Prognostic factors for outcomes of idiopathic Sudden onset Sensorineural Hearing Loss: the SeaSHeL national prospective cohort study.
Based on recent discoveries in the molecular mechanisms that lead to sensorineural hearing loss, novel treatments are being developed for patients with idiopathic sudden onset sensorineural hearing loss (SSNHL). To allow for such trials, there is an urgent need for information on patient numbers, geographical distribution, demographics, treatment pathways, and outcomes.
The SeaSHeL study aims to collect these data through an ENT trainee and Audiologist led prospective cohort study of adult patients presenting with idiopathic SSNHL within the NHS.
Objectives are as follows:
- To map the patient pathway and identify the characteristics of adult patients presenting to NHS ENT and hearing services with Idiopathic SSNHL
- To develop a prediction model to predict recovery for patients with Idiopathic SSNHL
- Establish the impact of Idiopathic SSNHL on patients’ quality of life (QoL).
Each year, approximately 20 people per 100,000 experience sudden loss of hearing that is sensorineural in nature. ‘Sensorineural’ indicates an abnormality of the cochlea, the auditory nerve, or higher central auditory pathways. When the hearing loss is of 30 dB (decibel) or more, over at least 3 contiguous frequencies and within 3 days, the condition is termed sudden onset sensorineural hearing loss (SSNHL). SSNHL is predominantly unilateral and the hearing loss can range from mild to profound. Reported causes of SSNHL include infectious and otologic diseases; trauma, including noise-induced, barotrauma or head trauma; vascular or haematological; neoplastic; and other. In 71% to 90% of cases, the cause is unknown despite investigation, and these cases are termed idiopathic. Associated symptoms include tinnitus, vertigo and aural fullness. Idiopathic SSNHL is a serious condition, adversely impacting people’s lives with research indicating associations with emotional distress, depression, difficulties at work and impaired social integration. Its prognosis is poorly understood and may depend on age, comorbidities, degree of hearing loss, audiometric configuration, presence of vertigo, treatment received, time between onset of hearing loss and treatment and other factors. It is estimated that 32% to 65% of cases of idiopathic SSNHL recover spontaneously, although clinical experience suggests that this may be an overestimation, with further research required in this area. Current care pathways for patients suffering from idiopathic SSNHL appear to vary considerably in terms of the type of service patients first present to, their subsequent referral, length of time between onset of symptoms, presentation and start of treatment, the treatment plan as well as follow-up. Treatment options for idiopathic SSNHL include systemic and intratympanic steroids, antiviral agents, rheological agents, diuretics, hyperbaric oxygen treatment, and observation alone. The lack of evidence regarding the comparative effectiveness of these treatments is recognised by clinical guidelines published by National Institute for Health and Care Excellence (NICE), the American Academy of Otolaryngology-Head and Neck Surgery (ORL-HNS), and the British Academy of Audiology.
Based upon recent discoveries in the molecular mechanisms that lead to sensorineural hearing loss, biotechnology and pharmaceutical companies are developing new treatments for patients with idiopathic SSNHL. These treatments require rigorous testing in clinical trials before they can become available for application in a clinical service setting. To allow for such trials to be run effectively reliable information is required on where patients with idiopathic SSNHL present and can be recruited from within the optimum timeframe from onset of symptoms to start of treatment based upon the preclinical profile of the drug. This means that there is an urgent need for information on patient numbers, geographical distribution, demographics, patient and treatment pathways, as well as outcomes. This study proposes to collect these data through an ENT trainee and Audiologist led nationwide prospective cohort study of adult patients presenting with SSNHL within the NHS. Importantly, this study will not only provide key data to inform future trial design and delivery, but also a unique dataset to develop a prediction model to predict recovery for patients with SSNHL.
To develop a prediction model to predict recovery for patients with SSNHL.
P – Adult patients diagnosed with idiopathic SSNHL in NHS ENT and hearing services
I – Demographic and disease-specific variables (of which treatment is one variable)
C – None
O – Hearing levels, quality of life
- To map the patient pathway and identify the characteristics of adult patients presenting to NHS ENT and hearing services with SSNHL.
- To develop a prediction model to predict recovery for patients with SSNHL.
Establish the impact of idiopathic SSNHL on patients’ quality of life (QoL)
National multicentre prospective observational cohort study. The study will be reported in accordance with STROBE and ‘Transparent Reporting of a multi variable prediction model for Individual Prognosis or Diagnosis’ (TRIPOD) reporting guidelines for observational studies.
A multicentre study taking place at NHS centres providing ENT and Hearing Services.
Adult patients (male or female) aged over 16 years of age presenting to NHS ENT and hearing services with SSNHL
Diagnosed with a hearing loss in one or both ears of 30 dB HL or more, over at least 3 contiguous frequencies, between 250, 500, 1000, 2000, 4000 and 8000 Hz.
Willing and able to provide written informed consent.
