Lansoprazole for persistent throat symptoms in secondary care: the TOPPITS RCT

Article history

The research reported in this issue of the journal was funded by the HTA programme as project number 12/01/04. The contractual start date was in January 2014. The draft report began editorial review in September 2018 and was accepted for publication in June 2019. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Copyright statement

© Queen’s Printer and Controller of HMSO 2021. This work was produced by Wilson et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

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Background

TOPPITS addresses the problem of adults with persistent throat symptoms, such as globus pharyngeus (hereafter referred to as ‘globus’), catarrh, throat discomfort, clearing, recurring dysphonia or excess mucus. In one UK survey,2 6% of the middle-aged female population reported a persistent feeling of something in the throat (globus) in the previous 3 months. Globus is also reported to account for up to 4% of ear, nose and throat (ENT) referrals to secondary care. 3 Throat clearing is the commonest single symptom in any voice clinic. Equally familiar are intermittent hoarse voice and postnasal drip. 4 It is claimed that 55% of patients referred to a voice clinic have symptoms of extraesophageal reflux (EOR), and an English study of primary care attenders indicated that 25% had recent experience of persistent upper respiratory symptoms. 5 In the general population, the lifetime incidence of milder variants of globus is > 40%. 6 There were 1,142,404 first ENT consultations in England in 2010–11. 7 A conservative estimate is that 5% of these patients were referred for very common throat symptoms, such as throat clearing, fluctuating voice change, catarrh and chronic throat discomfort, which equates to over 57,000 NHS patients referred to secondary care that year in England alone. 7 Some patients experience anxiety as they fear that they may have throat cancer. Even if they have no features and no risk factors for cancer, they may be referred in for urgent ENT clinic assessment, a process that prolongs the anxiety and, at times, the symptoms. In the absence of good-quality treatment algorithms, patients also undergo invasive and costly assessments, such as rigid endoscopic examination of the upper aerodigestive tract under general anaesthesia, which typically reveals no significant abnormality, and empiric trials of acid suppression, typically with proton pump inhibitors (PPIs).

Rationale

Upper airway symptoms are known to have a strong placebo response. 8 Early evidence from animal experiments gave rise to the term ‘acid laryngitis’ 40 years ago. 9 Intracellular reactivation of acidified pepsin may explain pepsin activity at weakly acid pH levels. 10,11 Despite a growing trend to treat throat symptoms empirically with PPIs, controlled studies fail to demonstrate a significant benefit of PPI over placebo. 12–14 An evidence-based medicine EOR conference concluded that work assessing PPIs in throat symptoms had variable study design and quality, small numbers and heavy selection bias, with inconsistent treatment regimes, and that the small proportion of controlled studies demonstrating overall benefit of PPI over placebo15 may reflect the prompt response of heartburn to antacid treatment. 16,17 There was little evidence on other pharmaceuticals, such as H₂ antagonists. 18,19 In the patient and public involvement background work for this proposal, individual interviews were conducted with several patients, encompassing both young professionals and the retired. All fully supported the research proposal. It was also clear, even from a small sample, that patient views on PPIs vary widely, but all had been treated at some point with PPIs, sometimes on more than one occasion.

Over half of UK otolaryngologists prescribe PPIs for persistent throat symptoms in the absence of structural pathology. 20 Our early systematic review12 of studies that used PPIs as an empiric treatment modality for suspected laryngopharyngeal reflux (LPR) identified 14 uncontrolled studies, one unblinded, non-randomised study with a control group of healthy volunteers and six double-blind, placebo-controlled randomised trials from 1994 to 2004. A lack of common outcome measures, selection bias and inadequate blinding of the results were among the typical limitations. Although uncontrolled series reported positive results, randomised controlled trials (RCTs) demonstrated no statistically significant differences for changes in severity or frequency of throat symptoms between PPIs and placebo. It appeared that empiric treatment of suspected LPR with PPIs, by far the most common ENT practice in the UK, is based on poor levels of evidence from uncontrolled studies. A later meta-analysis21 included further studies, notably that by Vaezi et al. ,22 and concluded that PPI therapy ‘may offer a modest but non-significant clinical benefit’ over placebo. The authors also concluded that validated diagnostic guidelines may facilitate the recognition of likely responders. The 2007 meta-analysis13 included five RCTs, only two of which had more than 22 participants, and only one randomised over 100 participants. The conclusion was that there was no overall benefit of therapy and that further work was needed to identify likely responders. 13 Finally, the most recent meta-analysis included seven placebo-controlled trials totalling 396 participants with varying doses over 4 to 16 weeks, and again showed that PPI therapy lacked evidence of efficacy in those suspected to have LPR. Rather, high placebo response levels suggested a more complex and multifactorial pathophysiology. 23 Like previous authors, the reviewers concluded that further studies are needed to characterise subgroups of patients with reflux-associated laryngeal symptoms who might benefit from treatment with PPI.

The perception in primary care is that PPIs are a reasonable ‘empirical’ treatment strategy for this group of patients. Almost since their introduction in the late 1990s, PPIs have constituted the largest part of the NHS community drugs bill: £238M in 1999 (5.6%). 24 PPIs are highly efficient in reducing gastric acid secretion. The annual NHS expenditure on PPIs is > £300M (generic omeprazole, lansoprazole and pantoprazole are the NHS Quality, Innovation, Productivity and Prevention-endorsed low-cost PPIs). The practice of giving ‘all comers’ with upper respiratory symptoms anti-reflux therapy misses the opportunity to explore other potentially beneficial approaches, such as speech therapy or management of fatigue. 25

Measuring treatment responses in throat symptoms

The most frequently used primary outcome measure in the assessment of persistent, hard-to-explain throat symptoms is the Reflux Symptom Index (RSI). This nine-item, self-administered questionnaire is scored on a Likert scale with a total score of 0–45. 26 A higher score indicates more severe symptoms. The nine-item RSI total score allows comparison with previous studies as it offers 10 years of comparative data in the literature. The RSI remains the ‘area standard’ and, despite well-rehearsed limitations, remained our chosen primary outcome measure. Some reported studies have a baseline RSI only just above the normal level and others have a considerably higher baseline RSI. An observational study included 455 participants in South Korea, in whom the mean RSI score fell from 15 at baseline to 5.6 after 12 weeks of the PPI rabeprazole. 27 Baseline RSI scores in a much smaller but comparative study of 62 participants treated with esomeprazole were considerably higher (> 20). 28 On the other hand, a rabeprazole RCT,15 like the Korean descriptive study, had baseline RSI scores around 14, closer to those of Lee et al. 27 Despite these differences in baseline severity, both of these more recent trials showed a benefit from a 3-month trial of acid suppression, but Lam et al. 15 continued follow-up for a further 6 weeks, when the effect disappeared, whereas Reichel et al. ’s28 final measurement point was the end of therapy.

The RSI has a number of limitations, which we have addressed in derivation of our own participant-reported outcome measure: the Comprehensive Reflux Symptom Score (CReSS). 29 The CReSS is a 34-item questionnaire of oesophageal and extraesophageal symptoms, which has been tested on groups of ‘throat’ patients, healthy controls and those attending for an upper gastrointestinal endoscopy. It has three statistically robust symptom factors: (1) gastrointestinal; (2) an upper airway factor relating to cough, breathing, mucus and hoarseness; and (3) an obstruction/choking globus factor. The continuing use of the RSI alongside other variables by ourselves and others has at least allowed the summation of studies in some of the prior attempted evidence synthesis exercises. One factor to be borne in mind in the application of any throat symptom questionnaire, however, is the baseline incidence of throat symptoms in the community. The upper limit of normal in the RSI is said to be 12 in the general population. The first UK study to assess RSI scores in general practice attenders identified 252 participants with a score of > 10. 5 However, only 29% had a zero rating on the integral heartburn/dyspepsia item (which accounts for up to 5 of the 45 points), which is as one would expect given that about 30% of the population have some symptoms of lower gastroesophageal reflux.

When this gastroesophageal item was excluded from the RSI analysis, 8% of general practice attenders had a RSI of > 10 owing to the remaining extraesophageal items. A more recent UK report of the population distribution of RSI values sampled 2000 adults who were also questioned on their health and lifestyle. 30 The mean RSI score was 8.3; 30% of participants had a RSI score of > 10, of whom 25% had a zero score on the gastroesophageal reflux disease (GORD) item, thus giving a 7.5% overall prevalence of suspected LPR, similar to that observed in general practice attenders. 5 Over the past 5 years, we have continued to refine our improved participant report tool, the CReSS. 29 We have demonstrated wide separation of 103 volunteers, with a mean score of < 7, from 177 throat participants, with a mean score of 31 [95% confidence interval (CI) 28 to 35]. Factor analysis in a total of 422 participants shows the CReSS to have three subscales. The greater level of detail of the CReSS and the likely better discrimination of normal from abnormal scores at baseline make it an invaluable secondary outcome variable. Such an approach addresses the research need identified in prior review work, namely that of better characterising the subgroup of suspected LPR patients who may benefit from acid suppression therapy.

Description of the Comprehensive Reflux Symptom Score questionnaire

The CReSS29,31 is a 34-item questionnaire of oesophageal and extraesophageal symptoms that has been tested on groups of ‘throat’ patients, healthy controls and those attending for an upper gastrointestinal endoscopy. It has three subscales [oesophageal (17 items), upper airway (nine items) and pharyngeal (five items)] on a large-scale factor analysis:

• The total score has 34 items, each scored from 0 to 5, so the range is 0–170. Higher values indicate worse symptoms.

• The oesophageal subscale has 17 items – heartburn, flatulence, regurgitation, acid/sour taste in mouth, gurgling, nausea, vomiting, bloating, belching, pressure in the chest, low appetite, feeling full too early in a meal, indigestion, stomach acid, back pain, headache and bad breath (each item is scored from 0 to 5, so the total range for the subscale is 0–85).

• The upper airway subscale has nine items – throat clearing, excess mucus, mucous drip, coughing when upright, coughing after eating, coughing when lying down, wheezing, difficulty breathing and hoarseness (each item is scored from 0 to 5, so the total range for the subscale is 0–45).

• The pharyngeal subscale has five items – lump in the throat, swallowing food, swallowing liquid, throat pain and feeling of things stuck in throat (total score out of 0–25).

Quality-of-life impact of throat symptoms: the Laryngopharyngeal Reflux Health Related Quality of Life questionnaire

Patient-reported generic health-related quality-of-life scores are abnormal in patients with throat symptoms,32 who show abnormalities of health-related quality of life in social functioning, pain and general health perception,33 but there is a perceived need for a disease-specific instrument to assess the impact of reflux on health-related quality of life. 34 This need led to the development of the Laryngopharyngeal Reflux – Health Related Quality of Life (LPR-HRQL),35 which has been validated in a Swedish population. 36 Its 43 items are grouped into four domains and an overall impact category (which includes general questions on relationships, sleep and lifestyle). The LPR-HRQL has been used in at least one prior RCT22 and shown to respond to change, and is a secondary outcome measure of TOPPITS.

The questionnaire contains questions about LPR (acid reflux into the upper throat and how it affects the patient).

Most questions are scored from 0 to 6, describing how often the patient experiences that symptom. The code for the scores is as follows:

1. 0 = none of the time (never in the past month)

2. 1 = rarely (once in the past month)

3. 2 = a little of the time (2–3 days in the past month)

4. 3 = some of the time (about once a week)

5. 4 = a lot of the time (about 2–3 days a week)

6. 5 = most of the time (4–5 days a week)

7. 6 = nearly all of the time or always (6–7 days a week).

After a set of questions that relate to a particular symptom, there is a question rated on a scale from 1 to 10 known as a ‘thermometer’, which asks the patient to summarise the overall impact of those symptoms on their life, in which 1 represents ‘no effect’ and 10 represents ‘an enormous effect’ on their quality of life.

Finally, at the end of the questionnaire, there are a number of questions that use the 1–10 scale. These seek to quantify how much the symptoms effect energy levels, productivity at work, social relationships, marital relationships, sexual relationships, sleeping, ability to lie comfortably in bed, the way they feel about themselves, lifestyle (such as exercising, eating and drinking) and ability to do the things they enjoy.

A summary of how these component questions are combined to assess quality of life is given in the following section.

Trial objectives

TOPPITS aimed to quantify, and to characterise, the effect of PPI therapy compared with placebo. Our comprehensive package of patient-centred outcomes allows us to assess which specific throat symptoms respond, to assess whether or not any patient characteristics can predict any measured treatment response, to derive improved estimates of impact on quality of life and to define the proportion of likely non-responders for whom alternative therapeutic approaches may be more appropriate. Definitions in the RSI literature to characterise responders include 50% reduction and final score within the normal range. Here we use a normal-range end point for response.

Treatment choice in TOPPITS

Proton pump inhibitors suppress gastric acid secretion by specific inhibition of the H⁺/K⁺-ATPase enzyme pump at the secretory surface of the gastric parietal cell. There is now a wide range of available PPIs. The best-value PPIs, and the most prescribed in the UK, are omeprazole and lansoprazole. The class of drugs is generally well tolerated. The frequency of adverse effects associated with PPIs (5%) is similar to that of placebo. The commonest complaints are headache, diarrhoea, abdominal pain and nausea. Except for diarrhoea, whose incidence is < 5%, the adverse effects of PPIs seem to be independent of age, dosage or duration of treatment. The diarrhoea seems to be due to altered gut microbiome secondary to the loss of acid secretion.

