Do you think you have received traditional acupuncture?” The response options will be “Yes,” “No,” or “Unclear.”. The study protocol is illustrated in Figure 1.
This clinical trial will adhere to the principles of the Declaration of Helsinki and has been approved by the Ethics Committee of the Guang’anmen Hospital (2018-137-KY-01) (See Additional file 1).
One hundred eligible participants with AV will be recruited in the trial.
- Individuals aged between 18 and 48 years who qualify the diagnostic criteria for AV [22, 23];
- GAGS score between 19 and 38 .
Participants with any of the following conditions will be excluded:
- Individuals with polymerization acne, explosive acne, drug acne, premenstrual acne, cosmetic acne, occupational acne, or any other subtypes of acne;
- Individuals with other severe diseases that may affect the acne, such as polycystic ovary syndrome, thyroid disease, or atypical congenital adrenal hyperplasia;
- Individuals with other skin diseases that may influence the assessment of AV, such as rosacea, folliculitis, or other skin diseases;
- Individuals who have received antibiotics, retinoic acid, steroids, or anti-inflammatory drugs in the preceding one month;
- Individuals with severe heart, liver, kidney, hematopoietic system or autoimmune disorders, or severe systemic malnutrition;
- Pregnant and lactating women or those planning to conceive within 12 months;
- Individuals who have received acupuncture treatment in the past 3 months.
All participants will receive treatment for 4 weeks with 3 sessions per week (ideally every other day), for a total of 12 sessions. Acupuncturists with undergraduate degree or above and clinical experience of over 1 year at the Guang’anmen Hospital will be responsible for treatment. Participants will be treated separately to avoid communication during the trial period. We will discourage all included participants to receive any other treatment for AV during the study period. If participants received any other treatment for AV, they will also be included in this study and all details of the other treatment for AV will be recorded in the case report form. We will compare the proportion of participants using other treatments between the two groups.
The locations of acupoints is described as per ‘the Nomenclature and Location of Acupuncture Points (National Standard of People’s Republic of China, 2006 [GB/T 12346-2006])’ . The selections of acupoints will be decided with reference to the ‘Guidelines for AV treatment in China’ (revised version 2014) . Participants in the acupuncture group will receive stimulation 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 disinfection, acupuncture needles will be inserted obliquely into CV14 to a depth of 30–40 mm at an angle of 15°–30°; acupuncture needles will be vertically inserted into bilateral LI11, bilateral LI4, bilateral ST36, and bilateral ST44 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 sham acupuncture group will receive sham acupuncture at sham CV14 (10 mm to CV14), LI11 (10 mm to LI11), LI4 (10 mm to LI4), ST36 (25 mm to ST36) and ST44 (10 mm to ST44) with disposable acupuncture needles (0.30×25 mm, Huatuo Brand, Suzhou Medical Appliance, China). Sham CV14, LI11, LI4, ST36, ST44 will be vertically inserted to a depth of 1–2 mm without any manipulation and de-qi. The treatment sessions will last for 30 minutes.
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.
Participants will not be encouraged to receive any other treatment or medication during the study period to prevent any influence on the results. However, in case of deterioration of the condition of AV during the 4-week treatment period and the 24-week follow-up, oral minocycline hydrochloride capsules will be prescribed to the patients (100 mg per day for 7 days) to relieve the symptoms of pain or itching. Details of the medication used will be recorded in the case report form. The proportion of participants using rescue drugs in the groups will be compared.
The primary outcome will be the change in the total score of Skindex-16 scale from baseline at the end of 4-week treatment. The Skindex-16 scale is a brief, skin-related, quality-of-life scale with satisfactory reliability and validity. It is used to evaluate the efficacy of acupuncture in improving the QoL of patients with AV [24, 25]. The scale includes a total of 16 items which are categorized into three domains: the symptoms of participants with AV, the emotions of participants with AV, and function of participants with AV [16, 17]. The Skindex-16 scale score ranges from 0 (best) to 100 (worst) with the minimal clinically important difference (MCID) as 10 [16, 17].
Secondary outcomes include:
- The change from baseline in the Skindex-16 scale total score at weeks 16 and 28;
- The change from baseline in the Skindex-16 subscale (the symptoms of participants with AV, the emotions of participants with AV, and functioning of participants with AV) scores at weeks 4, 16, and 28;
- The change from baseline in the Dermatology Life Quality Index (DLQI)  scale total score at weeks 16 and 28. DLQI scale is a tool to assess the health-related QoL of patients with skin diseases. It has a total of 10 items. The total score of DLQI ranges from 0 (best) to 100 (worst) with 10 as the MCID .
- The change from baseline in the total lesion (inflammatory and non-inflammatory lesions) counts (TLC) [30,31] at weeks 4, 16 and 28;
- The change from baseline in the inflammatory lesions counts (ILC)  at weeks 4, 16 and 28. The inflammatory lesions include the inflammatory papules, pustules, and cysts. The non-inflammatory lesions include the black and white head comedones. The lesions are assessed on the forehead, cheeks, nose, and chin. The inflammatory and non-inflammatory lesions are counted from the face pictures obtained using a digital camera by a dermatologist.
- The change from baseline in the degree of itch assessed by visual analogue scale (IVAS)  at weeks 4, 16 and 28;
- The change from baseline in the severity of pain assessed by visual analogue scale (PVAS)  at weeks 4, 16 and 28;
- 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.”.
The details of the evaluation of outcomes are shown in Table 1.
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. Any serious adverse events (SAEs) will be reported to the Ethics Approval Committee of the Guang’anmen Hospital of China Academy of Chinese Medical Sciences within 24 hours. The department of Acupuncture of the Guang’anmen Hospital of China will provide insurance coverage to compensate for any injuries related to the interventions during this study.
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 in the acupuncture and sham acupuncture groups was -12.50 ± 19.09 and 0.40 ± 21.12, respectively. Assuming an alpha risk of 5% and a beta risk of 20%, a sample size of 100 (50 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; non-normally distributed continuous variables will be reported as median (interquartile range). Categorical variables will be presented as frequency (%). For data pertaining to drop-outs, the actual observational value of the last observation will be used for statistical analysis. Between-group differences with respect to normally distributed continuous variables will be assessed using analysis of variance (ANOVA) and those with respect to non-normally distributed continuous variables will be assessed using the nonparametric tests for the primary outcome and the secondary outcomes. Data pertaining to the participants’ expectations of acupuncture and the safety evaluation will be analyzed using the Chi-squared test or the Fisher exact test. For the blinding assessment, the percentage of participants choosing traditional acupuncture will be assessed using the Chi-squared test. All P values will be two-tailed; P ≤ 0.05 will be considered indicative of statistical significance.
All researchers will receive 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. AEs will be recorded in detail, properly handled, and tracked. All trial-related procedures and data management will be supervised. The Data Monitoring Committee of the Guang’anmen Hospital will regularly monitor the recruitment and screening of participants, data collection, monitoring and verification of AEs to ensure that the study is conducted in accordance with the approved protocol.