SEARCH

SEARCH BY CITATION

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results and discussion
  6. Acknowledgements
  7. References
  8. Supporting Information

Background  The development of well-tolerated acid suppressant drugs has stimulated substantial growth in the number of trials assessing therapy options for gastro-oesophageal reflux disease (GERD).

Aim  To develop consensus statements to inform clinical trial design in adult patients with GERD.

Methods  Draft statements were developed employing a systematic literature review. A modified Delphi process including three rounds of voting was used to reach consensus. Between voting, statements were revised based on feedback from the Working Group and additional literature reviews. The final vote was at a face-to-face meeting that included discussion time. Voting was conducted using a six-point scale.

Results  At the last vote, 93% of the final 102 statements achieved consensus (defined a priori as being supported by ≥75% of the votes). The Working Group strongly supported the development of validated patient-reported outcome instruments. Symptom assessments carried out by the investigator were considered unacceptable. There was agreement that exclusion from clinical trials should be minimized to improve generalizability, that prospective evaluation ideally requires electronic timed/dated methods and that endoscopists should be blinded to patient symptom status.

Conclusions  Implementation of the consensus statements will improve the quality and comparability of trials, and make them compatible with regulatory requirements.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results and discussion
  6. Acknowledgements
  7. References
  8. Supporting Information

Over the past three decades, the development of well-tolerated acid suppressant drugs has stimulated substantial growth in the number of trials assessing therapy options for gastro-oesophageal reflux disease (GERD). There has been a substantial increase in awareness of the factors that influence the quality of clinical trials in general, and those in reflux disease in particular.1, 2 This report summarizes outputs of a workshop convened with the following aims: to review the logic and substance of information that has already moulded the evolution of clinical trials of therapy for reflux disease, to review the insights that are currently bringing about changes, and to identify areas that are in need of further critical evaluation and methodological development.

Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results and discussion
  6. Acknowledgements
  7. References
  8. Supporting Information

A modified Delphi technique (described in Ref. 3) was used to develop statements that drove the workshop agenda. The principal steps in the process were as follows:

  • (i)
    Working group selection. Members of the Working Group were selected using several criteria:
  • (a)
    individuals should have clinical trial knowledge/expertise in reflux disease as demonstrated by publications/research or participation in national or regional activities, or an interest in guideline development and dissemination;
  • (b)
    the group should have international representation and
  • (c)
    there should be a diversity of expertise (including clinical researchers and patient-reported outcomes experts).
  • The Working Group, which included the Core Group, was led by a nonvoting chairman (John Dent).

  • (ii)
    Systematic searches. Systematic literature reviews identified available evidence relevant to statements. Literature searches were conducted in Medline, Embase and CINAHL for studies of human subjects, which were reported in English, from January 1980 to May 2007.
  • (iii)
    Voting. The Working Group voted on three iterations of the statements. Between each of the three votes, statements were revised based on feedback from the Working Group and additional literature reviews, and some statements were added on matters not addressed previously. We sought and obtained input from the Montreal Definition group as part of the development of statements for the final Workshop. The final vote was at a face-to-face meeting that included discussion time. The Working Group agreed that Elaine McColl should abstain from voting on statements she felt were beyond her expertise as a nonclinician. Voting at the Workshop itself was anonymous. A six-point scale was used: 1, agree strongly (A+); 2, agree moderately (A); 3, just agree (A−); 4, just disagree (D−); 5, disagree moderately (D); 6, disagree strongly (D+). Agreement with the statement (A+, A or A−) by three-quarters (i.e. ≥75%) of the group was defined a priori as consensus. The level of agreement in the final vote is given for each statement, expressed as a percentage. Statements that did not reach consensus are listed at the end of the paper, with voting results and subtexts available as online supplementary material (Appendix S1).

Workshop organization and funding sources

The Workshop was organized and supported financially by INSINConsulting, Guelph, ON, Canada, using an unrestricted grant from AstraZeneca Research and Development, Sweden. AstraZeneca had no input into the content and conduct of the Workshop.

Results and discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results and discussion
  6. Acknowledgements
  7. References
  8. Supporting Information

Considerations generic to trials in all manifestations of reflux disease

Definitions and general principles.
1. Heartburn is defined as a burning sensation in the retrosternal area (behind the breastbone). Agree: 92% (A+, 58%; A, 33%; D−, 8%)
2. Regurgitation is defined as the perception of flow of refluxed gastric content into the mouth or hypopharynx. Agree: 92% (A+, 50%; A, 25%; A−, 17%; D, 8%)
3. The perception of flow of gastric content into the oesophagus without accompanying heartburn is a common symptom and warrants study in clinical trials. Agree: 100% (A+, 36%; A, 45%; A−, 18%)

The term ‘heartburn’ translates poorly into many languages. Hence, an internationally accepted operational definition that can be understood by patients and physicians is important in trial methodology. The literature shows a lack of consistency in the definition of regurgitation, which should be defined as the perception of flow of gastric content into the mouth or hypopharynx.3

Measurements of weakly acidic reflux with impedance monitoring have better defined the relationships of symptoms to reflux of gastric content with a wide pH range.4 Development of new forms of treatment that target transient lower oesophageal sphincter relaxations5, 6 and the recognition that reflux of weakly acidic material can cause symptoms in patients who are taking acid inhibitors4 make it important to clarify the terminology. Symptom assessments in clinical trials should endeavour to distinguish between symptoms (in addition to heartburn) caused by reflux that is fully contained within the oesophagus and symptoms caused by regurgitation.

4. Dysphagia is a perceived impairment of the passage of food from the mouth into the stomach. Agree: 76% (A+, 58%; A, 17%; D−, 8%; D, 8%; D+, 8%)

Oropharyngeal dysphagia is defined as difficulty with the movement of solids or liquids from the mouth to the oesophagus.3

5. ‘Continuous’ medical maintenance therapy is defined as the daily intake of a medication to prevent or minimize recurrent reflux-related symptoms or injury to the oesophagus. Agree: 100% (A+, 67%; A, 25%; A−, 8%)
6. ‘Intermittent’ medical maintenance therapy is defined as the use of courses of daily therapy for a predefined time period to treat relapse of reflux disease. Agree: 91% (A+, 73%; A, 18%; D, 9%)
7. ‘On-demand’ medical maintenance therapy is defined as the daily intake of a therapy when symptoms recur until the time when these symptoms are sufficiently improved or resolved. Agree: 91% (A+, 45%; A, 36%; A−, 9%; D, 9%)

Two main forms of medical maintenance therapy are used: continuous therapy and symptom-driven therapy. Two types of symptom-driven therapy have been evaluated in clinical trials: intermittent therapy, where medical therapy is taken for a predefined course (e.g. 2 weeks), and on-demand therapy, where the patient initiates and stops therapy based on symptom response.7, 8

8. ‘Step-down’ therapy is defined as the progressive reduction of long-term medical therapy to determine the lowest intensity of therapy with sustained effectiveness. Agree: 91% (A+, 73%; A, 18%; D−, 9%)
9. Management trials are defined as studies that compare the outcomes of alternative approaches to management of patients in a scenario representative of routine clinical practice. Agree: 92% (A+, 33%; A, 50%; A−, 8%; D−, 8%)

