Efficacy of acupuncture at three nasal acupoints plus acupoint application for perennial allergic rhinitis: A multicenter, randomized controlled trial protocol

All licensed acupuncturists have completed at least 5 years of undergraduate education and are registered TCM practitioners. All research assistants and licensed acupuncturists involved in the trial will receive a 2-day training session prior to the start of the trial. Both treatments will comprise 12 sessions, each lasting for 30 min, administered regularly over a 4-week period. The licensed acupuncturists will provide AAP thrice a week for 4 weeks.

The treatment group will receive AAP. Disposable and sterile 0.25 × 40 mm acupuncture needles (Suzhou Tianxie Acupuncture Instruments Co., Ltd., Suzhou, China) will be used. Acupoints include Yintang (EX-HN3), Yingxiang (LI20), and Shangyingxiang (EX-HN8) as well as Feishu (BL13), Dazhu (BL11), Fengmen (BL12), Taiyuan (LU9), and Zusanli (ST36), which will be located according to World Health Organization (WHO) International Standard Acupuncture Points. Participants will be positioned in the seated position during treatment sessions. After routine skin sterilization, needles will be inserted using the neutral reinforcing–reduced manipulation technique. Each needle will be rotated until the participant experiences the qi sensations of soreness, heaviness, and distension. The complete AAP formula used in this trial is not publicly available, but the primary herbal ingredients include Rhizoma corydalis, Semen sinapis, Ephedra sinica, Cortex cinnamomi, Euphorbia kansui, Syzygium aromaticum, and Asarum sieboldii Miq. These herbs are processed into powder, proportionally mixed at a ratio of 2:2:1:1:1:1:1, and blended into fresh ginger juice to create an AAP ointment, which is then mechanically poured into tubes. The resulting AAP ointment is stored in a refrigerator at 4 °C. The AAP ointment and matching placebo are both manufactured by the Pharmaceutical Preparation Department of the First People’s Hospital Affiliated to Shanghai Jiaotong University, and both meet the regulatory guidance requirements issued by the China Food and Drug Administration. For each acupoint, approximately 3 g of ointment is squeezed by assistants onto a 6-cm-diameter circular fabric. For each participant, the following six acupoints will be used, which are located according to the WHO International Standard Acupuncture Points: Dazhui (GV14), Feishu (BL13), Dingchuan (EX-B), and Tiantu (CV22). The treatment procedure has been standardized at each center by advance training (Table 2).

The control group will receive shallow needling at sham Yintang (EX-HN3), sham Yingxiang (LI20), sham Shangyingxiang (EX-HN8), sham Feishu (BL13), sham Dazhu (BL11), and sham Taiyuan (LU9). Each of these acupoints is a nonacupoint located at a different physical location to the actual acupoints. The placebo ointment is composed of buckwheat powder and coke, resulting in an ointment appearing similar to the AAP ointment.

In both groups, participants with severe symptoms will be allowed to use rescue medicine with documentation of the medication. The type of medicine, dosage, and usage will be recorded on diary cards for analysis. For more complicated chronic diseases, participants must continue to take their routine medication and to receive the necessary therapies. In their case reports, the research staff will record the names of these diseases and the names of medications and therapies used.

The intervention should be terminated in the case of severe adverse events, withdrawal of participants, and unpermitted medication use.

Demographic information will be collected using a custom-made, standardized survey form that includes the following items: center location, name, age, sex, address, telephone number, and employment. A custom-made form will be used to collect medical information including diagnosis, nasal mucosal examination result, allergen examination result, typical symptoms, occurrence time of symptoms, accessory examination of nasal mucosa and nasal sinus, relevant diseases (allergic asthma and allergic conjunctivitis), and medication history.

Change in TNSS will be measured for each participant by comparing the baseline score with the score at the end of the 4-week treatment. TNSS is determined by the severity of rhinorrhea, nasal pruritus, nasal obstruction, and sneezing.

Changes in TNSS will be measured by comparing the baseline score with the score at 2 weeks and 1, 3, and 6 months after treatment. VAS and TNNSS will be used to observe supplementary symptoms and severity of symptoms. These will also be evaluated at 2 and 4 weeks and 1, 3, and 6 months after treatment. Peripheral blood IL-4, IL-5, IL-6, IL-8, and IL-10 levels will be measured by Luminex to observe allergic reactions.