The clinical side effects of PPI use include rebound hypersecretion after cessation of PPI therapy, making it hard to wean some patients off of PPIs, and, of course, reinforcing the notion that they were necessary in the first place. 40,41 Rarer side effects include pneumonia,42 Clostridium difficile, infections, acute renal inflammation43 and fractures of hip, wrist and spine. 44

If a PPI is considered appropriate, there is no evidence that any one PPI is more effective than another, when used at therapeutically equivalent doses, but newer agents are considerably more costly:

• We used lansoprazole in TOPPITS as it is among those frequently recommended by commissioning groups45 and formularies; the choice is justified through its inclusion in National Institute for Health and Care Excellence guidance. 46

• In TOPPITS, as is typical of LPR studies, we used twice-daily treatment to minimise the risk of ‘breakthrough’ gastroesophageal refluxes occurring at night. 47

• Lansoprazole has a lower unit cost than omeprazole – NHS prescribing data (January to March 2010) indicate that omeprazole is the most commonly prescribed PPI (4.9 million items, unit cost £4.90, total cost £24.2M); lansoprazole totalled 3.8 million items, at a somewhat lower unit cost of £3.00 (total cost £11.4M). 48

Setting and conduct

This multicentre RCT was conducted at eight UK NHS sites, recruiting patients from 28 April 2014 to 28 February 2017. The final study visit was on 23 March 2018. The trial was conducted in accordance with the principles of International Conference on Harmonisation good clinical practice, received a favourable ethics opinion from the National Research Ethics Service Committee North East – Tyne and Wear South (reference 13/NE/0336) on 2 December 2013 and clinical trial authorisation from the Medicines and Healthcare products Regulatory Agency on 12 February 2014. The trial was managed by the Newcastle Clinical Trials Unit (NCTU) with a Trial Management Group, together with an independent Trial Steering Committee (TSC) and Data Monitoring Committee (DMC). Site monitoring was undertaken by staff at NCTU and the trial was audited by the sponsor, The Newcastle upon Tyne Hospitals NHS Foundation Trust. The clinical trial protocol was published in 2016. 1 A statistical analysis plan was in place prior to any comparative analyses. 49

Patient and public involvement

Several patients contributed to the design of the study and the development of the second-stage application. To canvass the views of a range of patients with different experiences of chronic throat symptoms and treatments, the patient contributors were young professionals and retired patients. These patients were identified from clinics in Sunderland by James O’Hara. Individual consultations with four patients with LPR were conducted by James O’Hara. Two of these four patients agreed to join the TSC.

There was full patient support for the research proposal; the length of time taken to treat this problem and the lack of knowledge of throat symptoms on the part of clinicians is a source of frustration. When asked about the collection of follow-up data, there was a preference for this to be conducted face to face. When discussing outcome measures, patients felt that the CReSS had greater symptom coverage than the RSI, which the team believed justified its inclusion as a secondary outcome measure. Other changes as a result of patient and public involvement are listed below:

• Duration of therapy. This was originally planned to be 2 months; however, our patient panel felt that this was too short and that a longer period (16 weeks) would provide a more definitive result.

• Number of follow-up visits. The patient and public involvement group had a preference for more-frequent follow-up visits but these were reduced to two in line with the Health Technology Assessment panel feedback.

• Data collection – remote versus face to face. The patient and public involvement group believed that, rather than complete questionnaires in their homes, people would prefer – and would be willing – to attend a clinic to complete the questionnaires.

• Outcome questionnaires. Some members of the patient and public involvement group felt that there was some ambiguity in the wording of the questionnaires. This was improved as far as possible, bearing in mind that the RSI in particular needed to be comparable to previously published studies.

Planned patient and public involvement for the duration of the trial

The plan at the application stage for patient and public involvement throughout the trial was to build on the individual consultations conducted and convene a trial user forum to obtain a group perspective. Once funding was confirmed, those involved in the consultations would be invited to join the TOPPITS User Forum (TUF). It was considered that the forum would yield better outputs if it were user led. We hoped for a group of six individuals, aimed to encourage a cross-section of views and experience and hoped to recruit representation from the voluntary sector (e.g. the British Voice Association and the British Laryngological Association).

This forum would be facilitated by the local network patient and public involvement lead. Although the frequency of meetings would ultimately be decided by the forum members, it was initially thought that they should meet prior to the TSC meetings. This would enable a member of the forum to attend the TSC, to represent the group and raise any issues or queries. The intention was that the TUF would assist the trial team to:

• develop the recruitment strategy

• inform the adequacy and accessibility of patient information

• encourage the TSC to stay focused on the needs of patients

• disseminate the findings – users may be co-authors and participate in presentations

• link to the voluntary sector (as described previously).

In return, the TUF would be offered:

• a group and personal role specification, so that we could go through the implications of joining with patients

• a meeting venue with project secretary support, ideally in a community setting, approximately three times per annum

• meeting support from the project secretary

• examples of user group formats from similar groups

• encouragement to develop its own pages on the trial website (www.TOPPITS.co.uk) and a link from this website to the INVOLVE website (www.invo.org.uk/)

• a discussion of learning and development requirements with the trial team, and regular feedback.

Trial design

This was a multicentre, Phase III, randomised, double-blind, placebo-controlled trial, with an internal feasibility pilot, carried out in secondary care. Patients with persistent throat symptoms were identified and recruited from NHS ENT clinics. This was a pragmatic trial designed to mirror current NHS clinical practice, and so patients were not subjected to the gamut of aerodigestive tract investigations that characterise many studies but do not routinely inform the patient pathway outside a research context. Patients were randomised in a double-blind fashion between two treatment groups in a 1 : 1 ratio, stratified by centre and baseline severity [on the basis of the RSI score omitting item 9: ‘Heart burn, chest pain, indigestion, or stomach acid coming up’ – hereinafter referred to as RSI-HB (Reflux Symptom Index minus the heartburn/dyspepsia item) (range 0–40)]. The ‘mild’ cohort had RSI-HB scores of 10–20 (inclusive) and the ‘severe’ cohort had scores of > 20. The heartburn/dyspepsia item was omitted to focus on throat symptoms rather than gastrointestinal symptom burden, although the total RSI was used as the primary outcome. Following successful demonstration of recruitment in three sites in the internal pilot, the main component of the trial recruitment was conducted over a total of 30 months (inclusive of the pilot phase).

Patients

Patients were adults who had been newly referred to secondary care otolaryngology clinics with persistent (> 6 weeks) unexplained throat symptoms, principally dysphonia, throat pain, globus sensation (feeling of something stuck in the throat), throat clearing, postnasal drip or mucus excess, and also night-time unexplained cough or choking. The clinics were in the following trial site hospitals:

• Newcastle upon Tyne – Freeman Hospital (The Newcastle upon Tyne Hospitals NHS Foundation Trust)

• Sunderland – Sunderland Royal Hospital (City Hospitals Sunderland NHS Foundation Trust)

• Nottingham – Queen’s Medical Centre (Nottingham University Hospitals NHS Trust)

• Brighton – Royal Sussex County Hospital (Brighton and Sussex University Hospitals NHS Trust)

• Glasgow – Glasgow Royal Infirmary (NHS Greater Glasgow and Clyde)

• Manchester – Manchester Royal Infirmary (Manchester University NHS Foundation Trust)

• Birmingham – Queen Elizabeth Hospital (University Hospitals Birmingham NHS Foundation Trust)

• Stockport – Stepping Hill Hospital (Stockport NHS Foundation Trust).

Inclusion criteria

• Referred with a persistent primary throat symptom: globus, hoarseness, throat clearing, throat discomfort, choking spasms, excess mucus/postnasal drip, otherwise unexplained night-time cough or choking of ≥ 6 weeks’ duration.

• Those with a score of ≥ 10 on the non-heartburn items of the RSI.

• Capacity to provide fully informed consent to participate in the study.

Exclusion criteria

• Patients whose RSI-HB score was < 10.

• Those unable to complete the TOPPITS questionnaires.

• Patients aged < 18 years.

• Patients who were unwilling to undergo flexible endoscopy to establish the findings below.

• Observed endoscopic laryngopharyngeal pathology that would typically require specific surgical intervention or investigations (e.g. suspected neoplasia/dysplasia, prominent Reinke’s oedema or unilateral vocal fold polyp, vocal cord palsy or chronic inflammatory diseases).

• Confirmed or suspected current or prior malignancy of the head and neck or oesophagus.

• Performing voice users: singers, actors, media workers.

• Pregnant or lactating woman. Woman of childbearing potential must be using adequate contraception.

• Currently on acid suppressants, acid neutralisers and alginates and unwilling to discontinue these for (1) a 4-week pre-study washout period in the case of PPI usage or (2) a 24-hour period for alginate or acid neutraliser. For those discontinuing PPI, ad hoc alginate use was allowed until the final 24–48 hours of the washout period prior to reassessment to confirm ongoing eligibility.

• Prior adverse reaction to PPIs.

• Severe hepatic dysfunction.

• Patients taking warfarin, phenytoin, digoxin, ciclosporin, methotrexate, erlotinib, lapatinib, tacrolimus, sucralfate, citalopram, escitalopram, fluvoxamine, St John’s wort, clozapine, ulipristal acetate, cilostazol or systemic antifungals (itraconazole, ketoconazole, posaconazole or voriconazole).

• Human immunodeficiency virus-positive patients/patients taking antiviral medications (atazanavir, nelfinavir, raltegravir, saquinavir or tipranavir).

• Use of other investigational study drugs within the preceding 30 days.

Patients meeting the eligibility criteria were provided with a patient information sheet (PIS) and were given time to consider participation and the opportunity to ask questions before agreeing to take part. Consent was obtained by a member of the site trial team, delegated with that task on the delegation log and reasons for non-participation were recorded on a screening log at each trial site.

Some patients were identified from routine ENT, voice or 2-week wait cancer clinics. Any patient scoring ≥ 10 on the RSI-HB, where this was in routine clinical use, and who was potentially interested in participating in TOPPITS was given a PIS. The potential participant was then invited to attend a dedicated TOPPITS clinic after a cooling-off interval of ≥ 48 hours. Some potential participants were also identified through primary care referral letters. The principal investigators at each site were responsible for posting an invitation letter and PIS detailing the study along with a clinic appointment card.

A screening log was completed for all potential participants who were screened, including the reason for ineligibility and/or refusal to participate.

Recruitment

Randomisation

A blocked allocation (permuted random blocks of variable length) system was used to allocate patients in a 1 : 1 ratio stratified by centre and baseline severity (two groups, on the basis of the RSI-HB score: group 1, ≤ 20; group 2, > 20). The overall RSI-HB range was 10–38.

Medication

The trial medication was manufactured by Piramal Pharma Solutions (Morpeth, UK); its provision was administered by MODEPHARMA Limited (Beckenham, UK). Three campaigns of trial medication, blinded and randomised at the point of manufacture, were used in the trial. Management and handling comprised:

• ensuring that sites had enough kits to ensure continuous provision to patients over three campaigns and 33 months

• co-ordination of requirements at sites with drug expiry dates

• liaison with site pharmacy staff to ensure accurate drug accountability record keeping

• organisation of the management of returns and their subsequent destruction at sites

• organisation of the destruction of the remaining kits at the end of the trial

• in-person monitoring of site pharmacies

• documentation of all stages of provision, dispensing, return and destruction of trial medication, at sites and centrally.

Blinding

Both the patients and the investigators/assessors were blinded to assignment to either the lansoprazole group or the placebo group (double-blind). A set of sealed code-break envelopes was kept either in the pharmacy or in the ISF at participating hospitals; these envelopes were opened only in an emergency, with authorisation from the chief investigator. When the code was broken, details including the patient number, who broke the code, why and when were recorded and maintained in the ISF. Code breaks were not routinely carried out for patients who completed study treatment. There were no code breaks throughout the duration of the trial.

At the second, end-of-therapy, visit, the integrity of the blind was assessed by a questionnaire item asking the patient if they thought that they had been taking lansoprazole or placebo or if they did not know.

The blind was maintained until all trial data were collected and the database was locked. Patients were offered the opportunity at their final visit to be informed of their allocated group, once data analysis was complete.

The active intervention was a 16-week course of a 30-mg twice-daily dose of the PPI lansoprazole. The control group received a 16-week course of twice-daily matched placebo. Patients received the intervention in capsule form and swallowed the capsules in the morning and in the evening. The allocation was blind to patients and research team staff and this was maintained throughout the trial.

Outcomes

The primary outcome measure was the raw total RSI score at 16 weeks after randomisation, which was collected at the first follow-up ENT outpatient visit. The RSI score is calculated from a nine-item, self-administered questionnaire scored on a Likert scale, with each item score ranging from 0 to 5, giving a total score range of 0–45. A higher score indicates more severe symptoms. Any missing component deems the total score missing. The nine-item RSI total score allows comparison with previous studies as it offers 10 years’ worth of comparative data in the literature. The RSI remains the ‘area standard’ and, despite well-rehearsed limitations, remained our chosen primary outcome. The treatment period of 16 weeks was selected on the basis of evidence that after 8 weeks there was very little further symptomatic improvement (as measured by RSI) in a validation sample of 40 patients. 50 A period of 8 weeks might, therefore, have seemed justified. However, owing to the fairly small and highly selected sample (all pH-metry positive) of this early report, we opted for a 16-week period in our definitive, larger study, with a view to maximising the impact and uptake of the TOPPITS findings. In other words, we chose this longer period so that we would not be open to criticism for having discontinued therapy too early.

Secondary outcome measures

• RSI changes at 12 months after randomisation.

• RSI score omitting item 9 (heartburn, chest pain, indigestion or stomach acid coming up), as the inclusion of dyspepsia symptoms has the potential to skew the results in favour of PPIs in past small trials.

• CReSS total subscales: oesophageal (14 items), upper airway (eight items) and pharyngeal (seven items).

• Quality of life: change in LPR-HRQL total score and subscales at 16 weeks and 12 months.

• Laryngeal mucosal changes recorded by RFS (total range 0–29), scored by an independent observer, outside any of the recruiting sites, who was blind to treatment group.

• The ability of RFS and patient characteristics (age, sex, smoking status and BMI) to predict any observed responses.

• Side effects, adverse events (AEs) and serious adverse events (SAEs).

• Use of over-the-counter medication.

• Patient-reported satisfaction with the trial using a five-point overall satisfaction scale. This asked if the patient was very dissatisfied, dissatisfied, neither dissatisfied nor satisfied, satisfied or very satisfied. Additional comments were invited.

