An healthy lifestyle consultant based on Traditional Chinese medicine versus routine patient education in the treatment of idiopathic sudden sensorineural hearing loss after failure of systemic therapy: Study protocol for a clinical randomized trial with a paired design

Background: Idiopathic sudden sensorineural hearing loss (ISSNHL) is an important cause of deafness. Despite advances of systemic therapy, some ISSNHL patients remains ineffective since the exact etiology for SSNHL is still unclear. Traditional Chinese medicine (TCM) has been used for treating disease for thousands of years. It is popular and widely practiced in Asia. TCM contains guidance on people's healthy lifestyle. In recent decades, the relationship between lifestyle and disease has been emphasized and unhealthy lifestyle may lead to illness. Thus, this study aims to compare the ecacy of the lifestyle modication based on TCM to the usual consultation of the ISSNHL after failure of two weeks systemic therapy, to provide a scientic basis for clinical decisions. Methods: This is a clinical randomized trial with a paired design which will include 58 patients diagnosed with ISSNHL, according to the American Academy of Otolaryngology-Head and Neck Surgery sudden hearing loss clinical guideline published in 2012, but incomplete recovery from ISSNHL after of initial management. Participants will be randomized to either healthy lifestyle modication group based on TCM or control group. All patients will be followed for 3 months. The primary outcome measure is the effective rate of hearing improvement (dened as the proportion of patients with at least 15- dB improvement in the average thresholds by the hearing loss frequency). Secondary outcome measures are the improvements in pure-tone average (PTA) of the impaired frequencies, Word Recognition Score (WRS), Tinnitus Handicap Inventory (THI) and ear blockage. The assessments of the participants will be made at baseline, after lifestyle modication in 1 month and 3 months. Discussion: This trial will determine the ecacy of healthy lifestyle modication based on TCM program for ISSNHL patients with incomplete recovery from after failure of initial systemic therapy. The results, if it is yielding positive results, will provide clinical evidence and TCM based healthy lifestyle could be recommended as salvage therapy for patients with ISSNHL.


Background
Idiopathic sudden sensorineural hearing loss (ISSNHL) is a common otologic emergency presenting mostly as an acute hearing loss with an abrupt occurrence and is de ned as a hearing loss of more than 30 dB that occurs in at least 3 consecutive frequencies occurring within 72 hours [1]. Apart from hearing impairment, ISSHNL can be associated with dizziness, tinnitus and/or ear fullness/blockage. The incidence of SSHNL is approximately 5-30/100.000/year in developed countries such as the United States, Sweden, and Japan by national surveys [1][2][3][4]. Only about 10% of patients with ISSNHL show a speci c cause by detailed investigation [5]. Although the precise cause of ISSNHL has not been identi ed, a number of pathophysiological mechanisms have been proposed, including microcirculation, autoimmune pathology, viral infection, intra-cochlear membrane rupture, or hematologic problems [6].
Various studies have suggested that ISSNHL may not be due to a single pathological change, but rather a spectrum of pathologies that affect the cochlea [7].
The most common treatment options for ISSNHL is corticosteroids within the rst two weeks [4].
49%-89% of patients with ISSNHL showed recovery within systemic steroid therapy whereas the others no effects [8]. It is noteworthy that spontaneous recovery occurs in 32%-65% of the cases, usually within the rst 14 days [9.10]. While after 2 weeks patients in whom there is no change would be unlikely to show much recovery [11]. Intratympanic steroid perfusion has been recommended as salvage therapy described in USA guidelines [1]. However, the clinical evidence is also controversial, and there is no consensus regarding the e cacy of intratympanic steroid therapy for ISSNHL [1,12,13]. Therefore, the Lifestyle has been suggested to use for some otology disease that is unable to be well controlled by medicine. Dietary habits such as low sodium can alter inner ear uid homeostasis and auditory function.
Endolymph compartment is maintaining a low-sodium concentration while keeping ionic balance with the surrounding perilymph and serum [14]. Evidence shows that more than 85% of the patients with Meniere's disease are helped by changes in lifestyle along with either medical treatment, or surgical procedures.
These lifestyle changes include to reducing the consumption of salt, caffeine products, chocolate, alcohol, salt products as much as possible [15].

