Participants, interventions and outcomes
The target population for this trial will be recruited from the respiratory clinic of Shanghai Children's Medical Center, a tertiary first-class paediatric hospital with a large number of outpatients with asthma and rhinitis and a professional respiratory medical team.
- Age 3 -12 years, male or female.
- Children diagnosed with AR in accordance with the 2019 guidelines for the diagnosis and treatment of allergic rhinitis. At the same time, the diagnosis will conform to the diagnostic criteria for childhood asthma formulated by the National Children's Asthma Prevention and Treatment Cooperation Group in 2016 .
- Maintained use of guide-based rhinitis and asthma control drugs for the past 1 month. Inhaled drugs such as budesonide suspension, fluticasone aerosol, salmeterol dry powder inhalation and budesonide formoterol dry powder inhalation can be chosen to control the condition according to age characteristics.
- Performance of the serum-specific allergen test, with the level of dust mite allergen sIgE > 0.35 IU/mL considered positive.
- Informed consent signed by the guardians of all subjects (approved by the Ethics Committee of Shanghai Children's Medical Center affiliated with Shanghai Jiao Tong University School of Medicine).
- Agreement to collect dust mites from indoor mattresses.
- Basic diseases such as congenital heart disease, immune deficiency, gastroesophageal reflux, bronchopulmonary dysplasia, and obliterative bronchiolitis.
- Inability to sleep in a separate bed.
- Participation in other clinical studies within the past 3 months.
Who will take informed consent ?
Hui Li, a staff member hired by the trial sponsor, will poste recruitment information on the WeChat official account "Respiratory Angel" of the Department of Respiratory Medicine of the Shanghai children's medical center and collect the information of the participants through Wenjuanxin, a platform providing functions equivalent to Amazon Mechanical Turk.Finally, Li Hui contacted the qualified patient's guardian through WeChat and got their paper consents.
Additional consent provisions for collection and use of participant data and biological specimens
On the consent form, participants will be asked if they agree to use of their data should they choose to withdraw from the trial. Participants will also be asked for permission for the research team to share relevant data with people from the Universities taking part in the research or from regulatory authorities, where relevant. This trial does not involve collecting biological specimens for storage. The informed consent form is available from the corresponding author on request.
Explanation for the choice of comparators
We will compare Hestelia Mite Bait containing 0.1% emamectin with a placebo that has a consistent appearance and odour but no acaricidal effect to investigate the change of dust mite exposure and the improvement in asthma and rhinitis symptoms after using mite bait indoors.
After recruitment (V0), the baseline medical characteristics of name, age, sex, diagnosis of asthma and rhinitis and allergen test report will be collected. The subjects will be randomly grouped. We stipulate that the children randomly assigned to Group 1 are first placed with package A for an 8-week intervention. All HDM species reach adulthood within 3 to 4 weeks. Once mature, adult mites have a life expectancy of between 4 and 6 weeks . To avoid the impact of the previous intervention on the second intervention, we have established a 4-week washout period according to the growth cycle of dust mites. Then, package B will be placed for an 8-week intervention after a 4-week washout period. In Group 2, package B will be placed for an 8-week intervention, followed by a 4-week washout period, and then package A placed for an 8-week intervention. Each child will undergo a total intervention period of 16 weeks, a washout period of 4 weeks, and a follow-up period of 4 weeks after the end of the second intervention. The flow chart of the study is shown in Figure 1.
At V1, V3, V4 and V6, the staff will collect indoor samples from mattresses with a glass fibre membrane mite-clearing vacuum cleaner. The components of dust mite antigens in the collected samples will be detected by ELISA. Parents will be asked to evaluate the AR and asthma symptom scores and clinical event records at V1-V7 (see the outcome indicators for details), as shown in Table 1.