Trials of healthcare interventions are often described as either exploratory (i.e. explanatory) or pragmatic.9, 10 Exploratory trials generally measure efficacy – the benefit a treatment produces under ideal conditions, often using well-defined and homogeneous populations in a research setting. Pragmatic trials measure effectiveness – the benefit the treatment produces in routine clinical practice. Management trials, a form of pragmatic trial, are designed to examine clinical management strategies in real-life situations, for instance, in a large randomized trial of step-up and step-down therapy in a managed-care setting.11, 12

10. Patients with unexplained alarm features must not be entered into trials if these features are not the focus of the trial. Agree: 91% (A+, 45%; A, 36%; A−, 9%; D−, 9%)
11. When patients have troublesome dysphagia, endoscopy should be performed and, if nondiagnostic, be followed by oesophageal manometry. Agree: 100% (A+, 91%; A, 9%)

Alarm features such as severe or progressive dysphagia, weight loss and gastrointestinal bleeding are generally regarded as indicators of severe underlying disease processes that need prompt attention, free from the constraints of a clinical trial protocol.13 Mild intermittent dysphagia is very common in reflux disease and should not be considered to be an alarm symptom,14, 15 nor an exclusion criterion.

12. Prespecified rescue medications for troublesome symptoms should be allowed and recorded. Agree: 100% (A+, 73%; A, 27%)

Ethical considerations require that some form of rescue therapy, usually antacids, be prescribed in the event of the patient experiencing severe GERD symptoms during a trial. Recording the use of rescue medication is important in evaluating treatment efficacy, particularly with trials of on-demand therapy where greater use of a rescue medication may be the only evidence of a less effective therapy.16, 17

13. Determination of the Helicobacter pylori status may help to explain differences in treatment outcome with acid-inhibitory agents but is not mandatory in all trials. Agree: 91% (A+, 45%; A, 36%; A−, 9%; D−, 9%)

Acid-inhibitory agents are more effective in patients infected with H. pylori.18 Therefore, trials of acid-inhibitory agents performed in countries with a high prevalence of H. pylori infection may yield better results than trials in countries where the prevalence of H. pylori infection is low. In this situation, recording of H. pylori status would be helpful. In randomized controlled trials performed within a single geographical population, the process of randomization should remove the confounding effects of H. pylori infection on efficacy.

14. Measuring comorbidities (e.g. irritable bowel syndrome (IBS), dyspepsia, anxiety, somatization, etc.) may help to explain the outcome of therapy and should be considered. Agree: 83% (A+, 67%; A, 17%; D, 17%)

IBS and other comorbidities often co-exist with GERD, and their symptoms may overlap and confuse the recording of GERD symptoms and their resolution.19 In trials of certain symptoms related to GERD, such as noncardiac chest pain,20, 21 psychological factors may be particularly important, and the effects of anxiety and somatization may be a cause for failed anti-reflux surgery.22 The Workshop supported inclusion of patients with common comorbidities in the interests of ensuring generalizability of trial outcomes, since adequately designed and powered studies should control for impacts of comorbidities on outcomes. Baseline comparison of groups with respect to comorbidities and/or the inclusion of comorbidities as covariates in analyses were/was recommended. Participants felt that it would be useful to explore the clinical relevance and possible common pathophysiological mechanisms of overlapping digestive syndromes.

15. The Consolidated Standards of Reporting Trials (CONSORT) guidelines should be followed for the conduct and reporting of studies. Agree: 100% (A+, 75%; A, 25%)

The CONSORT statement comprises evidence-based recommendations to improve the conduct and reporting of randomized controlled trials (http://www.consort-statement.org).1, 23

16. Non-inferiority and equivalence trials of medical therapy in reflux disease should follow the principles stated in the extension of the CONSORT guidelines. Agree: 100% (A+, 75%; A, 25%)

Equivalence trials aim to determine whether one (typically new) intervention is therapeutically similar to another, usually an existing treatment. A non-inferiority trial seeks to determine whether a new treatment is no worse than a reference treatment. A non-inferiority or equivalence trial requires that the efficacy of the control treatment is already established; the appropriate control group is therefore the established treatment and a placebo control group would be unethical. Recommendations on the conduct and reporting of these trials have been published.24

Inclusion/exclusion criteria.
17. The protocol should clearly define the time period that patients must cease the use of H2-receptor antagonists and proton pump inhibitors prior to enrolment in a trial of medical therapy. Agree: 100% (A+, 100%)
18. In a trial of medical therapy, subjects should have ceased H2-receptor antagonist therapy for at least 2 weeks prior to baseline assessment. Agree: 91% (A+, 64%; A, 9%; A−, 18%; D−, 9%)
19. In a trial of medical therapy, subjects should have ceased proton pump inhibitor (PPI) therapy for at least 4 weeks prior to baseline assessment. Agree: 82% (A+, 27%; A, 27%; A−, 27%; D−, 9%; D, 9%)
20. Anti-reflux therapy used in the 6 months prior to enrolment should be recorded. Agree: 82% A+, 55%; A, 18%; A−, 9%; D−, 18%)

The increasing use and availability of acid inhibitors make it difficult to find a pool of treatment-naïve patients to enrol in a trial. Yet, appropriate measurement of baseline symptoms and endoscopic findings requires a period of time without medication. The needs of the trial must be balanced against patient comfort and safety. Given the higher efficacy of PPIs, a period of 4 weeks off these medications was proposed by the Workshop. This is a compromise, as relapse can take up to 6 months after withdrawal of PPIs.25, 26

Previous therapy may have an effect on acid secretion by causing a rebound increase in acid production,27 or may influence the patient’s responses to questions regarding satisfaction with the new medication based on their earlier experience with therapy. Hence, recording of prior therapy is desirable.

21. In trials that evaluate symptoms that usually occur less than weekly, the duration of the baseline period should be chosen to allow an adequate number of events to be recorded. Agree: 92% (A+, 67%; A, 25%; D−, 8%)
22. In trials that evaluate symptoms that usually occur less than weekly, a baseline period that documents a frequency and severity of symptoms above a defined threshold should be a major determinant for inclusion. Agree: 100% (A+, 33%; A, 33%; A−, 33%)

The frequency of the key symptom is an important factor when designing symptom-based trials. For example, episodes of hoarseness or cough possibly related to reflux may typically occur less than once a week. A baseline observation period should provide a representative measure of symptoms before any intervention is performed. The duration of the trial treatment period should also be selected in the light of baseline symptom frequency.

24. Patients who require daily acetylsalicylic acid (≤325 mg) for neurovascular or cardiovascular protection should not be excluded from clinical trials. Agree: 91% (A+, 36%; A, 36%; A−, 18%; D−, 9%)
25. Patients who require a nonsteroidal anti-inflammatory drug or Cox-2 inhibitor therapy can develop confounding drug-related symptoms and mucosal changes, which should be considered in clinical trial design. Agree: 100% (A+, 67%; A, 25%; A−, 8%)

An estimated 41% of individuals over the age of 40 years in the US take aspirin for cardiovascular prophylaxis, and this figure is likely to grow in the future28 Aspirin and nonsteroidal anti-inflammatory agents (NSAIDs) have been associated with oesophagitis and complications of reflux disease such as strictures.29 Excluding patients who require aspirin or NSAIDs from trials would reduce the generalizability of the results and is, therefore, not recommended. Random allocation of patients should remove any confounding effect of aspirin or other anti-inflammatory agents on symptoms or oesophagitis.