Objective
This RCT trial will evaluate the effectiveness of healthy lifestyle treatment instructed by TCM therapy for ISSNHL patients who have no or insu cient recovery of hearing threshold after initial systemic therapy for 14 days and reluctant to continue receive medicine salvage therapy.

Study design
The trial will recruit 56 patients. The participants who meet the inclusion criteria and written informed consent will be enrolled in the trial, which last 3 months period. A ow chart of the trial procedure is shown in Fig.1.

Recruitment
Participants who diagnosed with ISSNHL but failed with initial systemic treatment at least 14 days will be recruited by posters in the West China Hospital of Sichuan University.

Participants
Inclusion criteria 1. Signed informed consent form. Participants must be willing and able to consent to participate in the study.
2. Diagnosis of unilateral ISSNHL, de ned as onset within 72 hours affecting three consecutive frequencies of unknown etiology [1].
3. Hearing loss occurred at least 14 days ago but less than or equal to a year.
4. Insu cient recovery of the ISSNHL at least 14 days after onset the patient received Chinese ISSNHL guideline recommended standard therapy.
5. Reluctant to receive drug including steroid therapy.
. Age is greater than 18 years old and less than 60 years old.
7. Hearing in the contralateral ear is at least 20 dB.
. Stop medication for more than 3 days. 5. Any reason, in the investigator's opinion, that prohibits inclusion into the study.

Randomization
To ensure each treatment condition has an equal proportion, a randomized paired design, a special case of a randomized block design, will be adopted. Participants will be matched and paired based on similar baseline assessment such as gender, age, the degree of hearing loss, duration of ISSNH at the time of study entry. Number each pair, such as 1-1,1-2,2-1,2-2….28-1,28-2. Within each pair, subjects are randomly assigned using a computer-generated random number to either intervention group or control group. The random Numbers prepared in advance and enclosed in a sealed envelope. It is also speci ed in advance that, in odd numbers, patients numbered 1 in the pair will be in the control group and patients numbered 2 in the pair will be in the experimental group, even numbers, just the opposite. The distribution ratio of the two groups will be 1:1. An independent researcher not involved in the study will be responsible for the randomization procedures.

