Objective
Given the significant spontaneous recovery rate and existing standard therapy for ISSNHL by using systemic glucocorticoids, patients will only be enrolled in the study if no or insufficient recovery of hearing threshold could be observed after the initial 14 days of systemic therapy and if they are reluctant to continue receiving salvage therapy. This randomised controlled trial will evaluate the effectiveness of healthy lifestyle treatment based on TCM therapy for ISSNHL patients who have no or insufficient recovery of hearing threshold after the initial systemic therapy for 14 days and are reluctant to continue receiving salvage therapy.
Study design
A total of 56 patients will be recruited for the trial. Participants who will meet the inclusion criteria and submit written informed consent will be enrolled in the trial, which will last for 3 months. A flowchart of the trial procedure is shown in Fig. 1.
This trial is registered in the China Clinical Trials Registry (Registration number: ChiCTR-INR-1701145) and has been approved by the Biomedical Branch of Ethics Committee of West China Hospital of Sichuan University (identifier: 2016-180). We will perform the study according to the Declaration of Helsinki guidelines for clinical trials. The protocol was written in line with the Standard Protocol Items: Recommendations for Interventional Trials checklist (Additional file 1), as shown in Fig. 2.
Recruitment
Participants diagnosed with ISSNHL but did not respond to initial systemic treatment for at least 14 days will be recruited by posters in the West China Hospital of Sichuan University.
Participants
Inclusion criteria
- Signed informed consent form; participants must be willing and able to consent participation in the study
- Diagnosis of unilateral ISSNHL, defined as onset within 72 h affecting three consecutive frequencies of unknown aetiology1
- Hearing loss occurring at least 14 days but less than or equal to 1 year
- Insufficient recovery from ISSNHL for at least 14 days after onset and after receiving the Chinese ISSNHL guideline-recommended standard therapy
- Reluctance to receiving drugs, including steroid therapy
- More than 18 years old but less than 60 years old
- Hearing in the contralateral ear of at least 20 dB HL
- Stopped receiving medication for more than 3 days
Exclusion criteria
- Previous disease or surgery in the affected ear
- Hearing loss from an identified aetiology, including head trauma, conductive hearing loss Meniere’s disease and tumour
- Patients’ inability to complete relevant assessments, such as cognitive impairment and mental disorder assessments
- Serious comorbid conditions, such as progressive central disorder or life-threatening conditions
- Any reason, in the investigator’s opinion, that prohibits inclusion into the study
Criteria for trial termination and dropout are as follows: if a patient develops a severe disease unrelated to participation in the trial; if a patient chooses other treatments and drugs; if a patient requests termination or withdraws; and if a patient no longer receives the trial treatment regimen and examination.
Randomisation
Patients who will meet the requirements and whose eligibility is confirmed will participate in sociodemographic and clinical data collection and complete the informed consent form during the first visit. The patients will be paired by sex (male and male and female and female), age difference (within 10 years) and hearing loss level. A total of 28 pairs of subjects will be numbered, with each pair having two numbers: 1, 2; 3, 4;…;55, 56. A statistician who is not part of the clinical intervention will use Statistical Package for Social Sciences SPSS 21.0 (IBM, Chicago, IL, USA) to generate a randomisation code, which will be embedded into opaque and numbered envelopes. Patients will be allocated to the intervention or control group. If a patient with a single number matches another with a singular number, they will enter the experimental group; meanwhile, the double number in the same pair will enter the control group, and vice versa.
Intervention
Participants in the control group will receive routine care, whereas those in the intervention group will receive additional lifestyle counselling based on TCM. In this system, patient care will focus on health maintenance and prevention by encouraging patients to adhere to simple health and lifestyle practices18.
Routine care includes the following two aspects:
- Educating participants about the natural history of ISSNHL and the limitations of existing evidence regarding efficacy; answering patients’ questions about ISSNHL
- Counselling participants about the benefits of amplification, hearing-assistive technology and other supportive measures, especially for those whose hearing loss has lasted more than 3 months
Lifestyle counselling will consist of four sessions. The first step is the completion of the lifestyle survey of each participant and one-to-one targeted counselling based on the survey results.
- Die According to the theory of Yellow Emperor’s Inner Canon (Huangdi Neijing), a classical Chinese medicine book19, yang qi is an important reason for maintaining normal human function and a food’s energy can have a remarkable effect on health. Therefore, diet should be dominated by staple food, whereas ‘cold’ energy food should be avoided. In simple terms, the central components of the dietary strategy are the staple Chinese food (‘neutral’ energy), such as rice and wheat. ‘Cold’ energy food includes most fruits from the TCM perspective. The diet adopted in this study will encourage participants to consume staple Chinese food.
- Sleep. Patients will go to bed at night, avoid staying up late and wake up at dawn. Patients will be recommended to fall asleep by 10m. to 11 p.m. and rise by 5 a.m. to 7 a.m., ensuring a sleeping window between 10 p.m. and 5 a.m. Thus, reducing water intake prior to sleep is necessary to avoid waking up at night to urinate. Participants should not sleep at daytime. A less than 30 min short nap before 2 p.m. will be advised for nonadaptive patients.
