Title: The NAtional Trial of Tonsillectomy IN Adults (NATTINA): a clinical and cost effectiveness study
Funder: Department of Health and Social Care

Abstract: Scientific Abstract Question: What is the clinical and cost effectiveness of tonsillectomy for the management of tonsillitis in adults? Design: A mixed methods study incorporating a feasibility study, internal pilot and a phase III, multicentre trial randomising patients to immediate tonsillectomy versus conservative management. Setting: 29 Ear Nose and Throat outpatient clinics, district and teaching hospital, 4 in Scotland and 23 in England and 2 in Wales. Target Population: Adults (16y+) referred to secondary care because of disabling recurrent sore throats. Interventions (health technologies) compared: Patients will be randomised on a 1:1 basis to: 1. Immediate tonsillectomy - dissection of the palatine tonsils 2. Conservative management. i.e. deferred surgery. Measurement of Costs and Outcomes Feasibility -engage NATTINA patient Forum; assess otolaryngologists’ willingness to randomise and patients’ willingness to be randomised, taking account of predicted variation in severity. Assess the acceptability of Early Maximum Medical Therapy pathway Finalise methods to input weekly sore throat day returns into trial database. Main Trial Set up of study sites and recruitment of 510 participants. Randomly allocate patients over a further 18 months, with 24 months follow-up Main Trial Primary Outcomes. Total number of sore throat days over the 24 months following randomisation. Secondary Outcomes. 1. Number of sore throat episodes and their key characteristics from NATTINA Sore Throat Alert Reports (STARs) i. category (a) mild or (b) moderate/severe ii. use of over-the-counter medication iii. use of any prescription therapy iv. number of days unable to undertake usual activities v. SF-12 general health questionnaire referring to the episode. 2. Tonsil Outcome Inventory 14 (TOI14) total and subscales (Throat, General Health, Resources and Social / Psychological) six monthly 3. SF- 12 general health questionnaire six monthly 4. Nature of any adverse events experienced 5. Evaluation of the impact of alternative sore throat patient pathways by observation and statistical modelling of outcomes against baseline severity, as assessed by total number of sore throat days recalled in the six months prior to recruitment plus TOI14 score at recruitment. Economic evaluation has three components (1) a cost-effectiveness analysis, based on the incremental cost per sore throat day avoided (2) cost-utility analysis, based on incremental cost per quality-adjusted life year (QALY) gained (3) cost-benefit analysis, based on patients’ willingness to pay to avoid a sore throat day. The SF-12 is sensitive to the outcomes of interest – the SF-12 physical subscale has an effect size of 1 from tonsillectomy. Health state utilities will be derived using the SF-6D algorithms and used to estimate QALYs. Costs measured will include those due to hospital visits, primary care visits, days of inability to undertake usual activities, over the counter medicines, the complications of surgery as well as the direct costs of the interventions. Modelling work in collaboration with prescribing data bases in England and Scotland and by direct access to participants’ primary care records will inform longer term and more extensive models of relative efficiency for the trial and the wider population. Qualitative Process Evaluation of pilot and main trial will address acceptability of trial/treatments and unforeseen consequences from the perspective of participants and stakeholders including primary care clinicians. Sample size: The total number recruited will be 510. By recruiting 510 patients we are allowing for a total loss to follow up of 25% over 24 months. Two groups of 191 patients (providing complete data at two years) gives 90% power to detect an effect size of 0.33(corresponding mean intergroup difference of 3.6 days of sore throat based on a pooled estimated standard deviation of 10.8 days) assuming a type 1 error rate of 5%. Project phases (months) -3 to 0 Ethical approval; staff recruitment; NATTINA Patient Forum set-up; 0-5 Feasibility study; 6- 42 main trial recruitment; 42 – 66 main trial follow-up; 66-69 analysis Team expertise - senior academic otolaryngologists, director of the Scottish Primary Care Research Network, clinical lead for the Primary Care Research Network Northern and Yorkshire, chair of the SIGN guideline on sore throat, an expert patient TSC representative and a provisional patient engagement group, the deputy director and senior trial manager of the Newcastle CTU, senior statistician, qualitative researchers, a highly experienced health economist, motivated clinical otolaryngologists with recruitment expertise, collaboration from a senior information analyst and clinical microbiology (Sunderland Royal Infirmary).