Intervention
Participants in the control group will receive routine care, while those in the intervention group will receive additional lifestyle counseling based on TCM.
The routine care includes the following two aspects.
Educate participants about ISSNHL natural history of the condition, the limitation of existing evidence regarding e cacy. Answer their questions about ISSNHL.
Counsel participants the bene ts of ampli cation, hearing assistive technology and other supportive measures, especially for those the hearing loss lasted more than three months.
The lifestyle counseling will consist of four sessions. The rst step is to complete the lifestyle survey of each participant, and then one-to-one targeted counseling based on the survey results.
Dietary According to the theory of traditional Chinese medicine, Yang qi is an important reason for maintaining normal human function and a food's energy can have a huge effect on your health. Therefore, the diet should be dominated by staple food, while paying attention to avoid eating "cold" energy food. In simple terms, the central components of the dietary strategy are the Chinese main food ("neutral" energy) such as rice and wheat meanwhile avoids "cold" energy food such as most fruits from the TCM perspective. The dietary adopted a principle encouraged participants to consume Chinese Main foods and stir-fry vegetables by "hot" energy pepper with a ratio of 7:3. Meanwhile, try to be avoided eating food with animal products. Because it contains too much fat.
Sleep Go to bed at night and avoid to stay up late, get up at dawn, just as nature does. It is recommended to fall asleep by 10-11 pm and rising 5-7 am, ensuring an in bed sleeping window between 10 pm and 5 am So it was necessary to reduce water intake before sleep to avoid getting up in the night to urinate. Participants had better not sleep at daytime. A less than 30 min short nap before 2 pm will be advised for those nonadaptation patients.
Mood The physician communication with participants to answer their doubts and discuss the relationship between mood and SSNHL and the importance of good mood to health. Reduce participants fear, despair and anxiety as much as possible.
Physical activity All participants were encouraged to be moderately physically active such as do Taiji (a kind of traditional Chinese sport), housework, walk and leisure activities. Patients should not recommend engaging in deliberate strenuous physical exercise, especially before going to bed or on a full stomach and avoid being too tired.
We will also take the following measures to improve patient compliance and reduce the drop-out rate.
All participants are entitled to free all assessment including audiology tests, one-to-one consultation, and lifestyle assessment. In addition, without registration fee for rst-level expert outpatient service of west China hospital. At the end of the experiment, a free online consultation service will be provided for one year.
Especially with the lifestyle modi cation group, we will provide the weekly one-to-one consultant with regular consultants, as well as periodic check-ins over the phone, in order to reinforce the importance and signi cance of the lifestyle change and answer their question about it. Encourage participants to keep a symptom log, includes ear associated symptoms and systemic symptoms. Symptoms will be recorded by means of recovery, partial recovery, no change, and aggravation. Meanwhile, providing daily email contacts about the journal of their lifestyle: Sleep and wake times, daily diet (see Additional le 2).
Participants will be required to ll 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.
The primary outcome measure The effectiveness hearing improvement, measured by pure tone average in their hearing loss frequency band. The effects will be divided into four categorize, according to patients gains pure tone thresholds.
Complete recovery de ned as hearing loss within 20 dB HL or reached the level of the normal unaffected ear. Signi cant recovery de ned as hearing gains more than 30 dB HL, effective recovery is gains of 15-30 dB H, and ineffective is gains of less than 15 dB HL [1,18 ].

Secondary outcome measure
Word recognition score (WRS) [19] for all participants. Participants with tinnitus will be measured by Tinnitus Handicap Inventory (THI) [20], and common company symptoms dizziness and ear blockage also be evaluated for those have it. Other outcomes that will be evaluated are impedance audiometry, distortion product otoacoustic emission, and lifestyle change based on the lifestyle questionnaire.

Blinding
The audiologist, research assistants and statisticians and participants involved in the study will blind with the allocations. As the nature of the counseling, it is impossible to blind in the consultant. During the process, consultant and other researchers will request not to communicate with each other about the patient group. Patients will also to keep their treatment methods secret. At the completion of the trial, patients in the control group will be offered access to be lifestyle modi cation intervention.

Sample size
To the best of our knowledge, no randomized pilot study has been conducted to assess the effectiveness of lifestyle changes on ISSNHL. We, therefore, could not calculate the sample size based on the previous studies. Basing on retrospective analysis, the e ciency ratio of the intervention group and the control group were conservatively estimated to be 50% and 10%. Using the following formula for calculated the sample size of optimal treatment in the clinical trial and considering α=0.05, β=0.1, by the table of normal distribution quanti ers U α . 1.65 U β . 1.28. A 23-patient sample size per group was required. We allow for a 20% loss to follow-up, giving a total sample size of 56 patients (28 per group) in the study.
Participants may withdraw from the study for any reason at any time. The researchers will record the reason in case report forms.

Statistical analysis
The data will be analyzed using the Statistical Package for the Social Sciences V.21.0 statistical software package (SPSS, Chicago, IL, USA), with the signi cance level set at 0.05(two-tailed) by statisticians who are independent of the research team. When testing the baseline differences between the two groups, continuous variables will be described using means and standard deviations and tested with t tests. Categorical variables will be presented using percentages and tested with chi-squared tests. The two-way ANOVA will be used to compare the effect of the treatments between the two study groups. Logistic regression will be used to describe data and to explain the relationship between effect and lifestyle. All analyses will utilize an intention-to-treat principle.