Criteria for discontinuing or modifying allocated interventions
If the research physician feels that it is not in the child’s best interest to continue participating in the study, for example, if there is an allergic reaction to the mite bait or placebo used, he/she may decide to withdraw the child from the study at any time. If the subjects’ parents fail to complete the questionnaire after 3 reminders or fail to cooperate with the indoor sample collections, the subjects will be considered poorly compliant and will be excluded from the study.
Strategies to improve adherence to interventions
First, we will explain our study to each child’s parents as follows: The enrolled children can receive regular follow-up, a questionnaire evaluation and standardized treatment by respiratory specialists at Shanghai Children's Medical Center. The detection of the HDM antigen concentration in the bedroom mattress is free of charge, and the mite bait and placebo package are safe. This is the only hygienic product for dust mite removal certified by the Ministry of Agriculture in China and has a product registration certificate (registration certificate number: WP20180004).During the study, professional staff will enter the room four times to clean the mattress with a mite-removing vacuum cleaner and collect attractors. The whole process requires the cooperation of the subjects' family members, and the subjects' parents will be able to complete the questionnaires in 10-20 minutes.
Second, during the implementation process, we will regularly remind parents to fill out the questionnaire via WeChat. The research team will also provide help and detailed answers to parents' questions during the trial.
Relevant concomitant care permitted or prohibited during the trial
The original asthma medication can be maintained during the trial. When acute asthma attack symptoms occur, β2 agonists will be used to relieve bronchospasm, and oral or intravenous corticosteroids will be used, depending on the clinical severity, until the symptoms are relieved. However, during the test, the children who go outside for long periods of time or who cannot guarantee living indoors in a room with mite bait or placebo will not be allowed.
Provisions for post-trial care
There is no anticipated harm and compensation for trial participation.
- VAS of clinical symptoms of AR
- In 1988, Linder first applied VAS to the assessment of AR symptoms, demonstrating its sensitivity and specificity . Patients will be scored with a VAS score for symptoms occurring in the past week, including sneezing, rhinorrhoea, nasal itching, nasal congestion, itchy eyes, teary eyes, foreign body sensation and red eyes, for a total of eight symptoms. The VAS uses a 10-cm-long ruler, 0 ~ 10, to show the severity of the patient symptoms ("0" for no such symptoms and "10" representing the heaviest of such symptoms), instructs the patients according to the symptoms, and directs the patients to mark the symptom scores on the scale.
- Change in RCAT
- The RCAT demonstrated adequate reliability, validity, and responsiveness and was deemed acceptable and appropriate by the patients. This tool can facilitate the detection of AR symptom-control problems, and its brevity supports its usefulness in clinical care. The RCAT has 6 items that include nasal congestion, sneezing, watery eyes, sleep problems caused by rhinitis, activity avoidance, and rhinitis symptom control. Responses are measured on 5-point Likert-type scales. RCAT scores range from 6 to 30, with higher scores indicating better rhinitis control. 
- Change in ACQ-5
- ACQ-5 is a scale composed of 5 simple multiple choice questions. The results are obtained by adding the total points and averaging them. It plays a significant role in evaluating whether asthma is controlled and can rapidly assess asthma control. The child will be asked to evaluate the level of asthma control in the past 1 week. The lower the score is, the better the control level.
- RQLQ for children with AR 
- In this study, children with rhinitis in the past 1-2 weeks will be evaluated on their own symptoms, psychological status, mental status, social communication and other aspects of 14 problems caused by rhinitis, 0 points: normal; 1 point: slight; 2 points: mild; 3 points: serious; 4 points: very serious. The higher the score is, the more severe the rhinitis effect on quality of life.
- Changes in levels of dust mite antigen in children's beds
- Three sampling points will be randomly selected for each mattress, and each sampling point will have a range of 30 cm2. Each sampling point needs to be vacuumed 10 times repeatedly with a glass fibre membrane mite-clearing vacuum cleaner (the bed area will be recorded at the same time). Dust on the glass fibre membrane in the vacuum cleaner will be put into a plastic bag and stored at -20℃ (killing the dust mites). Allergens will be extracted from samples from each family after weighing. The ELISA method (Indoor Biotechnologies, Charlottesville, VA, USA) will be adopted to detect dust mite antigens Der p2 (Dermatophagoides pteronyssinus) and Der f2 ( farinae) in the extracted solution.