26. Patients with clinically important comorbidities that may interfere with the conduct of a study should be excluded. Agree: 92% (A+, 67%; A, 25%; D, 8%)

Important comorbidities may need to be specifically sought and patients with these conditions excluded from some clinical trials. For example, a careful evaluation for cardiac causes of chest pain would be important in a trial of patients with chest pain; participants in a randomized trial of medical and surgical interventions should be medically fit to tolerate either treatment to avoid statistical imbalances caused by a greater drop-out rate in patients randomized to a surgical intervention.30

Exclusion from a trial should be limited as much as possible to preserve the generalizability of the results,31 and exclusion criteria should be explicitly justified.

27. Advanced age, by itself, should not exclude patients from clinical trials. Agree: 84% (A+, 58%; A, 25%; D−, 8%; D, 8%)

The severity of reflux oesophagitis appears to increase with age particularly in men, but older individuals have less severe GERD symptoms.32 Inclusion of the widest possible age range in clinical trials is important to maintain generalizability. There are also ethical arguments in favour of not having age restrictions, including equity of access and participation.33 Guidelines from the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)34 state that

‘drugs should be studied in all age groups, including the elderly, for which they will have significant utility. Patients entering clinical trials should be reasonably representative of the population that will be later treated by the drug.’

Clinical trial design and protocol requirements.
28. Whenever possible, a parallel group study design should be used. Agree: 100% (A+, 67%; A, 25%; A−, 8%)

Most GERD trials use a parallel group design rather than a crossover design. The principal disadvantage of the crossover trial is that the effect of one treatment may ‘carry over’ into the next treatment phase and alter the response to subsequent treatments. A washout (no treatment) period between consecutive treatments is therefore sometimes used to allow the effects of a treatment to wear off. As treatment effects can persist for a considerable time in GERD, this trial design is generally less preferable to parallel group designs, particularly in trials of treatment efficacy.35

29. A placebo control should be used when there is no approved intervention for the syndrome under study. Agree: 92% (A+, 67%; A, 17%; A−, 8%; D−, 8%)

Four types of concurrent controls are recognized: no treatment, placebo, different dose or regimen of study treatment, and different active treatment. In placebo-controlled trials, the new treatment and placebo may both be superimposed on existing standard therapy; this ‘add-on’ trial design is appropriate and useful when standard therapy is not fully effective.

30. The primary outcome and all secondary measures should be defined in the study protocol. Agree: 100% (A+, 92%; A, 8%)

Predefining the primary outcome and all secondary measures and proposed analyses before the trial begins is important to avoid analyses that are conducted post hoc as a ‘fishing expedition’ with undue emphasis given to any positive findings so identified.36 To be acceptable to the regulatory bodies, studies conducted for regulatory purposes require specification of primary and secondary outcome measures in the protocol and statistical analysis plan.37 Any revision of primary and secondary outcome measures once data are known, to suit research results obtained, should potentially be considered malpractice.

31. Adherence with treatment should be measured. Agree: 100% (A+, 75%; A, 8%; A−, 17%)
32. Adherence to medical therapy can be measured by patient interview, pill count of returned medication or special measuring devices. Agree: 100% (A+, 33%; A, 50%; A−, 17%)

Adherence with treatment is a problem in chronic diseases such as reflux disease. Measurement of adherence is an important practicality in clinical trials and is recommended in guidance to industry,38 albeit without consensus on the best methods for doing this. Adherence is particularly important in long-term studies because patients often do not take their medications on a regular basis and an apparent failure of treatment may be due to failure to persist with the recommended therapy.

33. The protocol should include a sample-size calculation based on the primary outcome measure. Agree: 100% (A+, 83%; A, 8%; A−, 8%)

A trial should be able to detect any statistically significant, clinically relevant effect and, if it is negative, be able to conclude safely that no benefit exists if it is not found in the trial.39 Sample-size calculations and assessment of risk of a type II error are still not universal practice in GERD trials, despite agreement on the need for this.40 Comparative trials designed to show that one drug is as good as another (equivalence trials) are often underpowered;24 such trials generally need larger sample sizes than superiority trials. Underpowered equivalence trials cannot validly conclude that there is no difference between the test therapies.36

Guidelines and processes for symptom evaluation.
34. Patient-recorded symptom assessments are preferable to investigator-assessed symptoms. Agree: 92% (A+, 42%; A, 33%; A−, 17%; D−, 8%)
35. Symptom assessments done by the investigator are not acceptable even as secondary outcome measures. Agree: 100% (A+, 67%; A, 17%; A−, 17%)

It is now generally accepted that symptom outcomes should be reported directly by the patients without filtration by investigators. Regulatory agencies such as the Food and Drug Administration41 and European Medicines Agency42 provide strong guidance in support of the use of patient-reported outcome measures in clinical trials, and it is likely that this guidance will translate into policy in the near future. There is evidence from trials in GERD and other therapeutic areas that investigators underestimate the severity of symptoms experienced by patients.43–45

36. Recording of symptoms should be done at regular, specified intervals (e.g. daily). Agree: 92% (A+, 58%; A, 33%; D−, 8%)
37. The frequency and severity of each of the symptoms that are relevant for the syndrome under study should be measured separately. Agree: 92% (A+, 42%; A, 17%; A−, 33%; D−, 8%)

There was general agreement that symptoms should be recorded at regular intervals and that all symptoms that are relevant for the syndrome under study should be measured separately. If a global outcome measure is the primary outcome and shows improvement, the cardinal symptoms of the syndrome under study should also improve.46 The frequency with which symptoms are recorded needs to be prespecified and will depend on the aim of the study.

39. Symptom recording methods that facilitate and time-stamp each datum entry are preferable to paper-based symptom diaries. Agree: 100% (A+, 33%; A, 67%)

The protocol must specify how the data will be recorded. Some questionnaires require the patient to describe their symptom experience during the previous days or weeks, an approach prone to recall bias. Daily completion of a questionnaire or a diary card provides longitudinal information (i.e. the response over a period of time), thereby theoretically reducing the problem of recall, but cannot prevent retrospective completion.46 Consequently, there is now a preference for timed/dated electronic data capture such as the use of an automated daily telephone dial-up recording system or a hand-held electronic data collection device, despite the greater cost and complexity of these methods.47–49

40. Validated scales should be used to measure the frequency and severity of each symptom of relevance. Agree: 100% (A+, 50%; A, 33%; A−, 17%)
41. A validated symptom measure needs to be developed for the measurement of regurgitation. Agree: 100% (A+, 75%; A, 17%; A−, 8%)
42. Validated measures need to be developed for the assessment of atypical GERD symptoms. Agree: 100% (A+, 83%; A, 8%; A−, 8%)

