Efficacy and safety of acupoint catgut embedding for perennial allergic rhinitis:study protocol for a randomized clinical trial (Preprint)
Authors: Cai Zijie 
Published: July 2024

BACKGROUND

Allergic rhinitis (AR) is a non-infectious chronic inflammatory disease of the nasal mucosa characterized mainly by itching, sneezing, nasal congestion, and rhinorrhea, mediated by immunoglobulin E (IgE). Allergic rhinitis is one of the most common allergic diseases globally, affecting 10-20% of the population worldwide(1), with some regions even reaching rates as high as 50%, posing a global health issue. The prevalence of allergic rhinitis has been increasing since the 1960s(2), with a significant increase in recent years(3). At present, modern medicine with desensitization therapy, the use of anti-allergic drugs, antihistamines, hormones, and other improved symptoms or immune regulation, but clinical near and long-term efficacy is general after stopping the symptoms are easy to repeat, and long-term drug toxicity side effects are obvious(4). Allergen-specific immunotherapy(AIT) is the only means of altering the natural immunological course of allergic diseases and achieving long-term remission. Pharmacological measures are able to suppress the immune response and/or ameliorate the symptoms but there is a risk of relapse soon after these measures are withdrawn(5). Currently, the main drugs for the treatment of allergic rhinitis are H1 antihistamines, nasal steroid hormones, and leukotriene receptor antagonists. The control and safety of nasal symptoms have been verified, but there are still deficiencies in the control of the recurrence of allergic rhinitis(6). Catgut implantation at acupoints is a subtype of acupuncture, which can be embedded in the acupoint by using a special needle. A period of time may be needed for the catgut to be completely absorbed by the tissue. Therapeutic effects can be achieved by continuing stimulation caused by the catgut at the acupoint. Therefore, catgut implantation at the acupoint may be effective in treating some chronic diseases such as AR.Although catgut implantation at acupoint has been used in treating diseases for a few thousand years in China,there have been very few clinical trials that have been strictly designed to verify the efficacy and safety of this treatment for AR(7). It is indeed necessary to obtain a level of evidence for catgut implantation at acupoints in the treatment of AR. Research on acupoint embedding therapy for allergic rhinitis (AR) primarily focuses on regulating cytokines, influencing neurotransmitters, and inhibiting immune molecules such as immunoglobulin E (IgE). At the cytokine regulation level, acupoint embedding research concentrates on interventions targeting inflammatory factors and transforming factors. Inflammatory factors include interleukin-17, interleukin-4, gamma interferon, etc., while transforming growth factors include transforming growth factor β1, among others(8–12). Acupoint embedding therapy intervenes in neurotransmitters mainly by participating in the release of various immunologically active substances, such as substance P. Research has found that embedding therapy can alleviate rhinitis-related symptoms by regulating substance P and nitric oxide levels(13–15). Initially involving mechanical stimulation and later biological and chemical stimulation. The process of softening, decomposing, liquefying, and absorbing the catgut thread within the acupoint generates long-lasting stimulation, making it less prone to recurrence. Therefore, the treatment interval can be extended to once every 10 days, greatly improving patient compliance. On the other hand, catgut thread, as an allogeneic protein stimulus, can better regulate the relative balance of the body's internal environment, enhance immune function and stress resistance, and reduce allergic reactions. Therefore, it is considered an excellent method for treating allergic rhinitis(16). A recently published systematic review confirmed the effect of acupoint catgut embedding therapy. However, it also pointed out that previous RCTs have suffered from a variety of methodological limitations, including the absence of sample size calculation, inappropriate control groups, and multicenter randomized controlled trials and blinded designs(17). Therefore, it is necessary to conduct large-scale and rigorously designed randomized controlled trials to overcome the identified methodological issues. The main objective of this study is to evaluate the efficacy of acupoint catgut embedding therapy for allergic rhinitis, with a focus on reducing recurrence. Secondary objectives include assessing whether acupoint catgut embedding therapy can (1) improve patients' quality of life, (2) change the dosage of rescue medication (RM).

