Self-administered acupressure for allergic rhinitis: Study protocol for a randomized controlled trial


 Background: Allergic rhinitis (AR) is an IgE-mediated inflammatory disease. Current conventional therapies for AR are unsatisfactory. Acupuncture has been recommended as an optional treatment for AR patients who are interested in non-pharmacotherapy in the new clinical practice guidelines for AR. Acupressure is a sub-type of acupuncture which is non-invasive with a low risk and can be self-administered. However, the current limited evidence is compromised by the high risk of bias and heterogeneity of methodology. Therefore, rigorously designed randomized controlled trials (RCTs) are needed. This proposed RCT aims to evaluate the efficacy and safety of self-administered acupressure for the management of AR.
Methods/design: We have designed a randomized, single blind, non-specific controlled, two-arm, parallel clinical trial involving a 2-week run-in period, a 4-week intervention period and an 8-week follow-up period. The eligible participants will be randomized into either specific or non-specific acupressure group. They will be required to perform self-administered acupressure on either 5 specific acupressure points or 5 non-specific acupressure points, one minute for each point, twice a day for 4 weeks. Participants will be asked to complete self-administered questionnaires for outcome measures including 7-point scale of symptom severity, Rhinoconjunctivitis Quality of Life Questionnaire with Standardized Activities (RQLQs), relief medication scores, adverse events and participants’ opinion of this study at the different assessment points throughout the trial period. Data will be analyzed by chi-square, t-test or ANOVA using Statistical Package for Social Science (SPSS) software.
Discussion: The findings from this study will provide scientific evidence for the efficacy and safety of self-administered acupressure for the management of AR. This study may assist to develop a non-cost, non-invasive self-management method for AR sufferers. 
Trial registration: Australian and New Zealand Clinical Trials Registry (ANZCTR): ACTRN12617001106325 (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373370). Registered on 28 July 2017. 
Keywords: Hay fever; allergic disease; acupuncture; self-massage; evidence-based Chinese medicine.


Introduction
Allergic rhinitis (AR) is an IgE-mediated immunologic inflammatory response in nasal membrane after exposure to certain allergens which include pollens, dust mites, moulds, smoke, animal dander, air pollutants and occupational agents [1][2][3]. Patients with AR present with nasal symptoms such as sneezing, nasal itching, nasal congestion and runny nose; which may be combined with non-nasal symptoms such as itchy and watery eyes, as well as itchy and sore throat [2,4]. AR has a high prevalence worldwide ranging from 10% to 30% of the population affected [5]. In Australia, AR is a common respiratory condition that affects approximately 20% of population and the cost of medication from the pharmacy suppliers increased from $107.8 million to $226.8 million between 2001 and 2010 [6,7] . The troublesome of AR symptoms have a significant impact on patients' quality of life such as work and school performance, sleep and mental health [2]. Moreover, AR has a high impact on asthma and is associated with rhinosinusitis and other comorbidities such as conjunctivitis and chronic cough [2,6,8].
Current management of AR includes allergen avoidance, pharmacotherapies (such as H 1antihistamine, corticosteroids, chromones, decongestants, anti-cholinergics and anti-leukriences) and allergen-specific immunotherapy [2]. Most of the medications for AR are over-the-counter in Australia [6]. However, these medications are unable to provide full symptomatic relief and some of them are associated with undesirable side effects such as drowsiness and dryness in nasal cavity. Systemic glucocorticosteroids cannot be used for a long term due to systemic side effects such as suppressed immune system, weakened bones, high blood pressure, diabetes, especially impacts on children's growth [2,3]. Those could be the major reasons for more and more patients with AR to seek help from complementary and alternative medicine including acupuncture [9].
Acupuncture has a long history for the management of AR. Currently it has been recommended as an optional treatment for AR patients who are interested in non-pharmaceutical therapies in the Clinical Practice Guidelines for AR developed by the American Academy of Otolaryngology -Head and Neck Surgery and endorsed by the American Academy of Family Physicians [10]. Acupressure is a sub-type of acupuncture. It is a non-invasive therapeutic method applying physical pressure to certain acupuncture points by finger, elbow, hand or with various devices to treat diseases [11]. The popularity of acupressure has been increased these years and it was the fourth preferred complementary and alternative therapies in hospitalized patients in Australia [12]. Several clinical studies have validated the effects of acupressure for various health conditions, for instance, nausea, vomiting and pain after caesarean delivery [13], hypertension [14] and constipation [15]. A systematic review of randomized controlled trials (RCTs) in acupressure for respiratory allergic diseases indicated that acupressure is safe for symptomatic relief on AR and asthma. However, no reliable evidence of efficacy could be identified due to the small number of included RCTs, heterogeneity of study design and high/unclear risk of bias [16]. There is a need to perform rigorously-designed RCTs to investigate the efficacy and safety of acupressure for the management of AR.
This study aims to investigate the efficacy and safety of self-administered acupressure on symptomatic relief and health-related quality of life improvement in adults with AR by conducting a RCT. The study will also explore whether self-administered acupressure is effective in reducing the usage of Western medications in the management of AR.

