Objective
Given the significant spontaneous recovery rate and existing standard therapy for ISSNHL by using systemic glucocorticoids, patients are enrolled in the study only if no or insufficient recovery of hearing threshold is observed after the initial 14 days of systemic therapy. In addition, patients are excluded if they are reluctant to continue receiving salvage therapy. This randomised controlled trial evaluates the effectiveness of healthy lifestyle treatment based on TCM therapy for patients with ISSNHL 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
Fifty six patients are recruited for the trial. Participants who meet the inclusion criteria and submit written informed consent are enrolled in the trial, which lasts for 3 months. Fig. 1 shows the trial procedure flowchart.
This trial is registered in the China Clinical Trials Registry (Registration number: ChiCTR-INR-17011459) and has been approved by the Biomedical Branch of Ethics Committee of West China Hospital of Sichuan University (identifier: 2016-180). The study is performed according to the Declaration of Helsinki guidelines for clinical trials. The protocol is 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 are 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 provide consent for
- Diagnosis of unilateral ISSNHL, defined as onset within 72 h affecting three consecutive frequencies of unknown aetiology1
- Hearing loss occurs 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 receive 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
- 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
The criteria for trial termination and dropout are as follows. The patient develops a severe disease unrelated to participation in the trial. The patient chooses other treatments and drugs. The patient requests termination or withdraws. The patient no longer receives the trial treatment regimen and examination.
Randomisation
When patients want to participate in the trial and meet the requirements, a research assistant who reviews and explains the study collects the patient basic demographic information and previous clinical data. Eligibility is ascertained in the patient, followed by written consent form. Before randomisation, the patients must have reassessed their hearing status with otoscopic examination, hearing threshold (air conduction hearing thresholds measured at 250–8000 Hz, bone conduction hearing thresholds measured at 500–4000Hz), word recognition scores and ear-specific immittance measurements (including tympanomentry, static immittance and acoustic reflex measures). These measures can assess the patient’s baseline hearing state and exclude conductive hearing loss. According to the classification standard of hearing loss degree published by the World Health Organization in 1997, the average values of hearing thresholds of 500, 1000, 2000 and 4000 Hz were calculated and then divided into mild (26–40 dB HL), moderate (41–60 dB HL), severe (61–80 dB HL) and profound (≥81 dB HL). Patients were stratified by gender, age and degree of hearing loss. Patients of the same gender, with age differences within 3 years and have the same degree of hearing loss were classified in the same stratification.
A statistician who is not part of the clinical intervention uses the Statistical Package for Social Sciences (SPSS) 21.0 (IBM, Chicago, IL, USA) to generate a randomisation code. This code is embedded into serially numbered, opaque and numbered envelopes. After a participant completes the baseline measures, and when the same stratification reaches two or even number of patients, another research assistant opens the next envelope in the series to determine the participant group allocation. Patients in the same stratification are randomised for the two treatments with 1:1.
Intervention
Participants in the control group receive routine care, whereas those in the intervention group receive additional lifestyle counselling based on TCM. In this system, patient care focuses on health maintenance and prevention by encouraging patients to adhere to simple health and lifestyle practices18.
Routine care includes two aspects, as follows:
- 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 consists 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 (Huang Di Nei Jing), a classical Chinese medicine book19, yang qi is an important reason for maintaining normal human function. In addition, 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. According to TCM principles, ‘cold’ energy food includes most fruits. The diet adopted in this study encourages participants to consume staple Chinese food.
- Sleep. Patients sleep at night, avoid staying up late and wake up at dawn. The recommended time range for the patients to fall asleep was10m. to 11 p.m. and they need to be up by 5 a.m. to 7 a.m., thereby 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 during the day. A less than 30 min short nap before 2 p.m. is advised for nonadaptive patients.
- Mood. A physician communicates with the 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 minimal.
- Physical activity. All participants are encouraged to be moderately physically active by doing taiji (a traditional Chinese sport) and housework and by walking and participating in leisure activities. Patients are discouraged from engaging in deliberate strenuous physical exercise, especially before going to bed. They are also discouraged to eat too much before go to bed.
The following measures are taken to improve patient compliance and reduce the 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 is required for the first-level expert outpatient service from the West China Hospital. At the end of the experiment, a free online consultation service is provided for 1 year.
Weekly one-on-one consultations and periodic check-ups are provided over the phone, especially with the lifestyle modification group to reinforce the importance of lifestyle change and answer related questions. Participants are encouraged to keep a symptom log on ear-associated and systemic symptoms. The patients need to provide daily email updates regarding their lifestyle journal, including information on sleep and wake times and daily diet (Additional file 2). Participants are required to fill in the form daily for 1 month.
Outcome measures
The outcomes are evaluated at baseline, 1 month and 3 months after intervention.
Primary outcome measure
The primary outcome measure will be the effectiveness of hearing improvement. It is the percentage of patients with an improvement of at least 15 dB in their impaired frequency compared with the baseline. On the basis of the 2012 practice guideline on ISSNHL 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, an improvement of 15–30 dB HL is defined as effective recovery. In addition, an improvement of less than 15 dB HL in PTA is defined as no recovery1,20.
Secondary outcome measure
Based on the visual analogue scale, the secondary outcome includes 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 are measured at the first and during protocol visits.
Blinding
The audiologist, research assistants and statisticians involved in the study are blinded to the allocations. Given the nature of counselling, blinding amongst consultants and patients is impossible. Thus, consultants and other researchers do not communicate amongst one another about the patient group during the trial. Patients also keep their treatment methods confidential. At the completion of the trial, patients in the control group are 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 are not able to 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 2 weeks is 10%9. Using a formula23 to calculate 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 are recorded by patients and data collectors. Participants may withdraw from the study for any reason at any time. The researchers record the reason in case report forms.
Statistical analysis
Data are 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 are summarised by a treatment arm by employing appropriate summary statistics to assess baseline comparability only. Data analysis is conducted with the intention-to-treat (ITT) principle and the per-protocol (PP) analysis. To ensure the comparability of baseline conditions between the two groups and allow the presence of noncompliant patients, the ITT population consists of all randomised participants. In addition, at least one follow-up was recorded after the intervention. According to the patients’ actual lifestyle adjustment after random grouping, the PP analysis the patients who completed the trial and did not violate the protocol. This process is an explanatory analysis as a supplementary, contributing to the study objectivity. We 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, visual analogue scale and WRS, are 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, such as different degrees of hearing loss, are compared using the Chi-square test or Fisher’s exact test. For dropout analysis, we use multiple imputations for ITT analysis. Sensitivity analysis is performed to assess the effect of missing data assumptions.
Data management
Data accuracy is ensured by completing the paper copies of the case report form. Two independent researchers blinded to the group allocation input the data on an Excel spread sheet, and the data are checked twice. Data are validated using original case report forms when any discrepancy is discovered. Paper files and electronic documents are stored in a locked filing cabinet and protected computer separately. Only the principal researchers are allowed access to data. Researchers are unable to modify the data and keep the information strictly confidential and shall not disclose it under any circumstances. The researchers sign a confidentiality agreement.