The need for validated outcome measures is well established.46 Methods that measure individual symptoms also need to be validated. A systematic review published in 2004 concluded that five scales met some of the ideal characteristics of a valid and responsive tool for reflux disease, but no single instrument fulfilled all the criteria of GERD specificity, multidimensionality, self-assessment, daily recording, psychometric validation and availability in multiple languages.50 The five scales were the Gastrointestinal Symptom Rating Scale,51 the GERD Score,52 The Ulcer Oesophagitis Subjective Symptom Scale,53 the GERD Symptom Assessment Scale (GSAS)54 and the Gastro-oesophageal Reflux Disease Activity Index.55 The review did not cover the Reflux Disease Questionnaire (RDQ),56 or the more recently published ReQuest questionnaire.57

44. The performance of clinical trials in GERD would benefit from better access to validated patient-reported outcome measures. Agree: 100% (A+, 67%; A, 33%)

The Workshop felt strongly that the proprietary nature of some recently developed instruments hampered the use of valuable outcome measures. Although the importance of intellectual property was recognized, it was felt that validated instruments should be made freely available in the public domain. For example, a validated, general measure of patient satisfaction with medication, the Treatment Satisfaction Questionnaire for Medication (TSQM and TSQM II),58, 59 is generally free for use in the noncommercial setting (with the permission of the copyright holders), although a charge may apply for studies sponsored by the pharmaceutical industry.

45. A Likert scale with between 4 and 7 response options is the best type of instrument for measurement of symptom status by patient self-report. Agree: 75% (A+, 50%; A−, 25%; D−, 25%)

The vote on this statement endorsed the multiple anchorage points provided by a Likert scale, as compared with a visual analogue scale which usually defines symptom status only at each end of the scoring line.46, 60 Most studies use 4–7 response-option Likert scales. Ideally, direct comparisons between four-, five- and seven-point Likert scales in clinical GERD trials should be performed to determine the optimal number of response options for each outcome. It is essential that patients are able to distinguish between adjacent response options within such a defined scale. Development and validation processes need to show that conceptual differences in the adjectives used in the different scales are understood by patients, especially when these labels are translated into different languages.

46. Whenever possible, trial-related endoscopic assessments should be done with the endoscopist blinded to patient symptom status. Agree: 100% (A+, 83%; A, 17%)

Though it seems obvious that the endoscopist may be influenced in reporting findings if he/she is aware of patient symptom status,61 blinding of endoscopists to this has not been a routine clinical trial practice.

47. Trials that include an assessment of anti-reflux surgery or other physical anti-reflux procedures should evaluate symptoms associated with increased resistance to flows across the gastro-oesophageal junction. Agree: 91% (A+, 45%; A, 36%; A−, 9%; D−, 9%)

Anti-reflux surgery may result in troublesome dysphagia, inability to belch and the ‘gas-bloat’ syndrome. Such symptoms need to be assessed at baseline and during follow-up to ensure that all symptoms that describe treatment outcome are captured.

Single symptom outcome measures.
48. The study protocol should define a treatment responder, i.e. the amount of improvement in a specific symptom that is considered to be clinically meaningful. Agree: 100% (A+, 58%; A, 33%; A−, 8%)

This vote strongly confirms that it is no longer sufficient to report the mean change in a score for each treatment group. The definition of a responder, which should be stated in the protocol, must incorporate the primary outcome measure. The main outcome should be the proportion of patients who achieve the stipulated amount of improvement necessary to be qualified as a responder (e.g. the proportion of patients who become symptom-free).

49. The proportion of patients who have no more than mild symptoms over a predefined period should be reported for each symptom of major interest. Agree: 83% (A+, 33%; A, 25%; A−, 25%; D−, 8%; D, 8%)
50. The minimum clinically meaningful change in each symptom of primary interest should be predefined and supported by previous data when this is available. Agree: 92% (A+, 42%; A, 42%; A−, 8%; D−, 8%)
51. Absence or near-complete relief of a previously troublesome symptom is the best measure of treatment efficacy. Agree: 84% (A+, 42%; A, 17%; A−, 25%; D−, 8%; D+, 8%)

For a treatment to be clinically meaningful there needs to be a clear improvement in the cardinal symptoms of the disease or syndrome that is being studied. There is agreement that either disappearance of a symptom or its persistence at no more than a mild severity is clinically meaningful.56, 62–65 There is evidence that the placebo response is the lowest when complete absence of symptoms is used as the outcome measure. This helps to determine the true effect size of the intervention.66

Composite/global outcome measures.
52. A global assessment of how much symptoms trouble patients before and during treatment is a useful, clinically relevant evaluation. Agree: 100% (A+, 58%; A, 33%; A−, 8%)

The Montréal Definition of GERD uses the term ‘troublesome’, as it satisfactorily describes the negative aspects of the symptoms from a patient’s standpoint with a word that is widely understood and recognizes the variability in how symptoms impact on individual patients.3 The term ‘troublesome’ needs to be operationalized for use as an outcome measure in clinical trials.

53. Neither ‘adequate’ nor ‘satisfactory’ relief of symptoms is sufficiently validated for use as a primary outcome measure. Agree: 83% (A+, 50%; A, 17%; A−, 17%; D−, 17%)

The Rome Committee on Design of Clinical Trials suggests ‘adequate relief’ and ‘satisfactory relief’ as the current standards for primary outcome assessment in functional gastrointestinal treatment trials.67, 68 However, the Workshop found these criteria unacceptable for trials in GERD for two main reasons: first, there were significant problems with the validation process for the IBS trials in which they were used;69, 70 and second, these outcomes do not consider the magnitude of improvement (i.e. ‘adequate relief’ from mild symptom severity is scored essentially the same as ‘adequate relief’ from symptoms that are severe).71

54. Health-related quality of life (HRQoL) is an important measure of the impact of the disease on the patient. Agree: 100% (A+, 50%; A, 25%; A−, 25%)
55. HRQoL should not be the primary outcome measure of a clinical trial in GERD. Agree: 75% (A+, 50%; A, 17%; A−, 8%; D−, 17%; D, 8%)

HRQoL is accepted as an important outcome. However, because GERD is a symptom-driven disease, the primary outcome should be the improvement of the cardinal symptom(s) of the syndrome under study, and should not be replaced by improvement in HRQoL.

56. ‘Willingness-to-continue’ is an inadequately validated outcome measure for on-demand studies. Agree: 100% (A+, 50%; A, 8%; A−, 42%)
57. A patient-recorded symptom assessment should be considered as a primary outcome measure of on-demand studies. Agree: 100% (A+, 42%; A, 58%)
58. A validated measure of patient satisfaction with treatment should be considered as a primary outcome measure of on-demand studies. Agree: 92% (A+, 42%; A, 42%; A−, 8%; D−, 8%)

Several trials have used ‘willingness-to-continue’ as a primary or secondary outcome measure for on-demand long-term therapy, mainly in patients with non-erosive reflux disease (e.g. Refs. 72, 73). There is marked variation among studies (14–51%) in the proportion of patients allocated to placebo who discontinued for any reason, suggesting that it is difficult to apply this measure in a consistent, clinically relevant way.8, 74 Despite this, in most trials, ‘willingness-to-continue’ correlates with other important endpoints, such as symptom scores, use of rescue medication (antacids) and quality-of-life measures.8

‘Willingness-to-continue’ has never been formally validated in reflux disease trials, and it is not clear if this measure is useful and valid in a routine clinical setting outside the framework of a clinical trial. Furthermore, it is not clear whether patients who remain in a study are all truly satisfied with on-demand therapy.75

New patient-recorded outcome measures are needed for on-demand studies. The Workshop supported the direct measurement of symptom experience or patient satisfaction with treatment,76 as well as measurement of use of rescue medication.