- Use of medicines for children's AR and asthma
- For children who, over the past 4 weeks, used anti-asthma drugs frequently for the control of rhinitis, the percentages are as follows: no use ever: 0%; a total of 1 week of use: 25%; and use every day: 100%. Specific drugs include physiological saline, nasal spray hormone (Mometasone Furoate Aqueous Nasal Spray, Fluticasone Propionate Nasal Spray, Budesonide Nasal Spray, etc.), oral allergy drugs (cetirizine, loratadine, levocetirizine, desloratadine, etc), Sinupret Drops, montelukast, traditional Chinese medicine (Tongqiao Biyan Granule, Biyuanshu Oral Liquid, Xinqin Granule), nasal allergy medications (levocabastine, azelastine hydrochloride), desensitization treatment (Dermatophagoides Farinae Drops), and inhaled hormones to control asthma (Budesonide Suspension For Inhalation, Seretide, Flixonase, Symbicort Turbuhaler).
- Number of asthma attacks, emergency visits, frequency of hospitalization
On the assumption that a reduction of 25% in VAS scores would be of clinical significance, 44 patients in each group are required at the 5% significance level (two-tailed), with a power of 90% to detect this difference between the two groups . Considering a 10% possible dropout, each group needs to enrol at least 49 people.
In this experiment, we will recruit 60 people for a placebo-controlled, double-blind crossover trial. After crossover, the placebo and experimental groups will each be increased to 60 people.
Recruitment information will be posted on WeChat official account "Respiratory Angel" of the Department of Respiratory Medicine of the Shanghai children's medical center.
Assignment of interventions: allocation
Random sequences will be generated by the random number table.
Random sequences will be successively assigned to the subjects according to the enrolment order.
Odd-numbered subjects will be entered into Group 1, and even-numbered subjects will be entered into Group 2. Three copies of the generated distribution sequence table will be distributed among the designer, pharmacist and statistician. Each copy should be sealed with an opaque envelope and kept with a lock.
A special person who is not involved in the subsequent grouping and intervention is responsible for enrolling the test subject according to the selection and exclusion criteria. A random sequence is generated by the statistician. The test designer decides that odd-numbered subjects will be entered into Group 1, and even-numbered subjects will be entered into Group 2.
Assignment of interventions: Blinding
Who will be blinded
The placebo used in the study looks and smells indistinguishable from mite bait and will be labelled either A or B. The identities of Tag A or Tag B will be known only to the pharmacists and unknown to the subjects and researchers.
Procedure for unblinding if needed
When the trial is over, the number of each subject and the treatment plan received need to be checked, and the sealed distribution sequence needs to be decrypted. When unblinding, the intervention measures recorded in the assigned serial number were checked with the drug delivery record sheet, and the result data were classified for analysis by the test group and the control group.
Data collection and management
Baseline data and questions related to the outcome indicators will be designed into questionnaires at https://www.wjx.cn/ and will be regularly pushed to parents to fill out via WeChat. Parents who fill out questionnaires are usually a fixed one who is mainly responsible for the daily life of the child. During the follow-up period, once the questionnaire is completed and submitted, no one has the right to modify the contents of the questionnaire. In addition, there will be a fixed staff member to check whether the parents fill in the questionnaire and whether the questionnaire is completed. The staff member will not know the parent grouping and intervention. After the end of the whole experiment, all data will be exported in the form of EXCEL and analysed by SPSS 2.0 software.
