Title: A randomised, placebo controlled trial of extra-oesophageal reflux treatment in the management of upper respiratory symptoms.[TOPPITS:Trial of Proton Pump Inhibitors in Throat Symptoms]
Funder: Department of Health and Social Care

Abstract: Design: TOPPITS is multicentre, randomized double-blind, placebo-controlled trial, with internal feasibility pilot. It explores the theory that persistent throat symptoms are atypical manifestations of gastric reflux and hence responsive to proton pump inhibition. Consenting potentially eligible trial patients will attend a dedicated research clinic for further discussion, confirmation of eligibility, recording of baseline parameters, written consent, and randomisation, in a 1:1 ratio stratified by centre and baseline severity. Review appointments will take place at four and 12 months (the latter to assess the persistence of any treatment effect. The treatment allocation will be kept blind from the subjects and investigators unless code break is required for safety reasons. Setting: A group of eight Ear Nose and Throat outpatient clinics in UK district and teaching hospitals. Population: The target population is adult patients electively referred to secondary care clinics with a qualifying baseline severity score of persistent throat symptoms - such as feeling of something in the throat, throat clearing, mucus, catarrh, throat discomfort. Exclusion criteria: those under 18 years old; Pregnant or breast feeding; known vocal cord palsy or laryngeal malignancy; performing voice user; taking drugs which contraindicate the use of proton pump inhibitors, or sensitivity to these inhibitors. Intervention (health technology) being assessed: The active intervention is a four-month course of a 30 mg twice daily dose of the proton pump inhibitor lansoprazole. Comparator: matched placebo Measurement of Outcomes: The primary outcome measure is the four-month change from baseline on the Reflux Symptom Index self-report questionnaire, the most commonly used tool in this condition. Secondary outcomes include a more broad based and clearly itemised symptom checklist, the Comprehensive Reflux Symptom Scale – the patients’ preference as ascertained through our PPI consultations - and a throat symptom specific quality of life measure. The Reflux Symptom Index data will be analysed using analysis of covariance (ANCOVA) to compare the change on Reflux Symptom Index between the trial arms while adjusting for potential confounders (age, gender, Body Mass Index, smoking, baseline laryngeal appearances, centre and baseline severity. Should data be found to be non-Normally distributed the use of transformations or non-parametric approaches will be considered although ANCOVA is generally robust to departures from Normality. More basic exploratory analyses will also be undertaken. Secondary outcomes will be analysed in a broadly similar fashion. Sample Size: The trial is powered for an effect size of 0.4 on the Reflux Symptom Index. For a two-sample t-test, 90% power and at the 0.05 significance level, allowing for 20% loss to follow-up, we require 332 patients to be randomised Timetable: Year one is an internal feasibility pilot – TOPPITS 2 months set up; 6 months recruitment. Target = 30 randomised among three centres. Full trial recruitment (a further 302 patients recruited) over 6 centres equates to a target of five randomised patients per week over 18 months (rate of 40 active clinics per annum i.e. 60 weeks = 360 clinics among the eight sites (allowing for some clinics with no recruits). The projected 20% attrition yields our 133 completers per arm. Performance against Stop / Go criteria for the main trial will be evaluated at the end of the pilot. Participants will be followed up till 12 months following randomisation. TOPPITS Data analysis and preparation of HTA report and other dissemination media will take a further six months.