All outcome readings will be scored on quantitative scales and summarized as mean values and standard deviation.

Adverse events (AEs) are defined as at least four participants with the same symptom, i.e., any undesirable experience occurring to participants during the trial period. This may or may not be associated with the intervention. Participants are instructed to report any AE to the research team at any time. All details of AEs including time of occurrence, description of symptoms, duration of symptoms, severity, management measures, and causality to the intervention will be recorded on case report forms (CRFs). Common AEs related to acupuncture include local skin pain, itching, ulcers, needle left in place, nausea during acupuncture, fainting during acupuncture, severe sharp pain, sharp pain lasting for > 30 min, hematoma around the site of needling, bleeding, numbness, infection around the site of needling, sleeplessness after acupuncture, and dizziness after acupuncture [30]. Common AEs related to AAP include local itching, redness, and blisters [31]. The causality between AEs and the intervention is assessed according to the WHO Uppsala Monitoring Center System for Standardized Case Causality Assessment [32]. If AEs occur, the research staff will select an appropriate treatment method until the condition has stabilized. After the participant’s condition returns to normal, the research staff will decide whether further observation is required. Severe AEs must be reported to the safety monitoring board within 24 h of their occurrence.

The 4-week treatment period will be followed by a 6-month follow-up period, during which the research staff will continue to follow participants’ progress via telephone communication and text message. The frequency of follow-up will be monthly, and records of symptom assessment and medication compliance or changes will be recorded. In the event of discontinuation or deviation from intervention protocols, the research staff will record the reasons and medication details and then exclude the participants and their latest outcome data including symptoms and frequency of AEs from the trial.

For an overview of the recruitment timeline, interventions, and all time points of participant evaluation, see Fig. 2.

The research staff will be responsible for the collection of baseline characteristic data and medical results during the screening period. For convenience, all participants’ scores, observation times, AE records, and safety assessments will be consolidated into a single CRF. CRFs must be filled out immediately and accurately after each piece of information is acquired. Participants are required to record in their daily diary any other medications they take during the trial period. Outcome evaluators will examine the outcomes at baseline, 2 weeks (within treatment), 4 weeks (end of treatment), 1 month (within follow-up), 3 months (within follow-up), and 6 months (end of follow-up). Data on nasal and non-nasal symptoms will be collected.

Data monitoring and management will be performed every 3 months by the Clinical Research Center of First People’s Hospital Affiliated to Shanghai Jiaotong University. The clinical research monitor will monitor medical practitioners to ensure all processes are correctly implemented. A data monitoring committee (DMC) has been established independent of the sponsor, and no conflict of interest exists. The DMC is responsible for monitoring trial progression and guaranteeing participant safety. Interim analyses and termination plans for the trial have not been specified, but if the DMC requests interim analyses, these will be supplied. Two assistants will enter all data into an electronic database by double data entry. The statistical manager will be responsible for source data organizing, coding, range checking for data values, and converting data to ensure data quality. The database will be locked after all data have been cleaned. If participants withdraw from the trial, the reasons should be detailed and the rate of withdrawal should be statistically analyzed.

Before recruitment, the entire research staff involved in the trial including acupuncturists, operational assistants, and research nurses must receive training in advance. Training will include the method for correctly filling out CRFs, blood tests, details of AAP, use of scales, participants’ method of using the medication diary, and follow-up visit skills. Researchers will be examined after training to ensure strict adherence to the trial protocol and consistency of the trial administration process including acupuncture and AAP treatment and evaluation method. The entire research staff will be provided with a written protocol and standard operating procedure documents. All acupuncturists who apply the treatment must have acupuncture licenses from the Ministry of Health of People’s Republic of China and > 5-year clinical experience.

To improve the quality of trial reporting and conduct, we will develop a standard operating procedure manual according to the principles of the CONSORT Extension for Chinese Herbal Medicine Formulas [33] and will thoroughly train all investigators. Intervention details such as acupuncture rationale, needling details, treatment regimen, time selection, practitioner background and confidence, and adequacy of stimulation were extracted and evaluated by CZ and SX according to STRICTA [34].