Patients with mixed or conductive hearing loss (CHL). CHL will be defined as a ‘true’ air-bone gap of 15 dB HL or more in 3 or more contiguous frequencies between 500, 1000, 2000, 4000 Hz.
Age; gender; social class, presence of vestibular symptoms; precipitating illness; pattern of hearing loss; severity of hearing loss; time between onset of symptoms and treatment; treatment(s) received.
Pattern of hearing loss will be defined as: low frequency loss (250, 500 Hz), mid frequency loss (1000, 2000 Hz), high frequency loss (4000 Hz and 8000 Hz), flat (all frequencies), sloping (progressive loss across frequencies).
Severity of hearing loss (on presentation) will be defined as follows: Pure tone average (PTA) across 6 points, classified as: mild (25-40 dB loss), moderate (41-70 dB loss), severe (71-95 dB loss) and profound (>95 dB loss).
The change in auditory function in the affected ear from initial presentation to follow-up (at any one time between 6 and 16 weeks from onset of symptoms). Auditory function will be defined as the PTA of air conduction thresholds at 250, 500, 1000, 2000, 4000 and 8000 Hz. If multiple pure tone audiograms have been carried out between 6 and 16 weeks, the most recent pure tone audiogram will be used for the calculation of auditory function.
Change in auditory function classified as:
Full recovery: Final PTA in affected ear within 10dB of PTA of unaffected ear (≤10dB)
Partial to no recovery: Final PTA in affected ear ≥ 10dB of PTA of unaffected ear.
Degree of change in auditory function:
Complete recovery: Final PTA in affected ear within 10dB of PTA of unaffected ear (≤10dB)
Marked recovery: PTA improvement ≥30 dB (and final PTA in affected ear ≥ 10dB of PTA of unaffected ear)
Slight recovery: PTA improvement ≥10dB and <30 dB (and final PTA in affected ear ≥ 10dB of PTA of unaffected ear)
No improvement: PTA improvement <10 dB (and final PTA in affected ear ≥ 10dB of PTA of unaffected ear)
Quality of life:
Change in QoL score from initial presentation to follow-up at any one time between 6 and 16 weeks following treatment. QoL will be measured using the Hearing Handicap Inventory for Adults (HHIA) (for patients under 60 years of age) or Hearing Handicap Inventory for Elderly (HHIE) (for patients over 60 years of age) (see Appendix 1) and the Health Utility Index Mark 3 (HUI3) (see Appendix 2). QoL data will be only be collected in a selection of sites (see below).
The total sample size required to develop a binary logistic regression model has been estimated as per TRIPOD recommendations and Ogundimu et al. The number of events per variable (EPV) has been set at 15, producing a minimally required sample size of 550 patients (number of parameters = 15).
We will develop a multivariable prognostic model to predict recovery for patients with SSNHL in NHS ENT and Hearing services. Analyses will be conducted on the candidate predictors specified above (n=15). Missing outcome data at study end will be imputed using multiple imputation by a chained equations procedure. Internal validation will be performed to quantify optimism in the predictive performance (calibration and discrimination) of the developed model using bootstrapping techniques. Bootstrapping techniques provide information on the performance of the model in comparable datasets and generate a shrinkage factor to adjust the regression coefficients. Statistical analysis will be carried out using R software (version 3.5.1).
The mean change in HHIA, HHIE and HUI3 scores will be calculated from initial presentation to follow up (any one time between 6 and 16 weeks). We will use the non-parametric Wilcoxon and McNemar–Bowker tests with a significance level of 5% to compare results at patients’ initial presentation and at their final follow up. Statistical data analysis will be carried out using the SPSS program 19.0 (SPSS, Chicago, IL, USA). QoL data will be collected from a sub-set of sites (20%, n=20).
A working group will be established that will be responsible for study design, recruitment and delivery. This will consist of an Academic and Operational Team. All roles will last for the duration of the study, estimated at 18-24 months.
The Academic Team will be responsible for study design, methodology, ethics application, acquiring of research funding, NIHR CRN Portfolio adoption, data analysis and write-up (collaborative authorship). The Academic Team will also be responsible for secure data storage and compliance with General Data Protection Regulation (GDPR) requirements. The Academic Team will ensure that each Site: ENT Lead, Audiological Lead and Clinical Research Nurse has the up-to-date study protocol, consent form, patient information sheet (PIS), data collection sheet, QoL questionnaires and advertisement material. The Academic Team will obtain input from the INTEGRATE trainee collaborative and the NIHR CRN Audiology Champion Network on optimising data completion as well as efficient data processing and transfer. The Academic Supervisors will provide overall academic supervision for the study.