Trial design
The ethics approval has been obtained from RMIT Human Research Ethics Committee (HREC) (project number: 20742). The trial has been registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12617001106325) (Additional file 2).

Participants
The participants will be based at the general population in Melbourne, Australia and recruited through advertisements on internet, posters, notice boards, leaflets, media release, social media, local newspapers, and newsletters. Participation in this research project is voluntary. The participants will be selected according to the inclusion and exclusion criteria listed in Table 1 below.

Sample size
The sample size was calculated using the program G*Power 3.1.9 [20]. Calculation of the sample size of this study was estimated on the relief of severity of the total nasal symptom score in the previously published acupuncture study [21]. The effect size estimate is 0.6505. To achieve 80% power at the significance level 0.05 we need 45 subjects per group taking into consideration of a 10% dropout rate.

Recruitment
People who are interested in taking part in this trial will be provided with Participant Information Sheet with Consent Form (PIS-CF) and asked to complete a general questionnaire and screening questionnaire if they agree with PIS-CF. Written consent will be obtained from each participant before an initial interview. The activities in the initial interview will include allergen skin prick test, physical examination and Chinese medicine differential diagnosis [22] to achieve AR diagnosis. The participants meeting the inclusion criteria will enter the 2-week run-in period. During this period, every participant will be asked to conduct two sets of weekly baseline assessment including a 7-point scale symptom severity assessment form [23], a Rhinoconjunctivitis Quality of Life Questionnaire with Standardized Activities (RQLQs) [24] and a medication usage form. All baseline assessment forms will be submitted in the first intervention session. The Figure 1 outlines the procedures of the clinical trial.

Randomization and blinding
To minimize bias, eligible participants will be randomized into either the specific-acupressure treatment group or non-specific acupressure control group. Randomization will be conducted after baseline assessment using a computer program run by an independent researcher who is not directly involved in the trial. The randomization codes will be put into individually sealed opaque envelopes with sequel trial numbers. The sealed opaque envelopes contain the information on the location of specific or non-specific acupressure points for self-administered acupressure. Each participant will be asked to pick one sealed envelope from the pack of all the envelopes and pass it onto the registered acupuncturist. This acupuncturist is the only person who knows the participants' group allocation in the trial. Neither the participants nor other investigators (such as data entry personnel and data analyst) will know the participants' allocation to receive specific or non-specific acupressure treatment. The randomization codes and the allocation of the participants will be revealed once the RCT is completed. However, in the event of the need of this grouping information (e.g., a participant experiencing severe adverse events), the investigators will access the grouping data on the request of the medical doctor. The relevant information will be documented in the participant's case report form.

Interventions
After randomization, the registered acupuncturist will provide detailed instructions and training on self-administered acupressure techniques to each participant individually. A pictorial instruction showing the location of acupressure points will be provided to the participants for further reference.
Participants will be asked to perform self-administered acupressure on either five specific or nonspecific acupressure points following the sequence from point 1 to point 5, for at least one minute each point, twice a day for four weeks and complete the self-assessment on a weekly basis. During the treatment period, participants are required to have a weekly visit to the Clinical Trial Laboratory and the registered acupuncturist will monitor their skills to ensure the accurate performance of selfadministered acupressure techniques. Messages will be sent to each participant to remind them to continue performing acupressure and attend the Clinical Trial Laboratory during each week. The Figure 2 below illustrates the location of five specific acupressure points and five non-specific acupressure points.