Lay abstract: The role of surgery in the management of adult sore throat remains uncertain and there is considerable variation among UK regions in the rate of tonsillectomy. Thus, the NHS has commissioned a trial to compare the clinical effects and the cost effectiveness of tonsillectomy in adults versus nonsurgical management. The design of our study, the NAtional Trial of Tonsillectomy IN Adults (NATTINA), has been shaped by our patient and public engagement, including discussions with 18 Ear Nose and Throat department patients, and with two members of the North East Consumer Panel Project Steering Group. Our previous experience of a randomised trial of tonsillectomy in children, together with other published Ear Nose and Throat surgical trials, highlight the problem of retaining participants in the nonsurgical cohort. Our consumers feel that clinicians underestimate the severity of the illness which accompanies adult tonsillitis, and that few will agree to be randomly allocated indefinitely to a nonsurgical approach. Hence we use deferred surgery as the nonsurgical option. NATTINA lasts 69 months and has three stages 1. Feasibility study The aim is to assess willingness of clinicians to refer and randomly to allocate patients to the study groups; to test our processes of patient identification and recruitment; to address the feasibility of our proposed data collection methods. 2. Internal pilot We shall test our trial processes and ability to recruit sufficient number of patients. We shall randomly allocate 72 patients between surgery and deferred surgery in 6 centres. We shall also establish the NATTINA patient forum and website. Summary (in Plain English) 3. Main Trial A total of 510 patients (including the 72 above) will be recruited in 29 centres and allocated randomly to tonsillectomy or deferred surgery. Allowing for 25% attrition from all causes, this will yield two final comparison groups of 191 patients. We review patients at 12 and 24 months and send out interim questionnaire packs at 6 and 18 months. Trial Sites and PIs: Freeman Hospital (Newcastle),Sean Carrie,Newcastle upon Tyne Hospitals NHS Foundation Trust Sunderland Royal Hospital,Leon Lindsey,City Hospitals Sunderland NHS Foundation Trust. Ninewells Hospital (Dundee),Musheer Hussein,NHS Tayside Glasgow Royal Infirmary,Kenneth MacKenzie,NHS Greater Glasgow and Clyde Aberdeen Royal Infirmary,Kim Ah-See,NHS Grampian Bradford Royal Infirmary,Christopher Raine,Bradford Teaching Hospitals NHS Foundation Trust Birmingham University Hospital, Peter Monksfield,University Hospital Birmingham NHS Foundation Trust Guy’s and St. Thomas Hospital,Claire Hopkins,Guy's and St Thomas' NHS Foundation Trust Royal Albert Edward Infirmary (Wigan,Nirmal Kumar,Wrightington Wigan and Leigh NHS Foundation Trust Dorset County Hospital (Dorchester),Richard Sim,Dorset County Hospital NHS Foundation Trust Cumberland Infirmary (Carlisle,Sara Jane Jarvis,North Cumbria University Hospitals NHS Trust Frimley Park Hospital,Philippa Huchzermeyer,Frimley Health NHS Foundation Trust Royal Hallamshire Hospital (Sheffield,Jaydip Ray,Sheffield Teaching Hospitals NHS Foundation Trust Queen’s Medical Centre (Nottingham,Matija Daniel,Nottingham University Hospitals NHS Trust Pilgrim Hospital (Boston,Faiz Tanweer,United Lincolnshire Hospitals NHS Trust Salisbury District Hospital,Macrel Geyer,Salisbury NHS Foundation Trust University Hospital Crosshouse (Kilmanock),John Dempster,NHS Ayrshire & Arran Royal Gwent Hospital (Newport, Wales),Patrick Cuddihy,Aneurin Bevan University Health Board James Cook University Hospital (Middlesbrough), Anirvan Banerjee,South Tees NHS Foundation Trust West Suffolk Hospital (Bury St. Edmunds,Fahmy Fahmy,West Suffolk Hospital NHS Trust Royal Blackburn Hospital,Surya Narayan, East Lancashire Hospitals NHS Trust Worcestershire Royal Hospital,Tom Martin,Worcestershire Acute Hospitals NHS Trust Derriford hospital (Plymouth),Hisham