• Patient accuracy in determining which treatment they had received.

Sample size

The primary outcome measure was the change in the RSI score between baseline and the 16-week assessment. A mean difference of 3 points in RSI score at 16 weeks was felt to be a clinically relevant target based on clinical and co-applicant experience and prior LPR therapy studies. A mean difference of 3.1 points, with an assumed SD of 7.754 equates to a standardised mean effect size of 0.4. Furthermore, a 0.4 effect size is of smaller magnitude than the effect of phonomicrosurgery or speech therapy. 55 A total of 332 patients (166 in each group of the study) were required, to provide 266 patients (133 in each group) completing the trial intervention, to detect a standardised mean effect size of 0.4 with 90% power and 5% significance level allowing for 20% loss to follow-up. A 20% loss to follow-up rate was believed to be a realistic estimate. NHS experience of the investigators in TOPPITS suggested that this was overly optimistic for a trial of this kind.

There were no planned formal interim analyses or stopping rules.

Statistical methods

Descriptive statistics are used to summarise patient characteristics, treatment compliance, RSI and other secondary measures at randomisation and 16 weeks. The descriptive analysis is based on presenting:

• Underlying distribution of RSI reported graphically (histograms with normal curve overlaid).

• RSI scores at baseline and 16 weeks summarised by randomised treatment group, and overall, using descriptive statistics. Means, SDs, medians, interquartile ranges (IQRs) and ranges are reported, as the score was treated as a continuous measure but is integer in nature.

• RSI scores inside versus outside the published normal range. The percentage of patients in and out of normal range. The upper limit of normal in the RSI is said to be 12 in the general population. 26

The primary outcome measure was RSI score after 16 weeks. An unadjusted univariate analysis of 16-week RSI is presented. The primary analysis is a multivariable analysis using analysis of covariance (ANCOVA) and multilevel mixed-effect linear regression to compare the RSI at 16 weeks while adjusting for potential confounders. Although ANCOVA is generally robust to departures from normality, transformation is investigated and, if applied, is retained in the analyses throughout. Primary analysis adjusts for effects of stratification factors at randomisation [centre, as a random effect in the regression modelling, and baseline severity (mild RSI-HB of ≤ 20, severe RSI-HB of > 20), as a fixed effect in the regression modelling].

Data were analysed using a statistical software package [Stata^® version 14 (StataCorp LP, College Station, TX, USA)]. The primary hypothesis tested was H₀: the mean RSI at 16 weeks in the lansoprazole group is equal to the mean RSI at 16 weeks in the placebo group after adjustment for baseline stratification factors. Secondary analyses of the primary outcome measure considered adjustment for important clinical and demographic baseline factors, specifically sex, age, BMI, smoking status, alcohol consumption, baseline laryngeal appearance scores using the RFS, CReSS total and subscales and categories of symptoms. Three models were derived:

• Model 1 – adjusted for stratification factors used at randomisation [recruiting centre (as a random effect) and baseline severity, as defined by the binary RSI-HB cut-off value of 20 (as a fixed effect)].

• Model 2 – adjusted for baseline severity with RSI-HB as a continuous measure.

• Model 3 – adjusted for baseline severity (RSI-HB as a continuous measure) and other important clinical and demographic baseline factors, specifically age, sex, smoking status and BMI.

Continuous covariates were investigated for non-linear relationships with outcome using first-order fractional polynomial transformations, which were used if they substantially improved model fit based on the Akaike information criterion (AIC). The optimal model was derived using a forward selection method with comparison of –2log-likelihood for variable inclusion. Analyses were conducted at a two-sided 5% level of significance throughout. The impact of removing any covariates from the final model was assessed in order to derive the most parsimonious model.

The analysis of secondary outcomes followed a broadly similar strategy for the questionnaire scores. Safety data were not subject to statistical comparison. Analyses were carried out on a complete-case basis. Missing data were described. The use of multiple imputation techniques was considered for the primary outcome and covariate data, should data be missing for patients completing the study to a sufficient extent (approximately > 10%) and deemed missing at random.

No formal interim analyses were planned. A statistical analysis plan was in place prior to any comparative analyses.

Definition of ‘compliant intention-to-treat group’

Primary statistical analyses were based on a compliant intention-to-treat (ITT) group. The DMC recommended that a distribution approach should be employed to determine a clinically relevant compliance window to maximise inclusion of patients and exclude only significant outliers. Thus, the compliant ITT group was defined, prior to comparative analyses and documented in the statistical analysis plan, as those with all ineligible and protocol violator patients included in the analysis in their randomised treatment group and attending their 16-week follow-up visit between 14 and 20 weeks. The distribution of time from randomisation to completion of the follow-up visits is reported graphically in Figure 1 (see also Appendix 1, Table 29).

FIGURE 1.

Histogram of time between randomisation and the 16-week follow-up visit in 283 patients.

Sensitivity analyses are based on a pragmatic ITT group, with all ineligible and protocol violator patients included in the analysis on an ITT basis with patients kept in their randomised treatment group. This includes outcome measures completed at any time point.

On this basis, the power achieved was as follows:

• compliant ITT group – 82% power based on a minimum of 102 (lansoprazole) and 118 (placebo) participants

• pragmatic ITT group – 89% power based on a minimum of 127 (lansoprazole) and 140 (placebo) participants.

The per-treatment analysis of safety data reports the AEs that are related to the treatment. All randomised patients who start treatment were included in the analysis according to the treatment they received.

Data management

A study-specific database was designed, built and tested using Elsevier’s MACRO Electronic Data Capture (InferMed, London, UK) electronic data collection system. MACRO uses a secure web-based interface for data entry; no data are stored on computers at the site. Data for individual patients were entered by each principal investigator, or his/her delegated nominee, into the electronic case report forms. Each MACRO user is assigned role-based permissions specific to their site and role. MACRO has an inbuilt back-up facility, through Elsevier’s hosting partner Rackspace’s (Rackspace Ltd, Hayes, UK) secure premises in London, which is managed and supported by the Rackspace team.

Data entry and quality were monitored regularly by the Trial Management Group and sites were encouraged to enter all data as soon as possible. Frequent checks were made for missing and contradictory data, as well as ensuring that the data entered into the randomisation system matched those in MACRO. Data queries were raised with the sites on an ongoing basis, as necessary.

Screening and recruitment

Screening and recruitment activity are summarised in Appendix 1, Tables 27 and 28.

The trial opened to recruitment on 28 April 2014, but owing to slower-than-expected recruitment a no-cost extension was obtained; hence, the trial closed to recruitment on 28 February 2017. The original target recruitment figure was 332; this was revised following DMC recommendation on 29 January 2016 to allow recruitment to continue to 28 February 2017, at which point the number recruited was 346. This ensured that the numbers of participants reaching the 4- and 12-month trial visits were sufficient to satisfy the trial protocol (version 5.0, January 2017).

Randomisation

A blocked allocation (permuted random blocks of variable length) system was used to allocate patients in a 1 : 1 ratio, stratified by centre and baseline severity (RSI-HB mild, ≤ 20; RSI-HB severe, > 20).

Balance was confirmed by stratification factors. See Appendix 1, Table 30, for stratification by baseline severity in terms of RSI-HB and stratification by site in Report Supplementary Material 1, Table 1. Appendix 1, Table 31, gives details of patients who were mis-stratified.

Four ineligible patients were reported (see Appendix 1, Table 32).

Withdrawals

There were 125 patients who were reported as withdrawals (including losses to follow-up) with specified dates. Two patients did not complete the trial but did not have a withdrawal date and two patients did not have trial completion status confirmed (i.e. no date for completion of or withdrawal from the trial). A summary of the timing of withdrawals from the trial, with respect to the primary end-point visit, is given in Appendix 1, Table 33. Descriptive statistics for time to withdrawal from randomisation are given in Appendix 1, Table 34.

Baseline data

Demographic baseline characteristics (Table 1) show the two treatment groups to be balanced. The age and sex statistics are consistent with the population of participants with chronic throat symptoms.

Scrutiny of Table 2 confirms that the compliant ITT group is a representative subsample of the total trial population.

Data quality

Data were received for analysis from:

• MACRO – the trial data

• the NCTU randomisation service – randomisation data including details of stratification (Microsoft Excel^®, Microsoft Corporation, Redmond, WA, USA)

• RFS assessment – from an independent reviewer, validated by NCTU (using Microsoft Excel) (see Appendix 3, Table 41, for the RFS scoring scheme).

Data sets were merged according to the unique identifier allocated at randomisation.

Treatment received

The analysis set is the per-treatment analysis group defined in the statistical methods. Inclusion in the per-treatment set was based on capsule return at the 16-week primary end point. In total, 265 out of 346 participants (77%) had information on returned medication (including returned empty packaging for those who took the full course). Three patients did not take any trial medication and were removed from the per-treatment analysis group.

In total, 262 out of 346 trial participants (76%) are assumed to have taken at least one capsule of their trial medication and are included in the per-treatment analysis group [126 out of 172 (73%) in the lansoprazole group; 136 out of 174 (78%) in the placebo group]. Further details of dose taken are given in Appendix 2, Table 38.

Outcomes and estimation of treatment effects

Primary outcome measure

Compliance was assessed in relation to the time frame of 14–20 weeks post randomisation. The distribution of time from randomisation to the primary end-point 16-week follow-up visits (visit 2) is reported graphically in Figure 3. The graph shows how much time has elapsed since randomisation to the 16-week follow-up visit for all patients who attended the visit (n = 283). The dashed lines show patients included in the compliant ITT group (n = 220). Further information on compliance is given in Appendix 1, Tables 29 and 35. See Appendix 2, Tables 39 and 40, for details of individual RSI items.

FIGURE 3.

Histogram of time between randomisation and the primary end-point 16-week follow-up visit (overall). The dashed lines show patients included in the compliant ITT group (n = 220).

Reflux Symptom Index score at baseline for the compliant analysis group (n = 220)

The means (SDs) are reported with medians, IQRs and ranges as the (total) RSI score is treated as a continuous measure but is integer in nature (Table 5).

TABLE 5 - Primary outcome measure: RSI at baseline (visit 1) (compliant ITT group)

Baseline RSI	Treatment group		Total (N = 220)
	Lansoprazole (n = 102)	Placebo (n = 118)
Median (IQR)	20.5 (15–28)	21.5 (16–27)	21 (15.5–27)
Mean (SD)	22.0 (8.0)	21.7 (7.1)	21.9 (7.5)
95% CI of mean	20.4 to 23.6	20.5 to 23.0	20.9 to 22.9
Range	10–41	10–43	10–43

The summary statistics show that the randomised groups are similar at baseline.

The underlying distribution of the RSI at baseline visits is reported graphically in Figure 4 in the form of a histogram with both groups combined (n = 220) and normal curve overlaid.

FIGURE 4.

Underlying distribution of RSI at baseline (compliant ITT group).

Reflux Symptom Index score at 16 weeks (primary end point) for the compliant analysis group

Figure 5 and Table 6 show the underlying distribution and summary statistics of the RSI score at the primary end point of 16 weeks for the 220 patients in the compliant ITT group.

FIGURE 5.

Underlying distribution of RSI at the primary end-point visit (compliant ITT group).

TABLE 6 - Primary outcome measure: total RSI at the 16-week follow-up (visit 2) (compliant ITT group)

RSI at 16 weeks	Treatment group		Total (N = 220)
	Lansoprazole (n = 102)	Placebo (n = 118)
Median (IQR)	16 (9–26)	14 (7–23)	15 (9–24.5)
Mean (SD)	17.4 (9.9)	15.6 (9.8)	16.4 (9.9)
95% CI of mean	15.5 to 19.4	13.8 to 17.3	15.1 to 17.7
Range	0–41	0–44	0–44

A higher RSI score indicates more severe symptoms. RSI reduced overall from a median score of 21 at baseline to a median score of 15 at 16 weeks. RSI reduced overall from a mean score of 21.9 (SD 7.5) at baseline to a mean score of 16.4 (SD 9.9) at 16 weeks. The reduction in RSI is observed in both randomised treatment groups. The lansoprazole group has a mean 16-week score 1.8 points higher than that of the placebo group [17.4 (95% CI 15.5 to 19.4) vs. 15.6 (95% CI 13.8 to 17.3)], with overlapping CIs, indicating no statistical difference between the groups.

The primary outcome data for the compliant ITT group are presented graphically in Figure 6.

FIGURE 6.

Box plots showing medians, IQRs and overall ranges of RSI score at baseline and primary end-point visit (compliant ITT group). (a) Lansoprazole group (n = 102); and (b) placebo group (n = 118).

Univariate analysis of unadjusted primary outcome measure for the compliant analysis group

The underlying distribution of the primary outcome measure (see Figure 5) appears sufficiently normally distributed (overall mean = 16.4, median = 15) for parametric analysis of the primary outcome. The primary hypothesis to be tested is H₀: the mean RSI scores at the primary end point (16-week visit) are equal for both groups (lansoprazole vs. placebo). A two-sided significance level of p < 0.05 is used throughout. The null hypothesis is no difference between means for PPI (17.4, 95% CI 15.5 to 19.4) versus placebo (15.6, 95% CI 13.8 to 17.3). The test statistic was t = 1.402 and the two-sided p-value was 0.162, leading to the conclusion that there was no statistically significant difference in the RSI score at 16 weeks between lansoprazole and placebo.

Table 7 and Figure 7 show the change in RSI score (change RSI = 16-week RSI – baseline RSI) to the primary end-of-treatment end point.

TABLE 7 - Change in RSI (0 to 16 weeks) (compliant ITT group)

Change in RSI scores (baseline to 16 weeks)	Treatment group		Total (N = 220)
	Lansoprazole (n = 102)	Placebo (n = 118)
Median (IQR)	–4 (–10 to 1)	–5 (–13 to 1)	–5 (–11 to 1)
Mean (SD)	–4.6 (8.0)	–6.2 (9.0)	–5.4 (8.6)
95% CI of mean	–6.2 to –3.0	–7.8 to –4.5	–6.6 to –4.3
Range	–31 to 19	–29 to 11	–31 to 19

FIGURE 7.