Roles of physiological measurements and histology.
59. Histology of the oesophagus and physiological studies (e.g. pH-metry, impedance) have a role in aiding understanding of disease mechanisms and mechanisms of action of therapies. Agree: 91% (A+, 64%; A, 27%; D−, 9%)
60. Histological and physiological assessments are not appropriate surrogate endpoints for symptom response. Agree: 91% (A+, 82%; A−, 9%; D−, 9%)

Effects of therapy on oesophageal acid exposure are closely linked to clinical outcomes and so are a guide to optimal dosing.77

Symptomatic syndromes

Typical reflux syndrome.
61. Current evidence suggests that mild symptoms occurring on two or more days a week or moderate or severe symptoms occurring on one or more days a week can be considered to be troublesome. Agree: 100% (A+, 18%; A, 82%)

The Montréal Definition of GERD proposes that the term ‘troublesome’ should be used when reflux symptoms adversely affect quality of life.3 In a population-based study in Sweden, mild or worse symptoms were associated with a clinically meaningful reduction in well-being,78 whereas another study showed that mild symptoms on two or more days a week were associated with a significant reduction in quality of life.79 Not only for the purpose of enrolment in clinical trials, but also for the definition of treatment responders, operational definitions that include both frequency and severity (a derivative of both intensity and frequency) of symptoms are likely to be useful. The RDQ, which measures the frequency and intensity of heartburn, regurgitation and epigastric pain, showed a good correlation between the frequency and intensity of symptoms and the overall response to PPI treatment, as measured by a validated seven-point global outcome measure.50, 56, 80–83

62. The duration of therapy should be tailored to the anticipated response and justified. Agree: 100% (A+, 67%; A, 33%)

The duration of therapy in a clinical trial depends on the symptom frequency at baseline and the anticipated response. For example, a treatment period of 4–8 weeks is required to observe a response in patients who have reflux symptoms twice a week, but measurement of the response of reflux chest pain occurring as infrequently as once every week will require a longer treatment period.

63. Exploratory trials of medical maintenance therapy in the typical reflux syndrome should have a treatment phase of at least 3 months. Agree: 100% (A+, 27%; A, 45%; A−, 27%)
64. The duration of medical maintenance treatment trials following initial treatment of patients should be at least 6 months. Agree: 100% (A+, 64%; A, 18%; A−, 18%)

The optimum duration of follow-up in gastro-oesophageal reflux trials evaluating the efficacy of maintenance therapy depends on the question that is being addressed by the trial. A re-analysis of data from a Cochrane review of 28 randomized trials evaluating PPI therapy84 showed that the relative risk (RR) of relapse on PPI therapy compared with placebo was not constant over time, but that there was only a small change from 6 to 12 months. The Workshop concluded that 6 months was a pragmatic minimal duration of follow-up for trials of maintenance therapy following initial treatment. Follow-ups of longer than 6 months are encouraged. In particular, there are very few trials that have followed up patients for more than 1 year,7, 85 and there is a need for more data collected over these time scales.

65. Sleep disturbance is common in the typical reflux syndrome and can be a useful outcome measure. Agree: 82% (A+, 27%; A, 36%; A−, 18%; D−, 9%; D+, 9%)

Nocturnal reflux is common in untreated patients with reflux disease and has an impact on sleep.3 In a recent large telephone survey, 79% of respondents with symptoms of GERD reported nocturnal symptoms, and 75% of respondents reported that GERD symptoms affected their sleep.86 Sleep disturbance is a measure of the global burden of reflux symptoms, and episodes of nocturnal reflux symptoms have been shown to be associated with reductions in work productivity.87

67. Trials evaluating existing guidelines for the management of the typical reflux syndrome are required. Agree: 100% (A+, 50%; A, 50%)

There are few trials that evaluate existing management algorithms and/or compare currently competing treatment options. This is a significant deficiency, given the clinical importance of such evaluations. Guidelines are required for the planning of both exploratory and pragmatic trials.9

68. Entry and exit endoscopy are not mandatory in exploratory trials in the typical reflux syndrome. Agree: 82% (A+, 36%; A, 27%; A−, 18%; D−, 9%; D, 9%)
69. Entry and exit endoscopy are rarely justified in pragmatic trials in the typical reflux syndrome. Agree: 91% (A+, 36%; A, 36%; A−, 18%; D−, 9%)

In patients with the typical reflux syndrome with no evidence of erosive oesophagitis at baseline endoscopy, exit endoscopy has usually not been performed. The usual endpoint is based on symptoms staying below a defined level, or for patients to be willing to continue therapy.72 Patient-reported outcomes are now of growing importance in disorders such as GERD in which symptoms are the most prevalent issue and the role of exit endoscopy has been diminished following guidance from regulatory authorities.41 However, in the reflux oesophagitis syndrome, exit endoscopy is a critical aspect of most study designs.

70. The primary outcome measure of management strategy trials should be patient-reported response of heartburn. Agree: 75% (A+, 50%; A, 17%; A−, 8%; D, 8%; D+, 17%)
71. Management strategy trials of medical therapy should have a treatment phase of at least 6 months. Agree: 84% (A+, 42%; A, 17%; A−, 25%; D−, 8%; D+, 8%)

Management trials are designed to examine clinical management strategies in real-life situations (see subtext to Statement 9). Generally, a treatment phase of 6–12 months is needed to differentiate correctly between the effects of two different drugs, or between the effects of active drug and placebo.

Reflux chest pain syndrome.
72. For entry of patients into trials, screening should be done to exclude cardiac chest pain. Agree: 100% (A+, 45%; A, 45%; A−, 9%)
73. Absence of heartburn should not exclude potential reflux chest pain syndrome patients from study inclusion. Agree: 91% (A+, 55%; A, 27%; A−, 9%; D−, 9%)
74. Treatment trials in suspected reflux chest pain syndrome patients should be randomized, double-blind and have a placebo control. Agree: 100% (A+, 45%; A, 45%; A−, 9%)

Gastro-oesophageal reflux, identified by endoscopy and/or pH-metry, occurs in 17–100% of patients with noncardiac chest pain.88 There is evidence from treatment trials in patients with chest pain and normal cardiac investigations that PPI therapy reduces symptoms and may be useful as a diagnostic test in identifying subjects whose chest pain is reflux-related.89–94 The treatment effect size probably varies according to the proportion of subjects with suspected reflux chest pain syndrome who have oesophagitis or abnormal pH-metry. In published studies, the proportion of responders to active therapy varied between 40%90, 93 and 81%,89 whereas placebo response rates varied between 6%89 and 35%.93

75. Inclusion in a reflux chest pain syndrome trial should require a minimum chest pain frequency of one episode per week. Agree: 100% (A+, 9%; A, 64%; A−, 27%)

The patient population with noncardiac chest pain has a very variable frequency of symptoms, ranging from daily to a few times per year. The minimum frequency for inclusion in a trial depends on the magnitude of effect expected, and also on the length of the trial. It is impractical to include patients in treatment trials who have symptoms occurring less than once a week, as it would be difficult to assess the response.