OBJECTIVE

The main objective of this study is to evaluate the efficacy of acupoint catgut embedding therapy for allergic rhinitis, with a focus on reducing recurrence. Secondary objectives include assessing whether acupoint catgut embedding therapy can (1) improve patients' quality of life, (2) change the dosage of rescue medication (RM).

METHODS

Study design
This study is a parallel-group, patient-blind,placebo-controlled randomized controlled trial conducted in the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.Ningxia Hui Autonomous Region Hospital and Academy of Traditional Chinese Medicine,Yinchuan,China.Affiliated Hospital of Shanxi University of Traditional Chinese Medicine,Taiyuan,China.A flow chart of this trial is provided in Figure 1. The trial consists of 4 TSs conducted along with a three-month follow-up. After providing written informed consent, eligible participants were randomized at a ratio of 1: 1 into one of two groups: an ACE group receiving ACE treatment; a sham ACE group receiving sham ACE treatments; And both groups receiving conventional loratadine treatment.
Patient
Participants were recruited via advertisements, posters, leaflets about the trial, and doctor referrals from otorhinolaryngology clinics in the Third Affiliated Hospital of Sun Yat-sen University,Ningxia Hui Autonomous Region Hospital and Academy of Traditional Chinese Medicine and Affiliated Hospital of Shanxi University of Traditional Chinese Medicine Interested individuals need to contact research assistants by phone or email. Trial information and consent forms were sent to them to read prior to scheduling their first visit. In the first visit, screening evaluations were conducted and recorded to ensure the eligibility of each individual. For each participant who was eligible and willing to participate in the trial, research assistants obtained a signed consent form.Inclusion criteria for this trial required participants to meet the following: (1) be aged between 18 and 65 years old, (2) meet the diagnostic criteria for perennial allergic rhinitis and (3) be in the stage of symptomatic attack while able to accurately describe their condition, voluntarily provide informed consent, and agree to participate in the clinical study. Exclusion criteria included: (1) recent respiratory infection or acute paranasal sinusitis within the past 14 days, (2) evidence of inflammation on chest X-ray, (3) history of chronic paranasal sinusitis or current diagnosis via X-ray examination, (4) presence of organic lesions in the nasal cavity or recent nasal surgery, (5) diagnosis of paroxysmal respiratory diseases such as asthma, recent use of H1-antihistamines, steroids, decongestants, or other medications affecting the respiratory system within the past 14 days, (6) specific immunotherapy or systemic hormone therapy within the last year, (7) recent use of acupuncture, moxibustion, cupping, nasal inhalation of traditional Chinese medicine, or other traditional therapies within the past 14 days, and (8) determination by clinical investigators that participants are unable to cooperate with the treatment regimen.
Randomization and Allocation Concealment
A block randomization sequence was generated by SAS 9.2 software(SAS Institute Inc., Cary, USA), which was performed by GPHCM’s Key Unit of Methodology in Clinical Research(KUMCR). Eligible participants were randomly assigned to either the ACE group, the sham ACE group at a ratio of 1 : 1. An independent researcher prepared treatment cards, on which a serial number and one of two names were printed, each representing one of the two groups. This person was also responsible for selecting to add intestinal thread to the injection needles according to the respective groups. Treatment allocations were stored in password-protected files and held independently by a staff of KUMCR. While receiving the first treatment, participants were given sequential treatment cards from independent researchers to ensure adequate concealment. Participants were then allocated into one of two groups according to the name printed on their treatment card.

Blinding
The researchers assign intervention measures to the subjects according to the group information of the patients. Patients are blinded and the participants, operational assistants, data managers, and statisticians do not know the treatment allocations, The person in charge of the efficacy evaluation is a third party and will not know the grouping of patients. A first-level blind base is established for the database of data statistics. The statistician does not know the specific group situation. All operations are performed in accordance with established Standard Operation Procedure.After each treatment session, the participants in the ACE and the Sham ACE group completed a questionnaire on whether they believed ACE treatment was received, and how certain they were that active treatment was received on a 0–10 numeric rating scale, where 10 represented absolute certainty(18).Both the block randomization and the blinding questionnaire were exclusively administered by a single external party.