Khalil,Plymouth Hospitals NHS Trust Royal Preston Hospital, John De Carpentier,Lancashire Teaching Hospitals NHS Foundation Trust James Paget University Hospital (Great Yarmouth),Carl Philpott, James Paget University Hospitals NHS Foundation Trust John Radcliffe Hospital (Oxford),Konstantinos Chaidas, Oxford University Hospitals NHS Trust Walsall Manor Hospital, Attila Dezso,Walsall Healthcare NHS Trust Ysbyty Gwynedd (Bangor),Vishwanath Puranik,Betsi Cadwaladr University Health Board Outcome measures The primary NATTINA outcome is the comparison of the total number of sore throat days, recorded in weekly sore throat reports, by surgical and deferred surgery patients over the 24 months of the study. Other outcomes of clinical effectiveness are the numbers of a) mild and b) more severe sore throat episodes, and changes in the scores for the 14 item Tonsil Outcome Inventory. When patients in the study experience a sore throat they are asked to submit a Sore Throat Alert Return (or STAR for short). We wish to record the severity, the medications both prescribed and over-the-counter used, and whether and what category of NHS service was accessed. This information will be cross- referenced by the research team to national prescribing data bases in Scotland and England and to general practice records of primary care and other NHS provider contacts. (This will be facilitated by our proposed application of a unique NHS “Read” code for NATTINA participants). The Tonsil Outcome Inventory covers the prior six months and will be administered three times face- to-face (baseline 12 and 24 months) and at two interim points in a postal questionnaire pack alongside the general health status measure the SF 12. We have now accrued local data, some of it published, on the face, discriminant and sensitivity to change validity of the 14 item Tonsil Outcome Inventory questionnaire in the English-speaking population. It also appeared acceptable to our patient panel and a useful surrogate for baseline severity. This is important because the aim of NATTINA is not merely to assess cost efficacy of currently guidance but, through a close cooperation between secondary and primary care, to predict mathematically the health and economic implications in the event of new care pathways for adult sore throat. Without this approach, NATTINA would only be able to evaluate the cost effectiveness of current tonsillectomy guidelines, which were perforce drawn up without the benefit of high quality scientific data. Additional outcomes are quality of life and health economic evaluation - (1) a cost-effectiveness analysis, based on the cost of avoiding one per sore throat day by surgical and nonsurgical strategies (2) a cost-utility analysis, which will determine the cost of a quality-adjusted life year (QALY) gained and (3) cost-benefit analysis, based on patients willingness to pay to avoid a sore throat day. A strong qualitative component will contribute to feasibility, internal pilot and final interpretation stages. Collaboration One of our patients has agreed to participate in the Trial Steering Committee. He will facilitate the NATTINA patient forum which will reflect on trial progress throughout, contribute to our www.NATTINA.com website and, finally, assist with the design of future work. Team expertise includes two senior academic Ear Nose and Throat specialists, the director of the Scottish Primary Care Research Network, the clinical lead for the Primary Care Research Network Northern and Yorkshire, the chair of the sore throat national guideline group, the deputy director and senior trial manager of the Newcastle Clinical Trials Unit, a senior statistician, two qualitative researchers and a senior lecturer in health economics. We have collaboration from a senior information analyst and a clinical microbiologist

Research activity codes: 6.4 SURGERY;7.3 MANAGEMENT AND DECISION MAKING
Health categories: INFECTION