77. The primary outcome measure of a reflux chest pain syndrome trial should be a clinically meaningful reduction of chest pain. Agree: 100% (A+, 64%; A, 18%; A−, 18%)

Stringent criteria such as complete lack or resolution of chest pain may be unrealistic. At present, a reduction in chest pain intensity of at least 50% vs. placebo is commonly used, but this needs to be evaluated further.

Syndromes with oesophageal injury

Reflux oesophagitis syndrome.
78. The duration of initial medical treatment trials of healing of reflux oesophagitis should be 4–8 weeks. Agree: 84% (A+, 33%; A, 33%; A−, 17%; D−, 8%; D+, 8%)

A recent Cochrane review examined 134 treatment trials involving 36 978 oesophagitis patients and concluded that PPIs exhibited a better healing effect and faster symptom relief than did H2-receptor antagonists, which were in turn better than placebo.95 The duration of these trials was almost uniformly 4–8 weeks and there is clearly continued healing up to the 8-week time point, suggesting that this time span provides a reasonable estimate of effectiveness with currently available treatment options.

79. The Los Angeles classification is the preferred method for determining whether reflux oesophagitis is present, to grade its severity and to measure treatment effects on oesophagitis. Agree: 100% (A+, 55%; A, 45%)

Over the past 10 years, the Los Angeles classification has gained general acceptance.96–99 There is strong evidence that visible breaks in the mucosa are the most reliable endoscopic signs of oesophagitis. Other findings such as erythema or oedema of the distal oesophageal mucosa or an irregular Z-line have not been proven as reliable for diagnosis of non-erosive reflux oesophagitis, but new techniques including narrow band imaging,99 high-definition endoscopy and confocal laser endomicroscopy might allow application of new criteria in the future.100

80. Complete healing of oesophageal mucosal breaks should be the primary endpoint of trials. Agree: 82% (A+, 55%; A, 27%; D, 18%)

Desirable features of the primary endpoint of a clinical trial are that it should make the trial comparable to other clinical trials and that it be reproducible. Endoscopic healing of the mucosa is the defining primary endpoint of many trials of reflux oesophagitis with erosions.101 In large measure, this endpoint has been dictated by regulatory authorities who have insisted on an objective endpoint in reflux oesophagitis trials.

81. Trials that evaluate healing of reflux oesophagitis should also measure symptoms. Agree: 100% (A+, 83%; A, 17%)

Although oesophagitis is an objective measure of GERD severity, the more relevant patient-centred endpoint is the associated symptom burden. Quality of life deteriorates as the severity of GERD symptoms increases.51, 65, 102 As the presence of troublesome symptoms in the absence of oesophagitis still defines GERD, it follows that the documentation of effective treatment of oesophagitis must include both healing of mucosal breaks and resolution of symptoms.

82. The duration of trials of maintenance therapy following healing of reflux oesophagitis should be at least 6 months. Agree: 91% (A+, 55%; A, 36%; D, 9%)
83. Patients with healed reflux oesophagitis should be entered in a maintenance trial only if reflux-related symptoms are no longer troublesome. Agree: 91% (A+, 27%; A, 55%; A−, 9%; D−, 9%)

A maintenance trial in patients with reflux oesophagitis should test the ability of a treatment to prevent relapse of both oesophagitis and troublesome GERD symptoms. The duration of the maintenance trial should be sufficiently long to test the hypothesis that the treatment is better than placebo. After withdrawal of successful PPI therapy, symptoms and reflux oesophagitis relapsed in 80% of patients after 6 months,25 making this a reasonable minimum duration.

84. A reflux stricture is defined as a persistent luminal narrowing of the oesophagus caused by reflux disease. Agree: 100% (A+, 55%; A, 27%; A−, 18%)

A reflux stricture can develop as a result of severe GERD, when inflammation results in narrowing of the oesophageal lumen so that passage of food is impaired. This is seen in fewer than 5% of GERD patients.103

85. Patients with eosinophilic oesophagitis must be excluded from trials of reflux stricture. Agree: 100% (A+, 64%; A, 36%)

Eosinophilic oesophagitis is a disorder of the oesophagus, which is commonly misdiagnosed as GERD.104 A marked increase in the prevalence of eosinophilic oesophagitis mandates the need to be alert to exclusion of these patients from GERD trials. In adults, the most common presenting symptom is intermittent dysphagia and food impaction.105 One of the endoscopic findings is oesophageal rings that can be confused with reflux stricture or Schatzki ring.106 The diagnosis of eosinophilic oesophagitis requires multiple oesophageal biopsies; criteria have been developed for biopsy-based diagnosis of eosinophilic oesophagitis.107

86. Studies of Barrett’s oesophagus and oesophageal adenocarcinoma should use processes of consultation and consensus that minimize variability in the interpretation of histopathology. Agree: 100% (A+, 64%; A, 18%; A−, 18%)

An optimal definition of Barrett’s oesophagus should provide clear, accepted, reproducible and clinically relevant criteria with evidence that affected individuals have an increased risk of oesophageal adenocarcinoma.108 This requires a combination of endoscopic and histological criteria consisting of an abnormal appearing oesophageal mucosa with histological evidence of columnar metaplasia (with or without intestinal metaplasia).109 Both gastroenterologists and pathologists are often inconsistent regarding diagnostic criteria.110

87. The Prague C & M endoscopic criteria should be used to determine the presence and extent of endoscopically suspected oesophageal metaplasia. Agree: 100% (A+, 36%; A, 55%; A−, 9%)

The Prague C & M endoscopic criteria are the first consensus-based, formally researched guidelines for the accurate endoscopic recognition and grading of Barrett’s oesophagus.111 Prior to the development of the Prague criteria, studies found considerable inter- and intra-observer variation in estimates of the extent of Barrett’s oesophagus, even when an endoscopic length of more than 3 cm was assessed.112 Thus, utilization of the Prague C & M criteria is advisable in future studies.