Statistical methods for primary and secondary outcomes
SPSS 2.0 will be used to analyse the experimental data. Descriptive statistics will be used for the following data analysis: the categorical variables RCAT scores, ACQ-5 scores, drug usage for asthma and AR, and frequencies of acute asthma attacks, emergency visits and hospitalizations by frequency tables (i.e., number of evaluable subjects, frequency and percentage for categorical values) and the continuous variables VAS scores and RQLQ scores (i.e., mean, SD, minimum, median and maximum). One-way analysis of variance and two sampleT-test will be adopted for normally distributed data, and the non-parametric rank-sum test will be adopted for non-normally distributed data. Fisher's exact chi-square test will be used to compare classified data, and P<0.05 will be considered statistically significant.
At the end of the first phase of the test (V3),an interim analysis of the data from the previous stage will be conducted by the biostatistician of the data monitoring committee.Mainly analyze the size of the estimated effect in advance and the incidence of adverse events,If there is a lack of treatment effect or the incidence of adverse events is high, consider terminating the trial early. These results will be fed back to the trial sponsor, and he or she will decide whether to terminate the experiment.
Methods for additional analyses
When evaluating factors affecting rhinitis and asthma control, multiple linear regression or logistics regression is used.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data
For those that are randomised to the intervention but do not adhere to the intervention, if they completed first phase of the trial before the cross , we will retain the data and perform the shortest distance filling method or multiple filling method on the missing data, else, we will delete the observed samples.
Plans to give access to the full protocol, participant level-data and statistical code
The datasets analysed during the current study are available from the corresponding author on reasonable request.
Oversight and monitoring
Composition of the coordinating centre and trial steering committee
In this trial, the sponsor hired staff member Li Hui to publish recruitment information through the WeChat and collect the basic information of participants. The information will be aggregated to Yufen Wu in order to select qualified research objects. After confirming the eligibility, Hui Li will contact the child's guardian and get their paper consent form. Throughout the trial, we will have two professional staffs who are responsible for collecting samples indoor and replacing mite bait or placebo. At the same time, one staff is responsible for regularly pushing electronic questionnaires to the enrolled subjects to follow up the symptoms of the children and summarize the adverse events during the trial. Ming Chen evaluated the reliability of each follow-up questionnaire uploaded. During the trial, Trial Steering Committee is composed of Lirong Jiang and Yijiong Ren. They will review the progress and safety of the trial.
Composition of the data monitoring committee
The data monitoring committee includes a biostatistician, a respiratory professional physician, and a patient advocate, to advise the sponsors and principal investigators regarding the continuing safety of study patients and the continuing scientific merit of the study. It is independent from the sponsor and competing interests. The DMC is responsible for monitoring the recruitment of participants, compliance with the protocol and data quality, as well as monitoring for serious adverse events and other safety questions.
Adverse event reporting and harms
During the trial, we will collect and record the occurrence of adverse events, describe the date of onset and date of resolution, evaluate its severity, the causal relationship with the intervention, and other suspect drugs and the final outcome. And report it to the DMC and ethics committee.
The acute oral, transdermal and inhalation toxicity of the 0.1% emamectin in the mite bait slightly toxic, and the mite bait is placed under the mattress and is not in direct contact with the child. Therefore, it has high security. For some adverse events that may occur with emamectin, including skin and eye irritation, nausea, vomiting, headache and dizziness, as well as fatigue and chest tightness, excessive sweating, salivation, blurred vision, convulsions, tachycardia or bradycardia.
Severity should be defined according to the following criteria:
Mild : Awareness of signs or symptoms, but easily tolerated
Moderate : Discomfort enough to cause interference with normal daily activities
Severe : Inability to perform normal daily activities
Life threatening : Immediate risk of death from the reaction as it occurred
All adverse events will be tracked until the incident is resolved or the study is over.
Frequency and plans for auditing trial conduct
Project Management Group meet to review trial once a month.The Trial Steering Group and the independent Data Monitoring and Ethics Committee meet to review conduct throughout the trial period 12 months after the trial is approved.
Investigators and sponsor will communicate trial results to participants, healthcare professionals, the public, via WeChat Official Accounts "Respiratory Angel" and publication .