To ensure data authenticity, a special research team from the Clinical Research Center of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, independent of the investigators and sponsors, will externally monitor the trial at the three hospitals every 3 months. An advisory board will follow the trial and provide advice when necessary.

To improve intervention adherence, free treatment and blood tests will be provided to the treatment group for 4 weeks. To ensure that treatment and follow-up run on schedule, participants will be assured of and given monetary compensation at the end of the follow-up period.

The trial will test two groups in parallel. Sample size calculation was performed using SAS 9.3 (SAS Institute Inc., Cary, NC, USA) at the Clinical Evaluation Center of First People’s Hospital Affiliated to Shanghai Jiaotong University. The mean change in TNSS before and after treatment was used as the indicator of efficacy evaluation in sample size calculation. Other research has shown a mean TNSS change of 2.53 ± 4.74 after acupuncture treatment [22] and 2.75 ± 1.06 after AAP [35]. Based on these findings, the appropriate trial sample size with power of 80%, alpha value of 0.05, and acceptable delta value of 0.2 was calculated. The results show that a clinically important difference can be detected by a sample size with at least 49 in each group. Accordingly, this number was increased to 60 per group (a total of 120) to allow for a predicted 20% dropout rate.

Statistical analysis will be performed using SPSS 16.0 (SPSS Inc., Chicago, IL, USA) at the Clinical Evaluation Center of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine.

The size and dropout rate for each dataset will be described. Clarified reasons for any participant’s withdrawal from the trial will be provided.

Baseline adjusted analyses will be provided for center and severity variables, and the baseline value of the corresponding outcomes will be assessed. Descriptive statistics will be used to compare baseline measures with participant characteristics. If an imbalance occurs in baseline characteristics between the two groups, analysis of covariance will be applied.

Efficacy data analyses will be conducted on an intention-to-treat population. All participants initially included in any group will be considered in statistical analysis. Analysis of efficacy will be performed per-protocol and will include all participants who complete the entire research. Descriptive statistics will be used to compare serum indicators between the two groups. Regarding the primary and secondary outcome measures, a two-sample t test or Wilcoxon rank-sum test will be used to compare differences between both groups from baseline to the end of treatment (p < 0.05 will be considered statistically significant). The mean and standard deviation values of these parameters will be reported. Regarding repeated measures data, repeated measures analysis of variance will be performed after meeting spherical symmetry requirements. SPSS 16.0 will be used for all statistical calculations.

According to the definition of AEs, AEs will be recorded, along with their severity level, causes, and explanations. The number of AEs and rate of AEs will be described statistically. If AEs need to be compared between groups, χ² test or Fisher’s exact test will be used.

All data used in the main statistical analysis should be collected by the fourth week of the treatment and by the 6-month follow-up. To avoid missing data, participants who complete the trial and provide completed data will be financially compensated. The investigators have a wealth of experience from previous trials in managing participants and collecting data. Participant contact information will be recorded and researchers will keep in touch with them through various means of communication during the treatment and follow-up periods.

If data are not obtained, the time and reason for missing data will be recorded and the assumed missing data mechanism will be analyzed. For these missing data, a multiple imputation adjustment approach will be used. After the main analysis, sensitivity analysis will be performed for the various datasets to enable the assessment of the impact of missing data on the results.

A detailed statistical analysis plan will be written by an independent statistician.

Following the completion of data analysis, Chinese and English dissemination is planned. Regardless of the findings, the trial results with be disseminated via conferences or publications.

The entire research staff who participated in the organization, implementation, data management, and statistical analysis will be affirmed in the authorship, and there is no intention to use professional writing services.

There is no plan to permit public access to the full protocol, participant dataset, or statistical code. However, if necessary, individuals can gain access to the full protocol through the Ethics Committee of the Institute of Shanghai General Hospital Affiliated to Shanghai Jiaotong University.

This protocol was written following the SPIRIT checklist (see Additional file 1). The future report will follow the CONSORT guidelines [29], Revised STRICTA guidelines [28], and extension of CONSORT for reporting single-blind randomized trials.