Box plots showing medians, IQRs and overall ranges for change in RSI score from baseline to the 16-week follow-up (compliant ITT group). (a) Lansoprazole group (n = 102); and (b) placebo group (n = 118).

The overall mean reduction in RSI score from baseline to 16 weeks is 5.4, which is observed across both randomised groups: lansoprazole group, 4.6-point reduction; placebo group, 6.2-point reduction (with overlapping CIs indicating no statistical difference between the groups). The lansoprazole group had a mean reduction of 1.6 points less than the mean reduction observed in the placebo group.

Multivariable analysis of primary outcome for the compliant intention-to-treat analysis group

The primary outcome measure was RSI score after 16 weeks and was initially analysed using ANCOVA methods in order to compare the 16-week RSI scores between the treatment groups while adjusting for potential confounders, as specified in the protocol (Table 8). Although ANCOVA was generally robust to departures from normality, normality was assumed (see Figure 5).

There did not appear to be a statistically significant difference in RSI at 16 weeks between randomised treatment groups (p = 0.106). In ANCOVA, site is not a reliable estimate as the algorithm deals with the location numerals as if they were quantitative data. Site is more properly modelled as a random effect in a multilevel model.

Statistical modelling of the primary outcome

A multilevel mixed-effect linear regression was used to model the primary outcome measure – 16-week RSI – on a complete-case basis. Three models were developed as specified in Statistical methods (see Table 12 for a summary of the model results for both the compliant and the pragmatic ITT populations).

Model 1

Model 1 adjusted for stratification factors used at randomisation as covariates in the analysis: (1) recruiting centre (as a random effect) and (2) binary baseline severity as defined by the binary RSI-HB cut-off value of 20 (as a fixed effect) (Table 9).

TABLE 9 - Results of multilevel mixed-effect linear regression (model 1), adjusted for stratification factors used at randomisation (site and baseline severity) (compliant ITT group) (n = 220)

SE, standard error.

Log-likelihood = –782.084; Wald chi-squared test = 76.78; p-value > χ² < 0.001.

Model	Type	Beta	SE	Test statistic	p-value	95% CI (beta)
Group: lansoprazole (reference = placebo)	Fixed	1.929	1.160	1.66	0.096	–0.345 to 4.203
Site (reference = Birmingham)
Brighton	Random	–6.010	4.727	–1.27	0.204	–15.275 to 3.254
Glasgow		–0.973	3.478	–0.28	0.780	–7.789 to 5.843
Manchester		5.123	3.576	1.43	0.152	–1.886 to 12.131
Newcastle		–1.871	3.047	–0.61	0.539	–7.843 to 4.101
Nottingham		–5.937	3.028	–1.96	0.050	–11.871 to –0.003
Stockport		–3.701	4.025	–0.92	0.358	–11.590 to 4.188
Sunderland		–3.385	3.216	–1.05	0.293	–9.689 to 2.919
RSI-HB baseline severity: severe (reference = mild)	Fixed	8.173	1.181	6.92	< 0.001	5.858 to 10.489
Constant		14.349	3.044	4.71	< 0.001	8.383 to 20.315

Modelling site as a random effect demonstrates no impact of site on RSI score at 16 weeks, as anticipated, and demonstrates the advantage of modelling these data more appropriately.

Binary RSI-HB at baseline is confirmed as being statistically significantly, related to 16-week RSI and justified as a stratification factor in the trial design. Patients in the severe severity stratum at baseline are estimated to have a RSI score that is 8 points higher (worse) at 16 weeks.

There is no statistically significant difference between randomised groups [lansoprazole compared with placebo (p = 0.096)] when adjusted for site and baseline binary RSI-HB. The difference between randomised groups, when accounting for site and baseline severity, indicates that lansoprazole patients are estimated to have RSI scores at 16 weeks that are 1.9 points higher (worse) than the scores of placebo patients (95% CI –0.3 to 4.2; p = 0.096).

Random errors are assumed to produce residuals that are normally distributed, as is the case for model 1, in which the residuals fall in a symmetrical pattern and have a constant spread throughout the range (Figures 8 and 9).

FIGURE 8.

Scatterplot of residuals for model 1 (both groups combined, n = 220) (compliant ITT group).

FIGURE 9.

Histogram of residuals for model 1 (both groups combined, n = 220) (compliant ITT group).

Further information on model 1 at 12 months, for the compliant ITT group, is given in Appendix 7, Table 53, and similarly for model 2 in Appendix 7, Table 54.

Model 2

Model 2 adjusted for the stratification factor recruiting centre (as a random effect) at randomisation and baseline severity in terms of RSI-HB as a continuous measure (as a fixed effect).

The continuous covariate (RSI-HB) was explored to assess whether or not transformation of RSI-HB was a better fit to the relationship with outcome than an untransformed continuous measure based on a reduction in AIC. There was no reduction in AIC, so to build the most parsimonious, clinically interpretable model, RSI-HB was retained as an untransformed continuous covariate, under the assumption of linearity with outcome (Table 10).

TABLE 10 - Results of multilevel mixed-effect linear regression (model 2), adjusted for the stratification factor site used at randomisation and continuous baseline severity (compliant ITT group) (n = 220)

SE, standard error.

Log-likelihood = –768.621; Wald chi-squared test = 115.42; p-value > χ² < 0.001.

Model	Type	Beta	SE	Test statistic	p-value	95% CI (beta)
Group: lansoprazole (reference = placebo)	Fixed	1.410	1.091	1.29	0.196	–0.728 to 3.549
Site (reference = Birmingham)
Brighton	Random	–1.300	4.493	–0.29	0.772	–10.106 to 7.506
Glasgow		–1.694	3.252	–0.52	0.602	–8.067 to 4.679
Manchester		3.003	3.359	0.89	0.371	–3.579 to 9.586
Newcastle		–2.785	2.840	–0.98	0.327	–8.351 to 2.781
Nottingham		–5.664	2.847	–1.99	0.047	–11.243 to –0.084
Stockport		–3.085	3.783	–0.82	0.415	–10.499 to 4.329
Sunderland		–2.759	3.027	–0.91	0.362	–8.693 to 3.174
RSI-HB continuous baseline severity	Fixed	0.721	0.079	9.10	< 0.001	0.566 to 0.877
Constant		4.320	3.274	1.32	0.187	–2.098 to 10.738

The log-likelihood statistics show that continuous baseline severity substantially improves the model fit (reduction in –2log-likelihood) compared with model 1, which included severity as a binary stratification factor.

A 1-unit increase in baseline severity is associated with a 0.7-unit increase (95% CI 0.6 to 0.9) in 16-week RSI.

There is no statistically significant difference between randomised groups [lansoprazole compared with placebo (p = 0.196)] when adjusted for site and baseline continuous RSI-HB. The estimated difference between randomised groups, when accounting for site and baseline severity, indicates that patients receiving lansoprazole are estimated to have RSI scores at 16 weeks that are 1.4 points higher (worse) than the scores of placebo patients (95% CI –0.7 to 3.5; p = 0.196).

Residual plots demonstrate the underlying assumptions of the model to not be substantially violated (Figures 10 and 11).

FIGURE 10.

Scatterplot of residuals for model 2 (both groups combined, n = 220) (compliant ITT group).

FIGURE 11.

Histogram of residuals for model 2 (both groups combined, n = 220) (compliant ITT group).

Model 3

Model 3 adjusted for baseline severity (RSI-HB as a continuous measure) and the baseline factors age, sex, smoking status (binary), alcohol consumption (binary) and BMI. Non-linear continuous covariates were explored but continuous covariates were retained as untransformed (Table 11).

TABLE 11 - Univariate relationships including transformed continuous covariates

SE, standard error.

Covariate	n	AIC	Beta	SE	Test statistic	p-value
BMI
Continuous	220	1634.002	0.017	0.110	0.15	0.878
Log-transformed		1634.017
Complex transformation (BMI–2)		1633.240
Age
Continuous	220	1633.977	–0.011	0.051	–0.22	0.826
Log-transformed		1633.791
Complex transformation (age–2)		1629.129
Smoking (binary)	219	1626.368	1.547	1.520	1.02	0.310
Sex (binary – male/female)	220	1632.896	1.423	1.343	1.06	0.291
Alcohol consumption (binary)	217	1611.289	–1.761	1.483	–1.19	0.236

As none of the potential covariates appears to have a significant univariate relationship with the RSI score at the primary end point, model 2 remains optimum.

Secondary analysis of the primary outcome measure using derived Reflux Symptom Index minus the heartburn/dyspepsia item

A secondary analysis of the primary outcome based on the reduced RSI score (derived from eight items excluding item 9, the dyspepsia and heartburn component – RSI-HB) was planned and undertaken. RSI-HB, scored out of 40, was calculated and analysed as was the primary outcome measure (complete nine-item RSI).

Means, SDs, medians, IQRs and ranges for RSI-HB are reported as the score is treated as a continuous measure but is integer in nature. The summary statistics show that the randomised groups are similar at baseline (Table 13).

A higher RSI score indicates more severe symptoms. RSI-HB reduced overall from a median of 19 at baseline to a median of 13 at 16 weeks. RSI-HB reduced overall from a mean score of 20.0 (SD 7.0) at baseline to a mean score of 15.0 (SD 9.2) at 16 weeks (Table 14 and Figure 12). The reduction in RSI-HB is observed in both randomised treatment groups. The lansoprazole group has a mean 16-week score that is 2.4 points higher than the score for the placebo group [16.3 (95% CI 14.5 to 18.1) vs. 13.9 (95% CI 12.2 to 15.5), respectively], with overlapping CIs indicating no statistical difference between the groups. The null hypothesis was that there was no difference between the means. The test statistic was t = 1.945 and the two-sided p-value was 0.0530.

FIGURE 12.

Box plots showing medians, IQRs and overall ranges of the RSI-HB score at baseline and 16-week follow-up (compliant ITT group). (a) Lansoprazole group (n = 102); and (b) placebo group (n = 118).

There is no statistically significant difference in the RSI-HB score at 16 weeks between the lansoprazole and placebo groups.

Change in Reflux Symptom Index minus the heartburn/dyspepsia item score from baseline to 16 weeks for the compliant intention-to-treat group

Table 15 and Figure 13 show the change in RSI-HB score (change RSI-HB = 16 weeks’ RSI-HB – baseline RSI-HB). The reduction in RSI-HB score from baseline to 16 weeks is similar between randomised groups.

TABLE 15 - Change in RSI-HB (compliant ITT group)

Change in RSI-HB scores (baseline to 16 weeks)	Treatment group		Total (N = 220)
	Lansoprazole (n = 102)	Placebo (n = 118)
Median (IQR)	–3 (–9 to 1)	–5.5 (–12 to 0)	–4.5 (–10 to 0.5)
Mean (SD)	–4.0 (7.6)	–5.9 (8.4)	–5.0 (8.1)
95% CI of mean	–5.5 to –2.5	–7.4 to –4.4	–6.1 to –3.9
Range	–31 to 17	–27 to 12	–31 to 17

FIGURE 13.

Box plots showing medians, IQRs and overall ranges of change in RSI-HB score from baseline to the 16-week follow-up (compliant ITT group). (a) Lansoprazole group (n = 102); and (b) placebo group (n = 118).

The overall mean reduction in RSI-HB score from baseline to 16 weeks is 5.0 (95% CI –6.1 to –3.9), a reduction that is observed across both randomised groups [lansoprazole, 4.0-point reduction (95% CI –5.5 to –2.5); placebo, 5.9-point reduction (95% CI –7.4 to –4.4)], with overlapping CIs indicating no statistical difference between the groups. The lansoprazole group had a mean reduction that is 1.9 points less than the mean reduction observed in the placebo group (see Figure 13).

Multivariate analysis and statistical modelling of the RSI-HB for the compliant group are given in Appendix 4. Appendix 4, Table 42, presents ANCOVA results, Table 43 presents the results of model 1 (adjusted for stratification factors) and Table 44 presents the results of model 2 (adjusted for stratification factor recruiting centre and for baseline severity in terms of RSI-HB as a continuous measure).

A sensitivity analysis based on the pragmatic ITT group including all patients with their 16-week primary end-point visit taking place at any time did not change the conclusions (see Appendix 6). Appendix 6, Table 51, shows summary statistics for RSI-HB for the pragmatic ITT group at baseline and the primary end point. In Appendix 7, Table 53, RSI-HB at baseline is confirmed as being statistically significantly related to 12-month RSI. Patients with greater severity at baseline are estimated to have RSI scores that are 8.2 points higher (worse) at 12 months.

Secondary outcome measures

Reflux Symptom Index at the 12-month follow-up for the compliant intention-to-treat group

The 12-month RSI scores were secondary outcome measures, both the complete nine-item RSI and the reduced eight-item RSI-HB. These 12-month scores were assessed descriptively in unadjusted models and in multivariable models adjusted by stratification factors (Table 16).

TABLE 16 - Descriptive analysis of RSI scores at 12 months (compliant ITT group)

RSI at 12 months	RSI 12-month follow-up (visit 3)
	Treatment group		Total
	Lansoprazole	Placebo
n	82	99	181
Median (IQR)	15 (6–24)	12 (6–19)	13 (6–21)
Mean (SD)	16.0 (10.8)	13.6 (9.6)	14.7 (10.2)
95% CI of mean	13.6 to 18.4	11.7 to 15.5	13.2 to 16.2
Range	0–43	0–41	0–43

The longitudinal changes in total RSI are summarised in Table 17 and Figure 14. Values show some further reduction in the post-treatment 8-month follow-up phase.