Academic Team Lead:
Mr Rishi Mandavia. (SFO Academic & Careers Lead, INTEGRATE Otology Subcommittee Member, NIHR CLAHRC BRC Clinical Research Fellow UCL Ear Institute)
Junior Academic Lead: Muhammad Ahmed – Medical Student, University of Leeds. MRes UCL
Academic Team Members:
Dr Yaamini Premakumar, Academic Foundation Year 2 Doctor, London North West
Timothy Chu – Medical Student, Newcastle University
Mr Joseph Manjaly – Consultant Otologist, Auditory Implant & ENT Surgeon, evidENT
Miss Maha Khan – ENT ST5 Health Education North West, SFO Committee Member, INTEGRATE Collaborator Engagement Officer;
Mr Nishchay Mehta -ENT ST8 North London, INTEGRATE Otology Committee Chair;
Miss Tanjinah Ferdous – Audiologist Royal National Throat Nose and Ear Hospital (RNTNEH) and NIHR CRN North Thames Audiology Champion;
Patient representative – The patient representative will advise on study design, the PIS, patient consent form as well as interpretation and dissemination of study findings;
Professor Anne GM Schilder – Professor of Otorhinolaryngology UCL Ear Institute;
Dr Gerjon Hannink – Methodologist, Radboud UMC Nijmegen, The Netherlands.
Mr Rishi Mandavia
This role will involve ensuring effective communication between the Academic and Operational Teams so that patient recruitment and data collection will take place as per study design. The Academic-Operational Liaison will chair working group meetings.
The INTEGRATE ENT Trainee Collaborative, and Student and Foundation Doctors in Otolaryngology (SFO-UK) will help recruit Operational/Regional leads and ENT Site Leads and advertise the study through their networks. Operational/ Regional leads and ENT site leads will be of Grade F2 and above.
The NIHR CRN Audiology Champions Network will similarly help recruit Audiology Site Leads and advertise the study through their networks.
Each Operational/Regional Lead will be responsible for coordinating patient recruitment and data collection in approximately 5 hospital sites. This role will involve monthly meetings with the Academic-Operational Liaison as well as Site Leads to evaluate monthly data collection and implement strategies to maximise data capture and accuracy.
The Publicity Officers will be responsible for working with Academic Team to develop and disseminate material for the study including presentations and publications. The Publicity Officers will also work with the Academic Team to organise local dissemination of project findings upon study completion. The Publicity Officer will work with the SFO UK website lead (Dheeraj Karamchandani) and INTEGRATE Collaborator Engagement Officer (Maha Khan); to establish the study on the SFO UK and INTEGRATE Websites. The Publicity Officers will also be responsible for organising working group meetings as well as documenting and circulating meeting minutes.
Each site will have an ENT and an Audiological Site Lead who will be responsible for registering the study for approval in each of their respective Research and Development (R&D) departments, advertising the study locally through presentations at departmental meetings, posters in ENT and Audiology outpatient departments, and through Trust websites and email notifications. ENT and Audiological Site Leads will also be responsible for recruiting patients for the study at their site; checking data accuracy as well as entering study data anonymously on Research Electronic Data Capture (REDCap) software (in accordance with data governance procedures – see below). In centres where QoL data will be collected (20 centres), ENT and Audiological Site Leads will require an up-to-date Good Clinical Practice (GCP) certificate and will be responsible for consenting patients.
NIHR CRN Research Nurses:
Adoption of the study onto the NIHR CRN Portfolio will give access to LCRN Research Nurses, who can assist in identifying potential patients and in consenting and recruiting patients into the study.
University College London (UCL)
Study site Recruitment
Eligible sites across the United Kingdom will be identified via SFO-UK (The Student and Foundation Doctors in Otolaryngology), INTEGRATE (The National ENT Trainee Research Network), The NIHR CRN Audiology Champion Network, and the NIHR CRN. Ninety-seven sites will be recruited in total.
All study staff recruiting patients in centres where QoL Data will be collected will require an up-to-date GCP certificate. The study will be conducted in compliance with the protocol, GCP and applicable regulatory requirements. Site Leads will be required to register the study with their local Research & Development (R&D) department, Caldicott Guardian and Information Governance department where available.
In line with GDPR, the sponsor, UCL, will be registered with the Information Commissioner’s Office. At the conclusion of the study, electronic files will be transferred and stored in accordance with UCL’s guidelines for electronic and hard copy records.
This research will comply with the: Data Protection Act (2018), Freedom of Information Act (2000); Human Rights Act (Article 8) (1998). The research will adhere to the Information Governance Framework of UCL.
Results will be presented at local and inter(national) meetings and published for the attention of a professional and scientific audience. Publication and presentation of the final results will be on behalf of all study sites and collaborators. A lay summary report will be published for participants and their families and friends.
Findings will be discussed at a dissemination conference, involving patients and their family members, clinicians, commissioners, guideline developers as well as industry. This will be a unique learning event, bringing together patients, the public and professionals to identify and prioritise areas for future research. This conference will also serve to raise awareness of SSNHL as an ENT emergency to patients and professionals.