Specific self-administered acupressure
Participants in specific acupressure group will apply self-administered acupressure on five specific acupressure points including LI4 Hegu, GV23 Shangxing, BL2 Zanzhu, LI20 Yingxiang and GB20 Fengchi. The acupressure points were selected based on the review of classical and modern literature [11,16,22,25].

Non-specific self-administered acupressure
Participants in non-specific acupressure group will apply self-administered acupressure on another five non-specific acupressure points which are true acupuncture points on the body but not specifically indicated for AR treatment according to literature including Extra Luozhen, GV20 Baihui, GB4 Hanyan, SI18 Quanliao and GB12 Wangu [11,25].

Symptomatic relief medications
Participants will be allowed to continue their existing management for AR, such as pharmacological therapy. They will be asked to record the details of all medications used in the medication usage form.

Outcome measures
Primary and secondary outcome measures will be included in this clinical trial. The comparison between two groups will be at baseline, at the end of the treatment period and at the end of the follow-up period. The RCT schedule of recruitment, interventions and assessments is shown in Figure   3.

Primary outcome measures
The primary outcome measure will be AR symptomatic relief measured by 7-point scale symptom severity with the score ranging from 1 to 7. It contains four domains including I (nasal symptom severity), II (non-nasal symptom severity) and IV (Quality-of-life assessment of rhinitis severity) where a higher score indicates severer symptoms and better quality of life (QoL) as well as III (Global assessment of nasal and non-nasal symptom severity) where a lower score indicates severer symptoms [23]. The primary outcome measure will be assessed in baseline and intervention period on a weekly basis and in follow-up period on a fortnightly basis.

Secondary outcome measures
The secondary outcome measures will consist of RQLQs [24], relief medication scores, adverse events and participants' opinion about this clinical trial. RQLQs is used to assess the patient's quality of life and daily activities which contain seven domains with scores from 0 to 6; a higher score indicates a severer impact on QoL [24]. The use of anti-allergic medication is calculated as each daily dose of antihistamines or decongestants nasal spray or eye drop was equivalent to 1 point; oral antihistamines as 2 points and steroid nasal spray or eye drop as 3 points [26]. If the participants use oral corticosteroids or acupuncture for AR during the trial period, they will be asked to discontinue the treatment and considered as withdrawal from this study. Adverse events will be self-monitored and recorded in the adverse events form. If there are severe adverse events from the self-administered acupressure, the relevant participants will be asked to terminate the study and contact the researchers immediately. They will be referred to general practitioners or the emergency department for management. All adverse events will be under investigations and reported in writing to the RMIT HREC immediately. A questionnaire will be used to seek participants' opinion on the expectancy of self-administered acupressure for AR and the credibility of the blinding method used in the study.
RQLQs and relief medication scores will be assessed at baseline, intervention period (weekly) and trial. However, participants will be blinded during the entire randomization and intervention processes. Selection of acupressure points in treatment and control groups can be challenging as the size of fingers limits the chance of choosing the non-actual points one to three centimetres next to the real points which is the most popularly used sham control method in acupuncture/acupressure RCTs [30,31]. This RCT adopts specific and non-specific points which are in the same area but three to four centimetres in between in the treatment and control groups which aims to maximizes the possibility to achieve successful blinding of participants [32]. In addition, all the interventions and the outcome measures will be administered by participants themselves, which avoids involving thirty party assessors to reduce potential performance bias since blinding of assessors is considered more important than blinding practitioners since blinded assessments less likely bring biases to subjective outcomes [33]. When dealing with missing data, we will utilize the worst scenario method and intention-to-treat approach to manage the attrition bias. It is ideal to employ objective measures such as serum allergen specific Immunoglobulin E (IgE) to further investigate the mechanisms of action of acupressure for AR management. However, it is not feasible in this proposed RCT due to limited funding.
In summary, this protocol offers a standard regime to guide the conduct of RCT. By performing the rigorously designed RCT, this research project will make a significant contribution to the literature on self-administered acupressure. It may lead to the adoption of self-administered acupressure as a lowrisk, non-invasive, non-pharmaceutical intervention for AR and could also assist the self-management of AR.

Trial Status
This protocol is version 1. The advertisement for the recruitment began in August 2017 after the ethics approval. It is anticipated that the recruitment will be completed by the end of November 2019.
The recruitment is currently in progress.   The location of five specific and five non-specific acupressure points The schedule of recruitment, interventions and assessments