TABLE 17 - Median, IQR and range at baseline, 16 weeks and 12 months and the associated median differences (compliant ITT group)

Green shading denotes the descriptive statistics for the change from baseline to follow-up points.

RSI score	Time point						Change
	Baseline		16 weeks		12 months		Baseline to 16 weeks		Baseline to 12 months
	Lansoprazole group	Placebo group	Lansoprazole group	Placebo group	Lansoprazole group	Placebo group	Lansoprazole group	Placebo group	Lansoprazole group	Placebo group
n	102	118	102	118	82	99	102	118	82	99
Median (IQR)	20.5 (15 to 28)	21.5 (16 to 27)	16 (9 to 26)	14 (7 to 23)	15 (6 to 24)	12 (6 to 19)	–4 (–10 to 1)	–5 (–13 to 1)	–6 (–13 to 0)	–8 (–14 to –3)
Range	10 to 41	10 to 43	0 to 41	0 to 44	0 to 43	0 to 41	–31 to 19	–29 to 11	–34 to 15	–27 to 22

FIGURE 14.

Box plots showing medians, IQRs and overall ranges of RSI score at baseline, 16 weeks and 12 months (compliant ITT group). (a) Lansoprazole group (n = 82); and (b) placebo group (n = 99).

Mean RSI reduces in both groups at 16 weeks and further reduces at 12 months.

Univariate analysis RSI scores were reported at 12 months for the compliant ITT group, in which the null hypothesis is of no difference between means. The test statistic was t = 1.583 and the two-sided p-value was 0.115, concluding that there is no statistically significant difference in the RSI score at 12 months between the lansoprazole and placebo groups.

Multivariable analysis of Reflux Symptom Index at 12 months for the compliant intention-to-treat group

Note that ANCOVA for RSI at 12 months (see Appendix 7) showed no statistically significant difference in RSI at 12 months between randomised treatment groups (p = 0.256), but site and baseline severity remain significantly related to 12-month RSI. Age and sex also appear to be significantly related to 12-month RSI when all are included in the ANCOVA analysis. The statistical modelling of the 12-month RSI for the compliant ITT group is also included in Appendix 7 and was conducted similarly to the prior modelling exercises.

The difference between randomised groups, when accounting for site and binary baseline severity, indicates that lansoprazole participants are estimated to have RSI scores at 12 months that are 2.5 points higher (worse) than those of placebo participants (95% CI –0.1 to 5.0; p = 0.06).

The underlying assumptions of the model were not substantially violated. As none of the potential covariates appears to have a significant univariate relationship with the 12-month RSI score, model 2 with continuous baseline severity (RSI-HB) and site remains the optimum. There was no statistically significant difference between the lansoprazole group and the placebo group when adjusted for site and baseline continuous RSI-HB. There is an estimated difference that lansoprazole participants have RSI scores at 12 months that are 1.7 points higher (worse) than those of placebo participants (95% CI –0.7 to 4.1 points; p = 0.157). Further information is given in Appendix 7, Table 54.

Reflux Finding Score for the compliant intention-to-treat group

The RFS was independently scored by a single expert rater (PC) who was blind to patient treatment group. Images were scored (Table 18) from 0 to 26 and assessed as a potential predictor of RSI at 16 weeks. There were a total of 256 RFSs for unique participants (see Appendix 3), of which 167 were for participants in the compliant ITT group.

Reflux Finding Score at baseline for the compliant intention-to-treat group

The means, SDs, medians, IQRs and ranges are reported as the score is treated as a continuous measure but is integer in nature (see Table 18).

A higher RFS indicates more severe laryngeal inflammation. Overall, RFS at baseline is, on average, 9.4 points (95% CI 8.8 to 10.0 points). The summary statistics show the number and value of RFSs to be similar in both treatment groups at baseline. Usable RFS assessments were available for 76% of participants in the compliant ITT analysis group.

The utility of the Reflux Finding Score as a response predictor for the compliant intention-to-treat group

The use of both first-order fractional polynomial transformations and a fourth model of primary outcome baseline RFS failed to find any significant relationship of baseline RFS with the RSI score at the primary end point (see Appendix 8).

Comprehensive Reflux Symptom Score

Baseline itemised severity score: Comprehensive Reflux Symptom Score

The item descriptive statistics for CReSS are listed in Report Supplementary Material 1, Table 12, for the whole trial population and in Report Supplementary Material 1, Table 13, for the compliant group.

The top five CReSS items, for both the trial population and the compliant group, in ranked mean endorsement severity were:

1. throat clearing

2. feeling things stuck in throat

3. lump in throat

4. excess mucus

5. hoarseness.

The relationship between the RSI at baseline and total CReSS at baseline for the compliant ITT group is shown in Figure 15, which demonstrates a linear relationship (i.e. an increased CReSS is associated with increased RSI score). (It should be remembered that the RSI symptom items were all purposively included in the CReSS and so the two are not independent of each other.)

FIGURE 15.

Scatterplot of the relationship between the total CReSS and RSI at baseline (compliant ITT group, n = 215).

Laryngopharyngeal Reflux – Health Related Quality of Life questionnaire

Patient quality of life was assessed using the LPR-HRQL. Higher scores indicate worse LPR quality of life. The total LPR-HRQL score and subscales at baseline and 16-week and 12-month follow-ups are presented for the compliant ITT population. Missing item rules dictate that three questionnaires with missing items can be imputed [two at baseline and one at the primary end point (16 weeks)].

Plots of laryngopharyngeal reflux health-related quality of life

Plots of LPR-HRQL (subscales and corresponding thermometer scores) are shown in Report Supplementary Material 1, Figures 1–8. Report Supplementary Material 1, Figures 9–18, shows the LPR-HRQL domain score graphs at baseline, 16 weeks and 12 months.

Overall subscale values are shown in Figure 16.

FIGURE 16.

The LPR-HRQL overall subscale scores aggregated at visits, by treatment group. (a) Lansoprazole group; and (b) placebo group.

The overall score is calculated by adding the thermometer scores [voice (question 13), coughing (question 20), clear throat (question 27) and general (question 33)] and the remaining domain scores (questions 34–43).

The mean voice, coughing, clear throat, general subscale scores and overall scores were relatively low at baseline and had reduced by 16 weeks in both groups, with further reduction at the 12-month visits. The same patterns are also reflected in the median thermometers, when a score of 3 or 4 indicates a small effect and scores of 2 and 1 indicate minimal to no effect on quality of life.

Each of the remaining domain scores used to calculate the overall score is also presented individually at baseline and 16-week and 12-month follow-up visits in Report Supplementary Material 1, Figures 9–18.

There is only a small effect on overall quality of life relating to individual domain scores.

The IQRs of the domain scores generally decrease from baseline levels by 16 weeks in both treatment groups.

None of the baseline median LPR-HRQL domain scores reflects a large impact of symptoms on the individual domains and the small reductions (improvements) by 16 weeks are similar across treatment groups.

Summary of Reflux Symptom Index, total Comprehensive Reflux Symptom Score and Laryngopharyngeal Reflux – Health Related Quality of Life scores for the compliant group at all three time points

Table 23 provides a summary of total RSI, CReSS and LPR-HRQL scores at three time points.

Patient satisfaction with TOPPITS

At the 12-month follow-up (visit 3), 213 out of 346 (62%) participants answered the satisfaction question, of whom 115 (54%) were very satisfied, 59 (28%) were satisfied, 29 (14%) were neither satisfied nor dissatisfied, five (2%) were dissatisfied and five (2%) were very dissatisfied.

Safety

Information was gathered on AEs at all three TOPPITS clinic visits. We recorded any untoward medical occurrence in a patient to whom a medicinal product had been administered, including occurrences that were not necessarily caused by or related to that product. In the protocol,1 it was stated that causality would be graded on a five-point scale [unrelated, unlikely, possible, probable and definitely related to the investigational medicinal product (IMP)]. MACRO was set up for data collection on a three-point scale (not related, possibly related and probably related). A file note was added to the trial master file detailing this change from the protocol.

Adverse event causality was reported on the three-point scale available from MACRO. The numbers of patients reporting any AE are reported, clarifying those deemed to be treatment related. SAEs and occurrence of suspected unexpected serious adverse reactions are also recorded by group. The clinical side effects of PPI use include gastrointestinal disturbance and rebound hypersecretion after cessation of PPI therapy. Rarer side effects include pneumonia, C. difficile infections, acute renal inflammation and fractures of the hip, wrist and spine.

Terminology

Persistent throat symptoms include chronic throat clearing, hoarse voice (dysphonia), sensation of a lump in the throat (globus) and increased mucus sensation (catarrh). The symptoms most commonly experienced by the TOPPITS participants were, in order of frequency, as recorded by the RSI severity endorsement [see Report Supplementary Material 1, Tables 16 (whole population) and 17 (compliant group)]:

1. lump in the throat

2. throat clearing

3. excess mucus

4. troublesome cough

5. hoarseness.

Similar frequencies were, not surprisingly, seen with CReSS:

1. throat clearing

2. feeling things stuck in throat

3. lump in throat

4. excess mucus

5. hoarseness.

Laryngopharyngeal reflux was promoted as an umbrella term in the mid-1990s and has since grown in popularity despite ongoing debate regarding pathophysiology, diagnosis and treatment. We aimed to quantify shifts in medical terminology for throat symptoms over time. Search terms included ‘throat clearing’, ‘reflux laryngitis’, ‘acid laryngitis’, ‘globus pharyngeus’, ‘globus sensation’, ‘globus hystericus’, ‘catarrh’ or ‘laryngopharyngeal reflux’ in the title or abstract. The total number of publications per decade was derived along with subtotals for clinical research and reviews. Catarrh (n = 473) and the various terms for globus (n = 468) featured prominently for the decades 1960s to 1980s, with fewer instances of acid/reflux laryngitis (n = 96). The 209 references to throat clearing date from 1980 (numerically the commonest symptom in most detailed surveys). There has been an exponential rise in LPR from the 1990s (n = 810), although fewer than one in five reports were classed as a ‘clinical study’. The predilection for LPR is no doubt supported by the fact that > 50% of the US general population has heartburn. 56 The use of anticholinergic medications, especially in combination, increases the odds of experiencing globus by a factor of 3.52. 57 An investigation of the frequency of throat clearing and cough and how often each is associated with a positive symptom index for reflux found a low probability of objective association. This is even less likely if both symptoms are present or if patients report an ‘excessive’ cough. 58

The premise for TOPPITS was that without a robust UK trial we saw nothing to question the increasing popularity of acid suppression medications as a prime therapy for upper respiratory symptoms. If all putative LPR patients referred to otolaryngologists were treated with PPIs, the costs are estimated at £4M per annum. Although the link between LPR and upper respiratory symptoms is little more than speculative or intuitive when close enquiry of the evidence base is made, the level of acceptance in primary care is also increasing. Many patients seen by non-TOPPITS otolaryngologists at participating centres might have considered TOPPITS had they not already had substantial trials of PPIs in primary care and thus never even reached the screening clinic.

There is no agreed, standard, core patient self-report outcome even for lower oesophageal reflux; the only COMET website reference to reflux is to a workshop that concluded that members strongly supported the development of validated patient-reported outcome instruments. This lack of a pre-eminent outcome tool led us to develop the CReSS. 59 The CReSS covers all oesophageal and extraesophageal reflux symptoms by incorporating all items from the original Gastrointestinal Symptom Assessment Score,60 together with all components of the RSI. CReSS totals are independent of age, and all items were endorsed by ≥ 17% of throat symptom patients. 61

The inexorable rise in popularity of LPR as the default term for persistent throat symptoms appears to have fuelled huge popularity for PPI therapy despite a lack of evidence. Attempts to reverse this trend, in view of recent adverse PPI publicity, will be supported by the overall negative finding of the TOPPITS data. Globus pharyngeus was described as a ‘tainted term’ in a recent opinion article due to its connotation of ‘globus hystericus’. 62 The authors propose that a feeling of having a lump in the throat on dry swallow is a normal sensation, accentuated by circumstances. Their proposed contemporary term is ‘troublesome Throat Awareness’ (tTA). However, this idiosyncratic acronym, although functionally useful, will not readily supplant the classical term.

Recent reports on epidemiology of persistent throat symptoms

The 1982 ENT outpatient globus prevalence figure of 4.2%3 has fallen little in the ensuing decades, being 3.8% in a recent report. 63 Despite its name, there is little evidence linking the symptom items of the RSI with any demonstrable oesophagopharyngeal reflux. Indeed, the very first attempt – almost 30 years ago – to treat a similar list of symptoms with H₂ antagonists yielded a negative result. 19 The RSI has nonetheless been used to assess ‘LPR’ in a number of recent studies. A population prevalence study approached 2000 UK-dwelling adults, who were sent the RSI and questions on their health and lifestyle. The mean RSI was 8.3; 30% had a RSI score of > 10, of whom 75% had symptoms of GORD. Patients with depression and irritable bowel syndrome were more likely to have higher RSI scores. In other words, in this population survey, correlates of the RSI questionnaire score appear to be gastroesophageal reflux, depression and irritable bowel syndrome. 30 In the general Greek population, the prevalence of ‘LPR’ was 18.8%, similar in both sexes (p > 0.05), with a peak age of 50–64 years and with a positive association with tobacco smoking and alcohol consumption. 64 A total of 3006 individuals surveyed in Guangdong Province, China,65 completed questionnaires about their physical and psychological characteristics and globus symptomatology, and our own, physician-generated Glasgow Edinburgh Throat Scale66 with questionnaires on quality of sleep and life. In this survey, those with no history of GORD, dysphagia, odynophagia or alerting symptoms, such as weight loss and hoarseness, were diagnosed as having globus. The overall lifetime prevalence of globus so defined was 21.5%, with a peak age at disease onset of 35–54 years, commoner in urban dwellers and with no sex bias. Anxiety (40%), depression (31%) and sleep disorders (24%) in respondents with globus were significantly commoner than in those without globus. 65 A more informal enquiry made by our group many years ago in a high street survey of UK shoppers indicated a (within the last 3 months) female population prevalence of globus in 6% of those questioned. 2

Perception of reflux causation of persistent throat symptoms in general practice

The risk of overattribution of throat symptoms to so-called LPR has been recognised in the specialist ENT literature for some time. A retrospective chart review analysis identified 105 patients in a private laryngology clinic setting with a previous diagnosis of LPR as the cause of hoarseness. After anti-reflux therapy, 82% had no improvement or felt worse, leading the authors to conclude that LPR was overdiagnosed, especially when no other explanation was readily apparent. 67 A similar reliance on a putative LPR diagnosis in the absence of clear evidence has filtered into the wider, non-ENT, medical community. A US web-based survey of 314 (13%) doctors (46% family practitioners) showed that 64% preferred to treat rather than immediately refer a patient with chronic (> 6 weeks’) unexplained hoarseness, most often with anti-reflux medication (86%), even in the absence of GORD symptoms and antihistamines (54%). 68 Pre-treatment appears to significantly delay diagnosis. A retrospective case review of 755 patients referred to a voice service in Kansas City69 reported that 244 patients (32%) received a diagnosis before attending, this being LPR in over half, and, of those, > 65% had no GORD symptoms. Over 80% of diagnoses changed following attendance at the voice clinic and so those with prior treatment had a median duration of symptoms that was 6 weeks longer than those without (p = 0.04). 69

Similar trends seem to prevail in the UK. Although only 27% of TOPPITS recruits had taken PPIs in the preceding 12 months (see Appendix 2, Table 36), many others who had previously had this treatment were understandably reluctant either to discontinue it simply to enter a RCT of the same medication or to return to it when it had previously failed, and so the figure of 27% under-represents the general laryngology referral population usage of PPIs.