Lay abstract: Throat symptoms such as throat clearing, feeling of a lump in the throat (globus), intermittent hoarse voice, discomfort, choking, or excess mucus - “catarrh” - are all extremely common conditions in the general population. At any one time 6% of women will have a persistent globus sensation; in general practice up to 25% of people will have significant trouble from throat symptoms and in secondary care these cases account for an estimated 57,000 referrals per annum to NHS Ear Nose and Throat clinics. Over the past 25 years, there has been a growing trend in the use of acid reflux treatments for throat symptoms. The theory is that stomach contents passing back up the gullet can cause inflammation to the upper airway – the throat and voice box, due to the effects of both acid and destructive enzymes, outwith their normal, stomach environment. As a result, many patients with unexplained throat symptoms are given traditional 'heartburn' remedies, most often proton-pump inhibitors such as lansoprazole, acid suppressing drugs which stop stomach cells secreting acid. In total this class of drugs costs the NHS over £300 million annually. Published research (usually small scale randomised trials) to date has shown little advantage over response to placebo or “dummy” drug, yet acid suppression therapy continues to be given by the vast majority of ear nose and throat specialists world-wide, and by increasing numbers of UK primary care doctors. Scrutiny of the results of these small trials, however, reveals a wide range of outcomes, and it is possible they have missed selective effects in certain categories of throat symptom, or in specific patient groups. Our proposed trial will compare proton pump inhibitors to a placebo, in substantial numbers of patients to avoid the limitations of previous research. It is timely as both patients and healthcare professionals are increasingly aware of the side effects of proton pump inhibitors – especially a rebound acid surge when patients stop taking the medication which leads to prolonged therapy periods, plus other chronic side effects such as osteoporosis. We aim to answer the question – how effective are proton pump inhibitors at improving persistent throat symptoms, compared with a placebo? We need a placebo as there is no current “best practice” or evidence based alternative treatment. Design: A multicentre, randomized double-blind, placebo-controlled trial, with an initial pilot phase. Patients who have been referred to a hospital clinic will be invited to take part in the trial. The baseline throat appearances will be photographed with a standard outpatient voice box camera. No additional investigations will be required. 332 patients will be recruited, 166 per arm, to yield at least 133 completers per arm. Staff will not know which treatment is to be given to an individual patient. Randomised patients will take lansoprazole or matched placebo 30 mg twice daily for 4 months. We shall use three standard questionnaires to assess the following at baseline: throat and reflux symptoms and throat related quality of life. The three questionnaires will be repeated, compliance (pill count), over- counter medication and side effects assessed, and further information gathered at the end of the four-month treatment period and at a final visit 12 months following randomisation. This will be blind to the participant's treatment group. We shall ask patients at the end if they have had a satisfactory outcome or feel the need to seek further care. Setting: A group of eight Ear Nose and Throat outpatient clinics in UK district and teaching hospitals. Target Population: Adult patients referred to hospital with a qualifying baseline severity score of persistent throat symptoms. Measurement of Costs and Outcomes: We will measure the four-month change from baseline on the Reflux Symptom Index self report questionnaire, the most commonly used acid throat questionnaire. Secondary outcome measures include a more broad based and clearly itemised symptom checklist, the Comprehensive Reflux Symptom Scale (in our consultations with a small group this was the patients’ preference) and a a throat symptom specific quality of life measure. We shall also record the proportions of patients in whom there is satisfaction with the overall outcome, and those who intend to seek further care. Reflux Symptom Index data will be compared between the trial arms taking account of age, gender, smoking, Body Mass Index, baseline laryngeal appearances and specific categories of symptom including the stratification variables. Secondary outcomes will be analysed in a broadly similar fashion. Results will be analysed to see if study site, baseline severity or other variables affect the response. Sample Size: We expect up to 20% of patients may drop out of the trial and have allowed for this such that we shall still have 266 completers. This sample is big enough to capture all but the smallest clinical difference. Timetable: Two months of set-up is followed by a six-month internal feasibility pilot. Our target is to recruit and randomise a minimum of 30 patients among 3 centres. The feasibility and progress to full trial will be evaluated at the end of the pilot. Full trial recruitment will take place for 18 months at eight sites, followed by 12 months to the end of final follow-up. Data analysis and dissemination will take a further six months. If a treatment response is demonstrated we have a sufficient sample size to identify response predictors, thus limiting needless prescriptions in future. Conversely if there is no response then even greater cost savings would ensue.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: ORAL AND GASTROINTESTINAL