Intervention
To ensure consistency of operation, all patients receive a unified treatment plan and are operated by the same doctor. The research assistant selected to add intestinal thread to the injection needles according to the respective groups.The ACE group underwent acupoint catgut embedding. After disinfecting bilateral YingXiang(LI20) point, YinTang(GV24+)point, QuChi(LI11) point, DanZhong(CV17) point and JianJing(GB21) point area. The patient took the supine position, located the acupoints on the body surface marked them with a marker, and disinfected them with iodophor cotton swabs.The performer wore aseptic gloves, cut the absorbable surgical suture around 1.5cm, and put it into the front end of the needle tube.The left thumb and index finger of the performer tightened the skin around the operation site, and the needle was inserted vertically with a catgut-burying needle in his right hand, with a depth of 1-1.5 inch, slightly lifting and stimulating acupoints, and pushing the needle core inward on his right thumb after getting qi. At the same time, the right hand withdrew the needle tube outward, and the surgical suture was embedded in the acupoint.After the stitches exit, press the pinhole with aseptic gauze for a while and cover the band-aid or infusion paste. Catgut was implanted once every 7 days for a total of 28 days and each participant took a prescribed dose of loratadine orally every day.The sham ACE group patient is placed in a supine position, the surface position of the acupoints is located, marked with a marker pen, and disinfected with an iodophor cotton swab. The practitioner wears sterile gloves inserts the needle into the skin and pulls out the needle after getting qi.After the operation, press the pinhole with aseptic gauze for a while and cover the band-aid or infusion paste.This procedure was also conducted once a week for four consecutive weeks. Each participant took a prescribed dose of loratadine orally every day.Participants from all two groups are instructed to stop symptomatic relief RMs during the one-week run-in and treatment periods. However, they can take RMs if needed during the follow-up period. These RMs are required to be documented in participants’ diaries.

RESULTS

Outcome Measurement
For the evaluation of the primary and secondary outcome measures, participants are required to complete two questionnaires, the total ocular symptom score (TOSS) and the Total Nasal Symptom Score(TNSS) at the beginning of each of four TSs (from 2nd to 5th weeks) and at the 8th, 12th and 16th weeks during each follow-up. During the follow-up process, patients need to independently record the scores of the rhinitis control assessment test (RCAT) weekly. In addition, participants are asked to complete diaries throughout the trial.The primary outcome is the Recurrence rate at 3 months after discontinuation. Once the treatment-effective subjects discontinue medication(RCAT score is less than 21 points), they immediately enter the follow-up period. If a relapse occurs, record the relapse time promptly and conclude the follow-up; otherwise, continue monitoring until 3 months after discontinuation of medication.RCAT is one of the commonly used rhinitis control scales, and its reliability, validity, and responsiveness have been widely verified. The score of 21 is the verified RCAT score of 25, which can reflect and identify the controlled state of rhinitis. When RACT ≤ 21, it can be used as the boundary of the uncontrolled state of AR and the starting point for treatment. RCAT is a simple self-rating scale that allows patients to assess their AR control at home and helps assess the success of long-term repeated treatment interventions(19,20).The TNSS evaluates four nasal symptoms: nasal obstruction, sneezing, rhinorrhea, and nasal itch. The symptoms are self-assessed and recorded by participants, using a five-point scale (0 = no symptoms;1 = mild symptoms; 2 = moderate symptoms; 3 = severe symptoms; 4 = very severe symptoms)(21). The TNSS ranges from 0 to 16, with low scores indicating lighter nasal symptoms.The Total ocular symptom score. Patients scored their eye symptoms for redness, itchiness, and tearing, each on a scale of 0–3 (absent to most severe symptoms), giving a total ocular symptom score (TOSS) from 0 to 9. The score represented an average for both eyes.Secondary outcomes include (1) the change of TNSS and TOSS score from baseline to the 8th, 12thand 16th weeks; (2) response to interventions, defined as participants with a change in TNSS score of ≥0.5 from baseline; (3) Detects TNF-α, NF-κΒ, IL-6, IRF3, and IRF7 from the venous blood.