Misuse of PPIs is also documented internationally in a wider context. Only 34% of Swiss GPs are reported to attempt dose reduction in long-term users. 70 An Italian primary care study found that almost 15% of a sample of over 6300 patients were taking PPIs – over 30% potentially inappropriately. 71 A Canadian study of over 870 patients presenting to the emergency department of a teaching hospital also found PPI prescription to be inappropriate in > 30% of participants. 72 An observational study of the patients admitted to an acute hospital in Ireland in February 201873 identified that almost half of the sample of 1764 patients were regular PPI users. Almost 55% had no documented indication. Polypharmacy in the elderly gave particular cause for concern. 73 Pre-admission and discharge prescriptions were reviewed in a tertiary teaching hospital in Singapore to determine continuation of pre-admission and new PPI prescriptions at discharge. 74 Of 150 patients, 53% received prescriptions for PPIs, of whom > 80% had no valid reason. 74

What does TOPPITS tell us about the impact of proton pump inhibitor treatment on throat symptoms?

The key messages from the trial are:

• There was no statistically significant difference between randomised groups, lansoprazole compared with placebo, when adjusted for site and baseline binary RSI-HB. This difference indicates that lansoprazole patients are estimated to have RSI scores at 16 weeks that are 1.9 points higher (worse) than placebo patients (95% CI –0.3 to 4.2; p = 0.096) (see Table 9).

• There is no statistically significant difference in the mean RSI score at 16 weeks between lansoprazole (17.4, 95% CI 15.5 to 19.4) and placebo (15.6, 95% CI 13.8 to 17.3) (p = 0.162). (See the t-test results in Chapter 3, Univariate analysis of unadjusted primary outcome measure for the compliant analysis group.)

• At 16 weeks, 43% of participants had RSI scores within the normal range, with no significant difference between the lansoprazole (41%) and placebo (45%) groups (see Report Supplementary Material 1, Table 15).

• Patient demographics39,75 were explored as potential baseline determinants of treatment response but age, sex, smoking status, alcohol consumption and BMI did not improve the RSI 16-week prediction (model 3; see Table 11).

• At 12 months, there is a further minor drop in RSI scores (see Table 17 and box plots in Figure 14).

• Baseline RFS does not predict PPI response (see Appendix 8, Table 56).

TOPPITS is a considerably larger trial than the majority of series included in recent meta-analyses. Pre TOPPITS, a trial in 146 selected patients, all with signs of posterior laryngitis,22 showed no symptom benefit from PPI therapy over placebo, but did not report RSI scores. Lee et al. 76 noted less marked PPI responses in older patients (to a lower-dose PPI regimen than was used in TOPPITS). However, this may have reflected the fact that the oldest cohort had the highest baseline RSI levels and/or that the authors used a dichotomous definition of response (i.e. a 50% drop in RSI) rather than a continuous variable assessment. Baseline severity was a major determinant of end-point severity in TOPPITS.

Awareness of treatment group by patients

We were interested to explore patient perception of their treatment group as there was a concern that those with more severe heartburn might recognise a prompt heartburn response as implying that they were in the PPI group. However, the awareness (true-positive opinion) of group was broadly equal in the cohorts (see Table 4). Of the PPI cohort, 42% correctly called their allocation, compared with 56% of placebo participants.

The recent TOPPITS context

The premise for TOPPITS was that, without a robust UK trial, we saw nothing to stop the increasing ‘belief’ in LPR as a prime cause of upper respiratory symptoms, as the theory was supported by prominent laryngological enthusiasts, some respiratory medicine experts and, of course, the pharmaceutical industry. If all putative LPR patients referred to otolaryngologists were treated with PPI, we would calculate the costs to be approximately £4M per annum. Although the link between LPR and upper respiratory symptoms is little more than speculative or intuitive when close enquiry of the evidence base is made, the level of acceptance in primary care is also increasing. Many patients seen by non-TOPPITS otolaryngologists at participating centres might have considered TOPPITS had they not already had substantial trials of PPI in primary care and thus never even reached the screening clinic.

A 2016 review52 of the evidence linking reflux and voice changes concluded that the association lacked supporting data from clinical trials. The authors describe using the Bradford Hill criteria to support their conclusion that ‘the evidence toward causality between reflux and voice is insufficient’. 52 Tantalisingly, however, the authors conclude by saying that a relationship ‘does exist which deserves careful consideration’ – despite having concluded that:

To date, neither clinical trials nor comparative observational studies have been able to demonstrate a strong dose response between reflux and voice disorders, temporality (reflux precedes dysphonia), consistent treatment effects or strength of association between anti-reflux treatment and improved voice among patients with presumed LPR.

Schneider et al. 52

Three meta-analyses have been reported since TOPPITS was designed. A 2014 meta-analysis of eight papers comprising 370 patients found no statistical difference in effect between PPIs and placebo. 77 Separate assessment of the impact on cough was also not statistically significant. 77 This result was in disagreement with two meta-analyses published in 2016. 78,79 Both of these reports include a subset of studies with RSI as primary outcome. Wei78 examined pooled relative risks for the response rate and standardised mean differences (SMDs) for RSI and RFS. Of 13 RCTs, five reported RSI (total n = 277, ranging from only 37 to 8215 participants per study). Pooled results are reported to demonstrate that the total RSI improved significantly more for PPI therapy than for placebo (SMD 3.65, 95% CI 1.56 to 5.75), although no significant difference was found in response rate (0.04, 95% CI –0.06 to 0.14) or RFS (SMD 0.91, 95% CI –0.53 to 2.35). Scrutiny of the tabulated and forest plot findings, however, indicates that, of the five trials in the RSI analysis, three favour PPI, but with highly significant heterogeneity (i.e. variability in results across studies), questioning the pooling of the data in the first place. The smallest mean difference in RSI was 0.26. The greatest SMD total RSI score (14.21 in 60 patients) is reported in Chinese with an English-language abstract. However, this was not a study comparing PPIs with placebo but of ‘golden voice capsule’ plus or minus PPI. 80 This study was omitted when Guo et al. 79 carried out a similar RSI meta-analysis on the remaining four studies (total n = 217). Despite dropping the outlying ineligible study, there remained highly significant heterogeneity (p < 0.00001), and the SMD had fallen to 1.65 (95% CI 0.15 to 3.14).

Reichel et al. 81 carried out a RCT of PPI in patients with throat symptoms, although the citation in Wei’s78 bibliography is of their publication of 49 patients on the lack of correlation between the symptom change after PPI with measurable 24-hour pH monitoring change. The actual RCT carried out by this group had RSI as the principal outcome in 58 patients. 28 (Moreover, the reference numbering in the table of all 13 included studies is awry78). However, the representation of Reichel et al. ’s81 data in the appropriate paper is accurate. Reichel et al. 81 included only patients with a RFS of > 7 and their sample showed a RSI SMD of 3.85 at 3 months. The TOPPITS median RFS was 9 at baseline (IQR 7–12) (see Table 18) (i.e. a majority of patients would meet Reichel et al. ’s81 qualifying criterion). The end of treatment mean change from baseline in the total RSI was 14.3 in the esomeprazole group, which was statistically greater than in the placebo group (7.8, SMD 3.85). 28 The authors note the marked placebo response, which was indeed greater than that in either group of the much larger TOPPITS cohort at 4 months (mean change from baseline in all patients = 5.3).

Other authors have considered whether or not oropharyngeal pH monitoring (Restech, Respiratory Technology Corporation, Houston, TX, USA) may predict PPI response. RSI, laryngoscopy and 24-hour oropharyngeal pH monitoring were undertaken in 22 patients who were given a 3-month course of 40 mg of pantoprazole twice a day. 82 A symptom response was defined as a 5-point fall in the RSI score. Laryngoscopic findings did not correlate with response and only nine patients (40.9%) had abnormal pH-metry, all being responders. Four pH-metry negative patient were also responders. Thus, oropharyngeal pH monitoring showed a sensitivity of 69% and a specificity of 100%. 82 In another report of 24-hour multichannel intraluminal oesophageal impedance/pH-metry, GORD was confirmed in < 40% of patients previously labelled as having LPR, which the authors attribute to ‘the low specificity of the laryngoscopic findings’. 83

Optimal administration of PPI usually takes place 30 minutes before food; > 30% of patients are suboptimal users. 84 (Esomeprazole seems not to lose efficacy when administered after meals. 85) Fifty-one patients with throat symptoms completed a face-to-face semistructured interview, a questionnaire and the RSI. Over 62% of participants described an incorrect routine in taking their PPI (taking it with other pills, taking it with food/drink and uncertainty about which pill is for reflux), although this did not have an impact on the RSI. RSI scores were moderately correlated with patient-reported reflux severity (r = 0.62, p < 0.0001, R² = 0.34). Even when PPI compliance was adequate, symptoms such as globus, mucus, voice dysfunction and dysphagia persisted. In addition to the dubious effect size of PPI therapy, there are now also increasing concerns about the safety of PPIs.

Proton pump inhibitor risk

The US veterans study86 of the impact of PPI use on all-cause mortality in almost 350,000 individuals found that, over a median follow-up of 5.71 years, PPI use was associated with an increased risk of death compared with the use of H₂ antagonist blockers [hazard ratio (HR) 1.25]. The risk of death was increased when considering PPI use versus no PPI and no H₂ blockers (HR 1.23). Among new PPI users, there was a graded association between the duration of exposure and the risk of death. The authors concluded that limiting PPI use and duration to instances when it is medically indicated may be warranted. 86 A systematic review of PPIs and cardiovascular events analysed five studies that directly compared the effect of PPI use on mortality and/or cardiovascular morbidity (including 22,427 patients in mortality data sets and 354,446 patients in morbidity data sets). For patients taking PPIs, all-cause mortality [odds ratio (OR) 1.68] and rate of major cardiovascular events (OR 1.54) were significantly higher, indicating a significant increase in morbidity due to cardiovascular disease. 87 Long-term PPI use has also been linked to acute interstitial nephritis, fractures, and C. difficile-associated diarrhoea, suggesting a need for cautious prescribing and regular monitoring, especially in older adults. 88

Gastric cancer risk with PPIs was assessed in over 63,000 individuals in Hong Kong who were given clarithromycin-based triple therapy for Helicobacter pylori. 89 During a median follow-up of 7.6 years, 153 people (0.24%) developed gastric cancer (HR 2.44); this was not observed with those taking H₂ antagonists (HR 0.72). The risk increased with duration of PPI use: the HR was 5.04 at 1 year and 8.34 after 3 years. The adjusted absolute risk difference for PPI use versus non-PPI use was a 4.29-fold excess of gastric cancer per 10,000 person-years. 89 Similar conclusions were reached in a contemporaneous meta-analysis of almost 1 million individuals in west China. 90

Using data from Danish nationwide registries and Cox models regressing for both propensity scores and drug use, a Danish group91 explored the current practice of using PPIs as an adjunctive therapy in cancer patients. Cancer-specific and non-cancer death among PPI users (two or fewer prescriptions within 6 months after diagnosis, n = 36,066) were compared with non-users (fewer than two prescriptions, n = 311,853) or users of histamine H₂-receptor antagonists (n = 5152). Adjusted HRs for cancer-specific mortality among postdiagnostic PPI users as compared with non-users or H₂-receptor antagonist users were 1.29 and 1.15, respectively, and the risk was greatest for ovarian cancer. Although the associations were stronger among new PPI users after cancer diagnosis, indicating potential confounding, and the impact of PPIs on mouse tumour models was variable, the authors raise concerns about PPI safety among cancer patients. 91

Alginate/alkaline water

The alginate preparation Gaviscon Advance [Reckitt Benckiser Healthcare (UK) Ltd] was assessed alone versus co-prescription with a PPI in an open-label study of ‘100 consecutive LPR patients’ with a RSI of > 10 attending a joint voice clinic. 92 All were treated with Gaviscon Advance four times daily. If patients had already been started on a PPI, this was optimised to a twice-daily dosing regimen. Follow-up RSI scores in 72 patients showed no significant RSI differences from the additional use of PPI.