- Mood. A physician will communicate with participants to answer their doubts and discuss the relationship between mood and ISSNHL and the importance of good mood to health. Participants’ fear, despair and anxiety should be reduced as much as possible.
- Physical activity. All participants will be encouraged to be moderately physically active by doing taiji (a traditional Chinese sport) and housework and by walking and participating in leisure activities. Patients will be discouraged from engaging in deliberate strenuous physical exercise, especially before going to bed or on a full stomach and avoid being too tired.
The following measures will be taken to improve patient compliance and reduce drop-out rate. All participants are entitled to free assessments, including audiology tests, one-to-one consultation and lifestyle assessment. In addition, no registration fee will be required for first-level expert outpatient service from the West China Hospital. At the end of the experiment, a free online consultation service will be provided for 1 year.
We will provide weekly one-on-one consultations and periodic check-ups over the phone, especially with the lifestyle modification group to reinforce the importance of lifestyle change and answer related questions. Participants will be encouraged to keep a symptom log on ear-associated and systemic symptoms. The patients should provide daily email updates about their lifestyle journal, including information about their sleep and wake times and daily diet (Additional file 2). Participants will be required to fill in the form daily within one month of treatment.
Outcome measures
The outcomes will be evaluated at baseline, 1 month and 3 months after intervention.
Primary outcome measure
The efficient rate is the percentage of patients with improvement in pure tone average (PTA) of impaired frequency that at least suggests effective recovery compared with the baseline. Effective recovery is defined as an improvement of 15–30 dB HL improvement in PTA (dB HL). On the basis of the 2012 practice guideline on sudden hearing loss published in America, an improvement within 10 dB HL of initial HL or within 10 dB HL range of the unaffected ear’s hearing threshold is defined as complete recovery; an improvement of more than 30 dB HL improvement in PTA (dB HL) from pretreatment hearing levels is defined as significant recovery; and an improvement of less than 15 dB HL in PTA is defined as no recovery1,20. Patients under the no recovery criterion will be excluded.
Secondary outcome measure
Based on the visual analogue scale (VAS), the secondary outcome will include improvement of adherence to TCM lifestyle, evaluation of changes in word recognition score (WRS)21, tinnitus handicap inventory (THI)22 for patients with tinnitus and change in common symptoms, such as dizziness and ear blockage. These outcomes will be measured at the first and during protocol visits.
Blinding
The audiologist, research assistants and statisticians involved in the study will be blind with the allocations. Given the nature of counselling, blinding amongst consultants and patients is impossible. Thus, consultants and other researchers will not communicate amongst one another about the patient group during the trial. Patients will also keep their treatment methods confidential. At the completion of the trial, patients in the control group will be offered access to the lifestyle modification intervention.
Sample size
To the best of our knowledge, no randomised pilot study has been conducted to assess the effectiveness of lifestyle changes on ISSNHL. Therefore, we could not calculate the sample size based on previous studies. On the basis of our retrospective analysis (unpublished) and clinical experience, the efficiency ratio of the intervention group is conservatively estimated to be 50%, and the natural recovery rate of over two weeks is 10%9. Using a formula23 for calculating the sample size of optimal treatment in the clinical trial and considering α=0.05, β=0.1, by the table of normal distribution quantifiers Uα(0.05)=1.65, Uβ(0.1) = 1.28, we require a patient sample size of 23 per group. We allow for a 20% loss to follow-up (approximately 10 cases), with a total sample size of 56 patients (28 per group) in the study.
n= (Uα+Uβ)2P(1–P)/(P1–P0)2
P=(P1+P0)/2×100%
P0: Original efficacy, P1: expected efficacy
Safety
Any adverse events and discomfort throughout the course of the trial will be recorded by patients and data collectors. Participants may withdraw from the study for any reason at any time. The researchers will record the reason in case report forms.
Statistical analysis
Data will be analysed using SPSS V.21.0 (Chicago, IL, USA), with the significance level set at 0.05 (two-tailed) by statisticians who are independent of the research team. Patient baseline characteristics will be summarised by a treatment arm by using appropriate summary statistics to assess baseline comparability only. Data analysis will be conducted with the intention-to-treat (ITT) principle and the per-protocol analysis. We will calculate the effective rates at 1 and 3 months for the primary outcome and compare the intervention and control groups by using the χ2 test. For secondary outcomes, continuous variables, including THI, VAS and WRS, will be compared between the two groups at all follow-up time points by using t-test or the Wilcoxon signed-rank test as appropriate. Categorical variables, including different degrees of hearing loss, will be compared using the Chi-square test or Fisher’s exact test. For dropout analysis, we will use multiple imputations for ITT analysis. Sensitivity analysis will be performed to assess the effect of missing data assumptions.
Data management
Data accuracy will be ensured by completing paper copies of the case report form. Two independent researchers blinded to the group allocation will input data on an Excel spread sheet, and data will be checked twice. Data will be validated using original case report forms when any discrepancy is discovered. Paper files and electronic documents will be stored in a locked filing cabinet and protected computer separately. Only principal researchers will be allowed access to data. Researchers will be unable to modify data and keep information strictly confidential and shall not disclose it under any circumstances. Meanwhile, researchers will sign a confidentiality agreement.