88. Appropriate histopathological evaluation of endoscopically suspected oesophageal columnar metaplasia within clinical trials first requires targeted biopsy of areas of metaplasia that have any surface irregularity and then, quadrantic biopsies of the metaplastic segment at no more than 2 cm axial intervals. Agree: 100% (A+, 18%; A, 64%; A−, 18%)

The convention of a systematic four-quadrant, 2-cm interval biopsy protocol using large biopsy forceps109 is supported by prospective studies that show that this protocol detects high-grade dysplasia at the baseline endoscopy in many patients who progress to cancer within 5 years.113, 114 A visible irregularity of the oesophageal mucosa is associated with a significant risk of cancer and should be biopsied first when mucosal visualization is not affected by bleeding.115 More specifically targeted biopsies may be possible with the use of narrow band imaging, autofluorescence endoscopy or vital dyes.116

89. In addition to patients with Barrett’s oesophagus and intestinal metaplasia, those without intestinal metaplasia are an important group to study for the risk of oesophageal adenocarcinoma. Agree: 100% (A+, 73%; A, 18%; A−, 9%)

The Montréal Workshop addressed the issue of how Barrett’s oesophagus should be defined and, for several reasons outlined in its report,3 rejected the definition widely used in North America. This definition stipulates that intestinal type metaplasia must be demonstrated in oesophageal columnar metaplasia before Barrett’s oesophagus should be diagnosed. The statement above, arising from the current Workshop, underlines the need for better data on the risk of oesophageal adenocarcinoma in patients with oesophageal columnar metaplasia in whom intestinal type metaplasia has not been demonstrated.

Extra-oesophageal syndromes

Reflux cough syndrome.
91. Trials for reflux cough syndrome need to be placebo controlled. Agree: 84% (A+, 67%; A, 17%; D−, 8%; D, 8%)

A Cochrane analysis of recent studies concluded that there is insufficient evidence in adults that PPI therapy is beneficial for cough associated with GERD.117 Thus, a placebo arm needs to be included in trials involving patients with this syndrome. It would also be acceptable to use a placebo in an add-on design (e.g. PPI + test drug vs. PPI + placebo).

92. Objective measurement of cough or a validated cough scale are acceptable outcome measures in trials of reflux cough syndrome. Agree: 100% (A+, 55%; A, 36%; A−, 9%)

As there is currently no validated instrument for assessing cough severity, the Workshop proposed ways in which cough might be measured. Treatment of a reflux cough syndrome is unlikely to lead to complete symptom resolution, making it necessary to establish what constitutes a ‘clinically meaningful improvement’. Conceivably, the number of cough episodes could be measured by means of ambulatory oesophageal manometry,118 or non-invasively using external measuring equipment,119 and this information could be utilized as a direct measure or for the calculation of a cough score. However, participants felt that an objective measurement of cough would not necessarily capture the extent to which a patient would find residual symptoms troublesome. This limitation would be overcome by the development of a validated patient-reported outcome measure.

Reflux laryngitis syndrome.
93. Trials of medical therapy in suspected reflux laryngitis syndrome should have a treatment phase of at least 4 weeks. Agree: 82% (A+, 18%; A, 36%; A−, 27%; D−, 18%)
94. A validated instrument assessing oesophageal symptomatology needs to be incorporated into treatment trials of suspected reflux laryngitis syndrome. Agree: 100% (A+, 45%; A, 45%; A−, 9%)

There are eight fully published randomized, placebo-controlled studies in suspected reflux laryngitis syndrome,120 and the study durations ranged from 8 to 16 weeks of therapy. The overall pooled risk ratio showed no significant difference between PPI therapy and placebo in the proportion of patients with ≥50% reduction of laryngeal symptoms [RR: 1.28; 95% confidence interval (95% CI): 0.94–1.74].120 A meta-analysis of five studies using high-dose PPI as intervention121 also showed no difference between PPI therapy and placebo in terms of symptom resolution or improvement (pooled RR: 1.18; 95% CI: 0.81–1.74).

The response rate as a function of PPI therapy duration in patients with chronic laryngitis has been addressed in one open label study (published in abstract form122). Maximum response to therapy was achieved by 30 days for the primary symptom, suggesting that a 4-week trial was sufficient. However, the optimal duration of acid suppressive therapy in chronic laryngitis remains uncertain, especially as open label studies and expert opinion generally suggest a minimum of 8–12 weeks of therapy, and ENT literature based on open label studies suggests that the resolution of laryngeal findings may take up to 6 months.123

96. There are no endoscopic criteria that enable an adequately sensitive and specific diagnosis of reflux-related laryngitis and its severity grading. Agree: 100% (A+, 27%; A, 64%; A−, 9%)

Endoscopic abnormalities of the true vocal folds are considered more useful diagnostically for the reflux laryngitis syndrome than other mucosal areas in the larynx and pharynx. Vocal fold granuloma and ulcer are abnormal findings that are recognized reliably and which respond to PPI therapy,124 but only a small minority of patients with suspected reflux laryngitis syndrome have these findings.

The more subtle findings of posterior laryngeal nodularity, erythema and oedema have no diagnostic validity, as they are considered to be present in up to 70% of healthy subjects.125 Furthermore, inter-observer agreement on the presence of these findings is unacceptably low.126, 127

97. Criteria for inclusion in a reflux laryngitis syndrome trial must include prespecified chronic throat symptoms and laryngoscopic findings. Agree: 100% (A+, 36%; A, 36%; A−, 27%)

Criteria for inclusion in a trial must be as well informed as possible about their limitations.

Reflux asthma syndrome.
98. Trials of anti-reflux therapy in the reflux-asthma syndrome should be placebo controlled. Agree: 92% (A+, 67%; A, 8%; A−, 17%; D, 8%)
99. Trials of anti-reflux therapy in the reflux asthma syndrome should have a treatment phase of at least 4 weeks. Agree: 100% (A+, 18%; A, 46%; A−, 36%)

The absence of a proven effective treatment for reflux cough, reflux laryngitis, and reflux asthma3 argues for placebo-controlled studies. A slight treatment effect coupled with substantial natural variation in the severity of asthma argues for a relatively long period of observation. Consistent with this, reflux asthma trials have usually been conducted over a 3- to 6-month time frame. However, two randomized controlled trials of anti-reflux surgery as treatment for asthma reported subsets of patients in the surgically treated arms who had complete asthma resolution.128–130 Also, the recent esomeprazole asthma trial131 demonstrated a response within 2 weeks in a predefined subset of patients with both GERD and nocturnal asthma symptoms (the study, however, failed to reach significance for the primary outcome measure).

100. An improvement in asthma attributable to anti-reflux therapy may be measured as an improvement in pulmonary function tests, on a validated asthma symptom scale, or as a reduction in asthma medication use. Agree: 100% (A+, 55%; A, 36%; A−, 9%)

A review of medical and surgical GERD therapy outcomes data showed significant improvement in asthma symptoms and significant reduction of asthma medication usage.130, 132 Subsequently, another trial of anti-reflux surgery found substantial asthma symptom improvement, but only a trend towards improvement of pulmonary function and no change in asthma medication usage.129 The esomeprazole asthma trial and another large PPI trial in asthmatics failed to show overall symptom improvement, improvement in pulmonary function or reduced asthma medication usage,131, 133 although the esomeprazole asthma trial demonstrated a slight but significant improvement in morning peak expiratory flow in a predefined subset of patients with both GERD and nocturnal asthma symptoms.131

101. The possibility that treatment may improve the natural history of dental erosions associated with reflux disease needs to be explored. Agree: 83% (A+, 25%; A, 25%; A−, 33%; D, 17%)

Two prospective consecutive series have demonstrated a greater prevalence of dental erosions in patients with reflux symptoms134 or GERD diagnosed by pH monitoring.135 A further study has found a positive correlation between oesophageal acid exposure and dental erosion score among patients with and without GERD.136 Although it is generally thought that the demineralization of dental enamel is pH-dependent and irreversible, this has not been the subject of clinical trials, leaving open the possibility that the natural history of dental erosions associated with GERD may improve with treatment.