At the cellular level, tissue-bound pepsin is fundamental to reflux pathophysiology. Human pepsin remains stable at a pH level of 7.4 and may be reactivated by hydrogen ions from any source. Most tap and bottled waters (typically with pH levels of 6.7–7.4) would not be expected to affect pepsin stability. Artesian well water containing natural bicarbonate (pH level of 8.8) irreversibly inactivated human pepsin (in vitro). In addition, it has good acid-buffering capacity. Thus, the consumption of alkaline water may have therapeutic benefits for reflux patients. 93 In vitro tests of the proprietary alginate Gaviscon Advance show that it can specifically remove both pepsin and bile acids, limit their diffusion and affect enzymatic activity of pepsin, hence the potential for oesophageal protection. 94 Gaviscon Advance, it should be noted, relies principally on its alginate raft and not on an acid-buffering capacity.

The Comprehensive Reflux Symptom Score

The advantages of CReSS include standardised, comprehensive capture of patient experience; discriminant validity of ENT and GORD patients from volunteers; and discrete oesophageal, pharyngeal and upper airway subscales. 31 The CReSS and RSI are correlated (see Figure 15) as they are not independent, the CReSS incorporating all RSI symptoms. However, the addition of the CReSS upper airway domain to RSI-HB improved the ability to predict RSI at 16 weeks (see Appendix 9, Table 62).

The Reflux Finding Score is unreliable

We felt that it was important to include a report on the endolaryngeal examination findings as scored by the RFS because of its common use in clinical practice. This is despite limited evidence to suggest that laryngeal mucosal changes – increased ‘Reflux Finding’ Scores – discriminate between ‘normals’ and general throat symptom patients. 95 Furthermore, the RFS has not been proven to be a valid tool to diagnose LPR. 17,51–53 In our study, the RFS was independently scored 0–26 and assessed as a potential response predictor (alongside patient characteristics of age, sex, smoking status and BMI), comparing it with the RSI at 16 weeks. The number and value of RFSs were similar in both treatment groups at baseline. Adjusted for important baseline factors and RFS baseline assessment, the RFS was not suitable for first-order fractional polynomial transformations and not considered for inclusion in the multivariable model. Thus, the total RFS was not subsequently considered as a predictive factor of treatment response. Several authors have suggested that one feature in the RFS – presence of pseudosulcus – is the best predictor of EOR,96,97 but this level of individual items analysis was not possible. Pseudosulcus has been reported generally as a rare finding. 97 Others have found that RFS raters are influenced by patient symptoms and so the reliability and objectivity of the RFS is questionable. 98 The RFS is also insensitive to postfundoplication symptomatic benefit. 99

In a selected series of 78 patients with chronic cough and/or suspected vocal cord dysfunction,100 87% had a RSI score of > 13 and 51% had a RFS of > 7. Salivary pepsin had a sensitivity of 78% and specificity of 53% for predicting a high RFS. There were significant correlations between the RSI and RFS (r = 0.51) and between the severity of laryngeal inflammation and the concentration of pepsin (r = 0.28). All cases investigated with pH-impedance study had objective evidence of proximal reflux. 100 However, these findings in selected patients do not mirror observations in the generality of those presenting to clinics with non-specific throat symptoms, who are the focus of TOPPITS.

Update on pH-metry and manometry in throat symptoms

Up to 50% of the patients suspected of reflux laryngitis syndrome fail to respond to acid suppression therapy. This has led to measurement of acid exposure times in an attempt to improve the specificity of the diagnosis. Using distal and cervical oesophageal pH-metry in 46 ‘LPR’ patients and 58 healthy control patients, the percentage of time that the pH level is < 4 and the number of LPR episodes emerged as diagnostic LPR criteria. 101 Up to 50% of the patients suspected of reflux laryngitis syndrome fail to respond to acid suppression therapy. Laryngopharyngeal bolus exposure time during multichannel intraluminal impedance and pH (MII-pH) testing was the best response predictor in one study. 102 Of 109 patients evaluated by MII-pH, 47% were classed as ‘positive’ for evidence of significant LPR, with an average of 46 episodes of proximal reflux exposure (either acid or non-acid). RSI scores were significantly different between positive and negative studies, whereas RFSs were not. 103

High-resolution manometry metrics in 24 globus patients were compared with 24 age-matched and sex-matched subjects with non-obstructive dysphagia and 21 healthy control patients. 104 In a multivariate model, receiver operating characteristic analysis identified a threshold of 0.4-mmHg upper oesophageal sphincter (UOS) residual pressure in globus patients (sensitivity 66.7%, specificity 71.5%, positive predictive value 55.2%, negative predictive value 80.0%). 104 Those globus patients who also have GORD may also have a longer UOS zone. 105 Repeated reactive dry swallowing and/or throat clearing might contribute to these observations, which may have a historical correlate in the so-called ‘inferior constrictor strain swallow’ described by Gray. 106

There is recent interest in ambulatory 24-hour oropharyngeal aerosol acid exposure assessment, which was used in 101 patients with GORD symptoms and cough, hoarseness, asthma symptoms or globus sensation alongside concomitant oesophageal pH monitoring. Oesophageal 24-hour pH-metry was positive in 66 patients (65%), of whom 39% also had evidence of aerosol oropharyngeal acid. Only eight of those with normal oesophageal pH-metry had oropharyngeal acid exposure. 107 Our own prior work shows that aspiration of bile acids may induce airway fibrosis through the production of transforming growth factor beta 1 and fibroblast proliferation. Early intervention to attenuate these processes may reduce fibrogenesis in various airway diseases associated with GORD. 108

Throat symptom patient-reported outcome tools

Three patient-reported outcome measures were utilised in TOPPITS. The RSI was considered the ‘market-leader’ in terms of popularity and its seemingly ubiquitous association with ‘LPR’. There was concern from the research team that the ninth questionnaire item groups four traditional GORD symptoms (heartburn, indigestion, chest pain and stomach acid coming up). It was hypothesised that this item could lead to overall PPI treatment response reporting given that these symptoms are commonly treated with PPIs, hence the rationale to refine the RSI into a score including and excluding this item for the purposes of baseline stratification. The CReSS questionnaire unbundles this item into distinct questions and has additional items cited as important by patients. The CReSS was included to assess whether or not the more comprehensive symptom profiling would allow greater sensitivity to change than the RSI does. In a study of the quality-of-life impact of throat symptoms in 80 patients, females experienced a greater impact on vitality and mental health than males did. 109 A South Korean study explored the added impact of throat symptoms (RSI) on quality of life in 300 GORD patients. Those with supra-oesophageal symptoms had lower quality-of-life scores proportional to the symptom severity. 110 The LPR-HRQL was included in recognition of the lack of quality-of-life measures or published outcomes in the field of chronic throat symptoms.

All three outcome measures show significant improvement in both the treatment group and the placebo group from baseline to 16 weeks and from baseline to 12 months. The ninth RSI item did not affect treatment reporting between the two groups, as was considered by the research team. The quality-of-life measure (LPR-HRQL) also demonstrated proportionate reductions at 16 weeks and 12 months. This again proves the significant throat symptom placebo effect (Reichel et al. 28). Presumably, both the experience of being in a trial and the additional clinical team contact contributed to the pharmacological component of the placebo response. Evidence suggests that a substantial proportion of patients with unexplained throat symptoms are susceptible to additional, unrelated medically unexplained symptoms. This would accord with the magnitude of the placebo effect in TOPPITS. 23 A person’s locus of control is either internal (believes to personally control his or her life) or external (believes to be controlled by others, by environmental factors that cannot be influenced or by chance). An external locus of control has been found to be related to higher placebo response. 111 Contrary to expectation, somatisation in a primary care study was found not to correlate with locus of control,112 and this whole territory in throat symptoms warrants further investment. Although antidepressants modulate oesophageal sensation and reduce functional chest pain,113 throat symptom patients regularly discontinue therapy. 114

Psychological aspects

In a study of US Vietnam War veterans,115 the prevalence of globus was 6.4%. Those men with globus had increased risks of being diagnosed with somatisation disorder, major depression, generalised anxiety disorder, post-traumatic stress disorder and drug abuse or dependence (OR 1.89), giving rise to the hypothesis that men may develop globus to ‘represent’ other, related and treatable psychopathology. 115 More widely, evidence suggests that a substantial proportion of patients with unexplained throat symptoms are susceptible to additional, unrelated medically unexplained symptoms. The propensity to multiple unexplained physical symptoms can be quantified by completion of a Review Of Symptoms or similar checklist. 116

In a recent therapy trial, 148 refractory globus patients were randomised to receive 6 weeks of paroxetine, amitriptyline or lansoprazole. Response (> 50% reduction on the Glasgow Edinburgh Throat Scale) was achieved by 72% of paroxetine users, 46% of those on amitriptyline and only 14% of the lansoprazole group. 117 In our own early study, 24 globus patients were assessed for current and past psychiatric illness and then received amitriptyline or placebo using a double-blind design. Nine patients met the criteria for psychiatric disorder in the past; six had suffered from panic disorder. Two further patients had been troubled by classic panic attacks. Nine of the 12 patients treated with amitriptyline and two of the placebo group discontinued treatment. Thus, the association of pathological anxiety with globus was associated with a high incidence of tricyclic antidepressant treatment failure. 114 Antidepressants modulate oesophageal sensation and reduce functional chest pain113 but more research is required on their potential in throat symptoms.

Psychophysiological mechanisms

Recent work from China118,119 suggested that serotonin transporter gene (SLC6A4) polymorphism may be associated with both globus pharyngeus and its antidepressant action. Globus patients were randomised into paroxetine or amitriptyline groups for 6 weeks. Treatment response was defined as a > 50% reduction in the Glasgow Edinburgh Throat Scale scores. A significant association between the genotype and the response to antidepressant treatment was observed. 118,119 A recent study of UOS and oesophageal body sensitivity and compliance between globus patients and healthy control patients found that somatisation, panic disorder and post-traumatic stress severity were significantly associated with globus. UOS compliance and somatisation were also found to be independently associated with globus, implying that globus is a complex disorder of the brain–gut axis rather than a ‘psychosomatic’ disorder or a peripheral oesophageal disorder. 120 Transnasal oesophagoscopy, high-resolution manometry and 24-hour MII-pH monitoring were conducted on 30 globus referrals in Helsinki. 121 There was no evidence of acid or non-acid GORD or elevated UOS pressure. 121

Potential methods to address the limitations encountered in TOPPITS patient and public involvement

The patient and public involvement strand of TOPPITS was drawn up with high hopes, and nurtured by the ongoing efforts of our qualitative researcher, Jan Lecouturier, yet proved relentlessly disappointing. The following proposals might have, on refection, mitigated the low patient and public involvement input:

• Enhanced budget to fund a team member to attend clinics alongside the research nurses to explore reasons for non-engagement.

• Much of the allocated patient and public involvement budget went towards developing the website.

• Enhanced sampling strategy seeking participation – targeting TOPPITS pilot study patients was not productive; we might have approached those who declined TOPPITS or patients with other throat problems.

• Enhanced buy-in from the site staff (i.e. research staff there lead on developing the materials?). Would this have raised the profile of the patient and public involvement and/or resulted in greater commitment?

Health-care implications

TOPPITS is a robust clinical trial that confirms the findings of other work (which found no evidence to support PPI treatment benefit in cohort studies of those with persistent throat symptoms). De-prescribing, defined as lowering dosage, switching to as-needed use or complete discontinuation, should be considered for many PPI users. 88 Current NHS guidance for the management of persistent throat symptoms is lacking. The TOPPITS outcome stands to contribute to future throat symptom guidance, particularly given the current popularity for primary PPI treatment. The TOPPITS results provide evidence that patients and clinicians need to consider in making shared decisions about PPI use for persistent throat symptoms.

This is important as the substantial gamut of adverse consequences of PPI treatment is only now becoming apparent. A reversal of the terminology trend towards LPR as the terminology of choice for persistent throat symptoms is also worthy of consideration. 122

Pursuit of alternative treatments

Other pathways/future work

Primary care offers unique insights into an individual’s history of multiple prior somatisation episodes; however, the rarity of laryngoscopic facilities in primary care distorts the management pathway for persistent throat symptoms. There is reassurance from adequate explanation of the vicious behavioural cycles that can perpetuate throat symptoms (dry swallow, throat clearing), together with an indication to patients of the common occurrence of their problems. All are preferable to universal PPI prescription for undiagnosed throat symptoms.

When there are atypical features, early referral for laryngopharyngoscopy may be unavoidable. Secondary care offers a more straightforward locus for research owing to the concentration of patients seen in every general ENT clinic. Psychological approaches may be offered by speech therapists or as primary therapy or pharmacological interventions in their own right. Cognitive–behavioural therapy could feasibly be part of a package for treating functional dysphonia,25,127–129 but the efficacy of cognitive–behavioural therapy in dysphonia and globus remains to be addressed in a substantive trial. The placebo phenomenon111 might also usefully be exploited by the use of traditional voice care measures: hydration, steam and honey. More work is needed on the role of antidepressants. 113,114,117,118,130 Speech therapy delivered by specialist practitioners can be a primary globus therapy,131 but needs to be explored in a wider range of practitioners.

Contributions of authors

Professor Janet A Wilson (https://orcid.org/0000-0002-6416-5870) was the chief investigator and designed and developed the trial protocol. She oversaw the running of the trial, the data analysis and the preparation of the final report and subsequent outputs.

Professor Deborah D Stocken (https://orcid.org/0000-0001-8031-1738) was the senior clinical trials statistician and contributed to the design, analysis, interpretation and reporting of the trial.

Miss Gillian C Watson (https://orcid.org/0000-0003-2466-0268) managed the trial on a day-to-day basis and contributed substantially to the preparation of the final report.

Mr Tony Fouweather (https://orcid.org/0000-0002-2292-0495) was the clinical trials statistician and contributed to the design and analysis of the trial and the presentation of data for this paper.

Mr Julian McGlashan (https://orcid.org/0000-0001-6716-6089) was the principal investigator at the Nottingham site and contributed to the trial design, interpretation and dissemination.