CONCLUSIONS

At present, there are still many deficiencies in the treatment of allergic rhinitis. Currently, the main drugs for the treatment of allergic rhinitis are H1 antihistamines, nasal steroid hormones, and leukotriene receptor antagonists. The control and safety of nasal symptoms have been verified, but there are still deficiencies in controlling the recurrence of allergic rhinitis(6).AIT is the only means of altering the natural immunological course of allergic diseases and achieving long-term remission. Pharmacological measures can suppress the immune response and/or alleviate the symptoms but there is a risk of relapse soon after these measures are withdrawn. Current AIT approaches depend on the administration of intact allergens, often comprising crude extracts of the allergen. We propose that the challenges arising from Accepted Article current approaches, including the risk of serious side effects, burdensome duration of treatment, poor compliance, and high cost, are overcome by the application of peptides based on CD4+ T cell epitopes rather than whole allergens(5).In contrast, ACE has the following advantages, involving mechanical stimulation and later biological and chemical stimulation. The process of softening, decomposing, liquefying, and absorbing the catgut thread within the acupoint generates long-lasting stimulation, making it less prone to recurrence. Therefore, the treatment interval can be extended to once every 10 days, greatly improving patient compliance. On the other hand, catgut thread, as an allogeneic protein stimulus, can better regulate the relative balance of the body's internal environment, enhance immune function and stress resistance, and reduce allergic reactions(16). Currently, research on acupoint embedding therapy for allergic rhinitis (AR) primarily focuses on regulating cytokines, influencing neurotransmitters, and inhibiting immune molecules such as immunoglobulin E (IgE). At the cytokine regulation level, acupoint embedding research concentrates on interventions targeting inflammatory factors and transforming factors. Inflammatory factors include interleukin-17, interleukin-4, gamma interferon, etc., while transforming growth factors include transforming growth factor β1, among others(8–12). Acupoint embedding therapy intervenes in neurotransmitters mainly by participating in the release of various immunologically active substances, such as substance P. Research has found that embedding therapy can alleviate rhinitis-related symptoms by regulating substance P and nitric oxide levels(13–15). Importantly, the current study found that ACE therapy decreased the release of IgG in vivo in mice, which was accompanied by a decrease in IgG1, histamine, and interleukin. The symptoms of AR in mice were likewise alleviated during this process(25). The purpose of this article is to reduce the recurrence of rhinitis, relieve symptoms, and achieve clinical benefit by using acupoint catgut embedding as a non-drug therapy. In addition, previous articles about acupoint catgut embedding in the treatment of allergic rhinitis lack placebo-controlled, high-quality research(26). Therefore, it is necessary to provide high-quality research for the domain.It is considered an excellent method for treating allergic rhinitis. To our knowledge, this is the first clinical study to investigate the efficacy of ACE for PAR compared to placebo treatment in a 2-armed clinical trial. Compared to previous studies of ACE in the treatment of PAR, this trial has a larger participant pool, clearer diagnostic criteria for the classification of AR, a more rigorous methodology, and a longer study period.This protocol describes a 2-armed randomized controlled trial to assess the efficacy and safety of ACE in the treatment of PAR. The results of this trial will provide high-quality evidence of the therapeutic effects of ACE in alleviating nasal symptoms and improving the quality of life among PAR patients.

CLINICALTRIAL

Ningxia Medical University Ethical Review Board B2014-014-01.Written, informed consent to participate will be obtained from all participants.