Data management
To ensure the accuracy of the data, two independent researchers blinded to the group allocation will input the data on the Excel spreadsheet, and the data will be checked twice. It will be con rmed with original case report forms when any different data entry is discovered. Paper les and electronic documents will be kept in a locked ling cabinet and protected computer separately. Only principal researcher will allow accessing. Researchers will be unable to modify data after it. The researcher shall keep the information of the impartments strictly con dential and shall not disclose it under any circumstances. Meanwhile, the researcher shall sign a con dentiality agreement.

Discussion
ISSNHL is an acute disorder that occurs throughout life and usually cannot nd etiology. Although 49%-89% cases have been returned to the normal hearing by existing therapy with oral or intravenous steroids and 32-65% spontaneous recovery rate, patients who have incomplete recovery from ISSNHL after the failure of initial management remains a problem. Some patients reluctant to receive recommend glucocorticoids treatment due to fear of side effects, contraindications, and drug-to-drug interactions. The salvage therapy recommended by the 2012 ISSNHL guidelines is IT steroid perfusion, hearing improvement ranging from 53% to 90% in the treatment group [22,23]. The dose and concentration of steroids vary, as do the criteria used to de ne hearing improvement.
Previous studies indicate that patients who do not show any improvement within the rst 14 days are unlikely to have much recovery afterward [9,10]. Thus the patient's usual loss hope to continue therapy. Therefore, an acceptable and simple therapy is required to improve the effects of refractory ISSNHL for these patients.
TCM has been used for thousands of years to treat diseases in China and Chinese people easily accept it. Lifestyle, as part of traditional Chinese medicine, has been integrated into Chinese culture. All the time, there is a tradition and sustained interest in the bene ts of TCM recommend lifestyle, especially for patients cannot be effectively treated by western medicine. We designed this trial with the hope of verifying that lifestyle based on TCM can provide help of hearing loss and concomitant symptoms in patients with ISSNHL. If successful, this intervention will at least help refractory ISSNHL patients in China.
The study has designed to explore the e cacy of TCM instructed lifestyle change for ISSNHL patients with no or insu cient recovery of initial systematic Western medicine treatment. Even though there are suggestion with IT steroid perfusion for this kind of ISSNHL in Western medicines, the evidence of their e cacy is still unclear. In this study, the effective rate of hearing improvement will be used as the primary outcome measure. It is the most common parameter for ISSNHL. The secondary outcome measures including WRS, THI and accompany system including dizziness and ear fullness. Because in addition to hearing loss, many people with ISSNHL complain of cannot hear clearly, tinnitus and dizziness. The exact mechanisms that explain lifestyle based on TCM effects on ISSNHL need further detailed research and discussion in the future.

Study limitations
One of the major drawbacks is the lifestyle questionnaire currently widely adopted are not used. The main reason is that we recommend the method is different from lifestyle which emphasis on the general trend rather than speci c quanti cation, the existing tools are not suitable. Since lifestyle includes sleep, diet, mood and exercise, the factor that play a key role is still unknown. Therefore, well-designed randomized controlled trials that compare different factor of lifestyle with each other are necessary in the future.

Declarations
Trial status The protocol was was registered on May 22, 2017 and the registration number is ChiCTR-INR-17011459. The participantr ecruitment began on August 9, 2017 and is ongoing at the time of manuscript submission. We expect this process to be completed in May 2019.

Ethics approval and consent to participate
This trial has been approved by the Biomedical Branch of Ethics Committee of West China Hospital of Sichuan University (identi er 2016-180). Study participation is voluntary and can be cancelled at any time without provision of reasons and without negative consequences for their future medical care. The informed consent will be obtained from all study participants before they enroll in the trail by us.

Consent for publication
All authors and investigators give their consent for publication.
Availability of data and material Figure 1 Trial ow chart. PTA pure tone average, WRS word recognition score, THI tinnitus handicap inventory. Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) Figure: proposed schedule for enrolment, intervention and assessment. PTA pure tone average, WRS word recognition score, THI tinnitus handicap inventory.