Mr Kenneth MacKenzie (https://orcid.org/0000-0002-2952-7717) was the principal investigator at the Glasgow site and contributed to the design, interpretation and dissemination of the trial.

Professor Paul Carding (https://orcid.org/0000-0002-4206-1827) provided the blinded assessment of baseline digital images and contributed to the design, interpretation and dissemination of the trial.

Mr Yakubu Karagama (https://orcid.org/0000-0002-6257-905X) was the principal investigator at the Manchester site and contributed to the design, interpretation and dissemination of the trial.

Mr Meredydd Harries (https://orcid.org/0000-0002-3026-5662) was the principal investigator at the Brighton site and contributed to data interpretation.

Dr Stephen Ball (https://orcid.org/0000-0002-5804-4466) was the principal investigator at the Sunderland site and contributed to data interpretation.

Ms Sadie Khwaja (https://orcid.org/0000-0001-7129-8789) was the principal investigator at the Stockport site and contributed to data interpretation.

Mr Declan Costello (https://orcid.org/0000-0001-6063-3211) was the principal investigator at the Birmingham site and contributed to data interpretation.

Ms Ruth Wood (https://orcid.org/0000-0002-8296-1774) designed and managed the database.

Dr Jan Lecouturier (https://orcid.org/0000-0002-5191-5804) advised on the patient and public involvement aspects of the trial.

Dr James O’Hara (https://orcid.org/0000-0002-4096-3296) assisted in the design and development of the protocol and was, for a time, the principal investigator at the Sunderland site.

Publications

Watson G, O’Hara J, Carding P, Lecouturier J, Stocken D, Fouweather T, Wilson J. TOPPITS: Trial of Proton Pump Inhibitors in Throat Symptoms. Study protocol for a randomised controlled trial. Trials 2016;17:175–83.

O’Hara J, Stocken DD, Watson GC, Fouweather T, McGlashan J, MacKenzie K, et al. Use of proton pump inhibitors to treat persistent throat symptoms: multicentre, double blind, randomised, placebo controlled trial. BMJ 2021;372:m4903.

Data-sharing statement

Anonymised data from this study may be available to the scientific community subject to regulatory and ethics approval. Requests for data should be directed to the corresponding author.

Patient data

This work uses data provided by patients and collected by the NHS as part of their care and support. Using patient data is vital to improve health and care for everyone. There is huge potential to make better use of information from people’s patient records, to understand more about disease, develop new treatments, monitor safety, and plan NHS services. Patient data should be kept safe and secure, to protect everyone’s privacy, and it’s important that there are safeguards to make sure that it is stored and used responsibly. Everyone should be able to find out about how patient data are used. #datasaveslives You can find out more about the background to this citation here: https://understandingpatientdata.org.uk/data-citation.

Disclaimers

This report presents independent research funded by the National Institute for Health Research (NIHR). The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Health and Social Care. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Health and Social Care.

Numbers analysed

Those participants included in each of the analysis sets are summarised in Table 28.

The stratified subgroups are summarised in Table 29. Table 29 shows the balance over treatment groups in terms of the baseline severity measured by RSI-HB, with a cut-off score of 20.

During the course of the trial, during analysis of recruitment data for DMC meetings, it was discovered that some patients were mis-stratified in terms of baseline severity, defined by their RSI-HB scores. This affected approximately 10% of patients, as outlined in Table 30.

Ineligible patients

Despite treatment withdrawal, patients were followed up in the trial whenever possible. All primary statistical analyses were carried out on an ITT basis, retaining patients in their randomised treatment groups and including protocol-violator and ineligible patients. Ineligible patients were classed as those randomised patients who were subsequently found not to have adhered to the eligibility criteria of the trial. Four ineligible patients were reported (Table 31).

A sensitivity analysis was not carried out as the ineligibility rate was not excessive (1%).

Withdrawals

In Table 32, the frequency column shows the number fitting the visit status in relation to the primary end point. The compliant column shows those with a primary outcome measure within the compliance window, as specified in Chapter 2, Statistical methods. The pragmatic column shows those with a primary outcome measure at any time, as specified in statistical methods section.

It is seen that 267 patients provided the primary outcome measure (RSI at visit 2), of whom 220 were compliant within 14–20 weeks of randomisation. In total, 125 participants withdrew/were lost to follow-up over the duration of the trial. Sixty of these provided the primary outcome measure. Of 60 withdrawals providing the primary outcome, 43 were compliant within 14–20 weeks of randomisation. The timing of loss or withdrawal is shown in Table 33.

Missing data in the primary outcome

The RSI data points that were missing are summarised in Table 34.

Per-treatment analysis

Concomitant medication

Some form of antacid medication was taken by five participants out of the total cohort at baseline (four in the lansoprazole group). At the end of therapy, six of the lansoprazole group and seven of the placebo group were taking antacid remedies of one sort or another. This had changed to 30 and 25, respectively, at 12 months – a notable rise bearing in mind the smaller total sample at this later time point.

Reflux Finding Score scoring schema and data recording

The RFS total values range between 0 and 26, including items for different subsites of the larynx, indicating level of abnormality. An outline of these areas and the range of scores for each item are shown in Table 40. 37 The ranking for each subsite is seen to be inconsistent. Some items have dichotomous scoring, others a 5-point score. The maximum score per feature is not uniform.

Not all laryngeal images were rated using the RFS. Some images were unusable owing to poor quality, particularly from one of the sites where equipment was of a lower grade. In the early stages of the trial, there was a problem with matching the TOPPITS trial identifier to patients’ names and this created potential transcription errors before independent assessment. This issue was addressed in the early phase of the trial. Any rating with uncertainty of the identified subject was excluded from the analysis of the trial. Some images were submitted to the secure server twice and were consequently rated twice. When there were two ratings and confidence in the identified trial number, the chronologically first rating was used throughout.

In all, 363 assessments had both a validated identifier and a RFS. Of these, 107 were duplicates, leaving 256 unique identifiable RFS assessments.

In summary, the patient identifier attributable to a small number of images was not certain. There were also some unusable images owing to poor image quality, particularly from one of the sites where equipment was of a lower grade.

Analysis of covariance for secondary analysis Reflux Symptom Index minus the heartburn/dyspepsia item: compliant intention-to-treat group

The outcome measure RSI-HB score after 16 weeks was initially analysed using ANCOVA methods in order to compare the 16-week RSI-HB scores between the treatment groups while adjusting for potential confounders. The ANCOVA results are shown in Table 41.

Adjusted for the effects of site and baseline severity, there is evidence of statistically significant difference in RSI-HB at 16 weeks between randomised treatment groups (p = 0.026) but not in favour of active intervention. There is evidence of dependence on baseline severity (p < 0.001). The randomised treatment group is not statistically significant when adjusted for other baseline factors. ANCOVA adjusted for stratification variables and other important baseline factors of RSI-HB for the compliant ITT group showed that the average RSI-HB score at 16 weeks in the lansoprazole and placebo groups remained no different once taking into account age, sex, smoking status, alcohol consumption and BMI.

Modelling was then undertaken as with the total RSI score.

Pragmatic intention-to-treat group

The pragmatic analysis group comprises those participants completing the primary outcome visit at any time point after randomisation. All 283 participants had second visits, of whom 267 (94%) had usable RSI data. Of these, 135 (48%) were in the lansoprazole group and 148 (52%) were in the placebo group. All total RSI scores were in the range of 0–44, with 40% falling within the RSI population reference range (0–12), balanced across randomised groups. The means and SDs are reported (Table 46), with medians, IQRs and ranges, as the RSI score is treated as a continuous measure but is integer in nature.

The RSI appears to have reduced from a median of 21 at baseline to a median of 15 at 16 weeks in both randomised groups. The underlying RSI distribution appeared to be sufficiently normally distributed (overall mean 16.5, median 15) for parametric analysis of the primary outcome (H₀ = mean RSI scores at 16 weeks are equal for both groups; two-tailed p < 0.05).

The test statistic t = 1.020 and p = 0.1544, concluding that there is no statistically significant difference in the RSI score at 16 weeks between lansoprazole and placebo. As predicted, therefore, the reduction in RSI score from baseline to the primary end point was similar across the randomised groups (mean –4.6 in lansoprazole, –5.9 in placebo).

Multivariable analysis of the pragmatic intention-to-treat group

The RSI score after 16 weeks was initially analysed using ANCOVA methods in order to compare the 16-week RSI scores between the treatment groups while adjusting for the effects of the stratification factors at randomisation: recruitment centre and baseline severity (mild: RSI-HB ≤ 20, severe: RSI-HB > 20) (Table 47). The null hypothesis of equality, p = 0.05, applied throughout.

A further ANCOVA analysis considered age, sex, smoking status, alcohol consumption and BMI.

The hypothesis to be tested is H₀: the average RSI scores at 16 weeks are equal for both groups (lansoprazole vs. placebo) with adjustment for baseline stratification variables and also other clinical and demographic baseline factors. A two-sided significance level of p < 0.05 is used throughout. Age and BMI were sufficiently normal to include as untransformed data. Alcohol consumption and smoking status had excessive zero scores, thus skewed to the left and so binary alcohol and smoking variables were created with response ‘yes’ or ‘no’ (Table 48).

Per-protocol population

During the DMC closed session held on 9 March 2018, the DMC discussed the different analysis groups. The chairperson felt that a sensitivity analysis including only patients who complied with the protocol (16 weeks ± 2 weeks) could be useful to support the primary analysis. The numbers available for this analysis are 178 out of 346 (51% of the trial population), with 82 out of 172 (48%) in the lansoprazole treatment group and 96 out of 174 (55%) in the placebo group.

The summary statistics showed the randomised groups to be similar at baseline and for the RSI score to reduce similarly in both randomised groups at 16 weeks (the primary outcome) (Table 49).

Overall, 47% of participants were within the normal range at the primary end point for the per-protocol population, balanced across randomised treatment groups. Proceeding to the previously employed multivariate strategies, the conclusion is not affected: site and baseline severity remain significantly related to 16-week RSI. Adjusted for the effects of stratification variables and other baseline factors, there was no statistically significant difference in 16-week RSI between randomised treatment groups (p = 0.586).

Model 1

Model 1 adjusted for stratification factors used at randomisation [recruiting centre (as a random effect) and binary baseline severity as defined by the binary RSI-HB cut-off value of 20 (as a fixed effect)] as covariates in the analysis (Table 52).

There is no statistically significant difference between randomised groups, lansoprazole compared with placebo, when adjusted for site and baseline binary RSI-HB. The difference between randomised groups, when accounting for site and binary baseline severity, indicates that lansoprazole patients are estimated to have RSI scores at 12 months that are 2.5 points higher (worse) than those of placebo patients (95% CI –0.1 to 5.0; p = 0.06). The underlying assumptions of the model were not substantially violated.

Model 2

Model 2 adjusted for the stratification factor recruiting centre (as a random effect) at randomisation and for baseline severity in terms of RSI-HB as a continuous measure (as a fixed effect) (Table 53).

A 1-unit increase in baseline severity of RSI-HB is associated with a 0.7-unit increase in 12-month RSI score (95% CI 0.6 to 0.9). There is no statistically significant difference between randomised groups, lansoprazole compared with placebo, when adjusted for site and baseline continuous RSI-HB. The difference between randomised groups, when accounting for site and baseline severity, indicates that lansoprazole patients are estimated to have RSI scores at 12 months that are 1.7 points higher (worse) than those of placebo patients (95% CI –0.7 to 4.1; p = 0.157). The underlying assumptions of the model were not substantially violated.

Model 3

Model 3 adjusted for baseline severity (RSI-HB as a continuous measure) and other important clinical and demographic baseline factors, specifically age, sex, smoking status, alcohol consumption and BMI (Table 54).

The reduction in AIC through simple log or complex (fractional polynomial) transformation was not substantial and continuous covariates were therefore retained as untransformed. As none of the potential covariates appears to have a significant univariate relationship with the 12-month RSI score, model 2 with continuous baseline severity (RSI-HB) and site remains the optimum model.

Relationship of Comprehensive Reflux Symptom Score and Reflux Symptom Index (primary outcome)

Simple log and fractional polynomial transformations were considered for CReSS total and subscale scores to investigate better fit than under the assumption of linearity with RSI at 16 weeks (see Table 57), when the best-fitting transformation is selected based on a reduction in AIC. The reduction in AIC through simple log or complex (fractional polynomial) transformations was not substantial. In order to build the most parsimonious, clinically interpretable model, the CReSS total and subscale scores were retained as untransformed continuous covariates, under the assumption of linearity with outcome.

Comprehensive Reflux Symptom Score univariate analysis

The univariate analysis is based on fitting a univariate model of each baseline CReSS domain score as a potential predictor of RSI at 16 weeks (Table 59).

Baseline CReSS total and subscales appear to be significant predictors of the primary outcome (RSI) at 16 weeks. All increases in CReSS domain scores result in an increase in RSI. A 1-unit increase in (1) baseline CReSS total results in a 0.18-unit increase in RSI at 16 weeks, (2) baseline CReSS oesophageal subscale results in a 0.23-unit increase, (3) baseline CReSS upper airway subscale results in a 0.50-unit increase and (4) baseline CReSS pharyngeal results in a 0.49-unit increase. It appears that baseline RSI-HB remains the single most important predictor of the primary outcome – a 1-unit increase results in a 0.75-unit increase in 16-week RSI.

Comprehensive Reflux Symptom Score multivariable analysis

Table 60 summarises each of the baseline CReSS domains’ individual significance (presented with RSI-HB) when included individually in a multivariable model for RSI at 16 weeks, adjusted by site and baseline RSI-HB.

Baseline CReSS total and subscales, with the exception of the pharyngeal subscale, are significant predictors of RSI at 16 weeks, independent of and in addition to RSI-HB. A 1-unit increase in all baseline CReSS domains results in an increase in RSI at 16 weeks (total score, 0.06 increase; oesophageal subscale, 0.09 increase; upper airway, 0.2 increase).