102. Trials of acid reflux therapy in sinusitis, pulmonary fibrosis, pharyngitis or recurrent otitis media must be placebo controlled. Agree: 92% (A+, 83%; A, 8%; D, 8%)

The limited published information relevant to these proposed disease associations has been reviewed recently.137, 138 Epidemiological studies have shown a slightly increased odds ratio of 1.6 (95% CI: 1.51–1.70) for sinusitis and pulmonary fibrosis in US military veterans with reflux oesophagitis,139 but evidence of causal linkage is lacking. Similarly, there is no persuasive evidence of causal linkage and no authoritative data that indicate that GERD is a clinically significant contributor to pharyngitis or otitis media. All of these limitations argue for use of a placebo control in clinical trials of anti-reflux treatment for these clinical entities.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results and discussion
  6. Acknowledgements
  7. References
  8. Supporting Information

Declaration of personal interests: B. Delaney, K. Haruma, E. McColl and V. Stanghellini: none. J. Dent has served as a speaker, a consultant and an advisory board member for AstraZeneca, and has received research funding from AstraZeneca. P. Kahrilas has served as a consultant and an advisory board member for AstraZeneca. N. Vakil has served as a speaker for AstraZeneca, Novartis, Takeda and TAP, as a consultant and an advisory board member for AstraZeneca, Medtronic, Novartis, Orexo, Procter & Gamble, Shire, TAP and Xenoport, has received research funding from AstraZeneca, Medtronic, Novartis, Nycomed and TAP, and owns stocks and shares in Orexo. S. Veldhuyzen van Zanten has served as a speaker for Abbott Laboratories, AstraZeneca and Janssen-Ortho, as a consultant and an advisory board member for Abbott Laboratories, AstraZeneca, GlaxoSmithKline, Novartis and Procter & Gamble, and has received research funding from AstraZeneca, Jansen-Ortho, Nycomed and Pfizer. P. Bytzer has served as a speaker, a consultant and an advisory board member for AstraZeneca, Eisai, Jansen-Cilag, Nycomed and Wyeth, and has received research funding from AstraZeneca. J. Hatlebakk has served as a speaker for AstraZeneca, Merck Sharp & Dohme and Pfizer. P. Moayyedi has served as a speaker, a consultant and advisory board member for AstraZeneca, Jansen-Ortho and Nycomed. J. Tack has served as a speaker for AstraZeneca, Axcan, Menarini, Novartis and Nycomed, as a consultant and advisory board member for Addex, AGI, Allergan, Aryx, AstraZeneca, Axcan, Bayer, Chugai, Dainippon, Gastrotech, GlaxoSmithKline, Johnson & Johnson, Leria, Medtronic, Novartis, Pfizer, Procter & Gamble, Rotta, Smartpill, Theravance, Transzyme, Wyeth and Yamanouch, and has received research funding from GlaxoSmithKline and Nycomed. M. Vaezi has served as a speaker for AstraZeneca, Santarus and TAP, as a consultant and advisory board member for AstraZeneca, Restech and TAP, and has received research funding from AstraZeneca, Restech and TAP. Declaration of funding interests: This Workshop was funded by INSINConsulting, Guelph, Ontario, Canada using an unrestricted grant from AstraZeneca Research and Development, Sweden. AstraZeneca had no role to play in the content and conduct of the workshop. Initial data analyses were undertaken by the authors. Writing support was provided by Dr Anja Becher of Oxford PharmaGenesis and funded by INSINConsulting.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results and discussion
  6. Acknowledgements
  7. References
  8. Supporting Information
  • 1
    Altman DG, Schulz KF, Moher D, et al. The revised CONSORT statement for reporting randomized trials: explanation and elaboration. Ann Intern Med 2001; 134: 66394.
  • 2
    Moher D, Schulz KF, Altman DG, et al. Revised recommendations for improving the quality of reports of parallel group randomized trials. 2001. Available at: http://www.consort-statement.org (accessed 19 July 2007).
  • 3
    Vakil N, Van Zanten SV, Kahrilas P, Dent J, Jones R. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol 2006; 101: 190020; quiz 1943.
    Direct Link:
  • 4
    Zerbib F, Roman S, Ropert A, et al. Esophageal pH-impedance monitoring and symptom analysis in GERD: a study in patients off and on therapy. Am J Gastroenterol 2006; 101: 195663.
    Direct Link:
  • 5
    Koek GH, Sifrim D, Lerut T, Janssens J, Tack J. Effect of the GABA(B) agonist baclofen in patients with symptoms and duodeno-gastro-oesophageal reflux refractory to proton pump inhibitors. Gut 2003; 52: 1397402.
  • 6
    Vakil N. New pharmacological agents for the treatment of gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2004; 19: 10419.
  • 7
    Bardhan KD, Muller-Lissner S, Bigard MA, et al. Symptomatic gastro-oesophageal reflux disease: double blind controlled study of intermittent treatment with omeprazole or ranitidine. The European Study Group. BMJ 1999; 318: 5027.
  • 8
    Pace F, Tonini M, Pallotta S, Molteni P, Porro GB. Systematic review: maintenance treatment of gastro-oesophageal reflux disease with proton pump inhibitors taken ‘on-demand’. Aliment Pharmacol Ther 2007; 26: 195204.
  • 9
    Roland M, Torgerson D. Understanding controlled trials: what outcomes should be measured? BMJ 1998; 317: 1075.
  • 10
    Schwartz D, Lellouch J. Explanatory and pragmatic attitudes in therapeutical trials. J Chronic Dis 1967; 20: 63748.
  • 11
    Howden CW, Henning JM, Huang B, Lukasik N, Freston JW. Management of heartburn in a large, randomized, community-based study: comparison of four therapeutic strategies. Am J Gastroenterol 2001; 96: 170410.
    Direct Link:
  • 12
    Inadomi JM, Jamal R, Murata GH, et al. Step-down management of gastroesophageal reflux disease. Gastroenterology 2001; 121: 1095100.
  • 13
    Talley NJ, Vakil N. Guidelines for the management of dyspepsia. Am J Gastroenterol 2005; 100: 232437.
    Direct Link:
  • 14
    Vakil NB, Traxler B, Levine D. Dysphagia in patients with erosive esophagitis: prevalence, severity, and response to proton pump inhibitor treatment. Clin Gastroenterol Hepatol 2004; 2: 6658.
  • 15
    Vakil N, Moayyedi P, Fennerty MB, Talley NJ. Limited value of alarm features in the diagnosis of upper gastrointestinal malignancy: systematic review and meta-analysis. Gastroenterology 2006; 131: 390401; quiz 659–60.
  • 16
    Talley NJ, Lauritsen K, Tunturi-Hihnala H, et al. Esomeprazole 20 mg maintains symptom control in endoscopy-negative gastro-oesophageal reflux disease: a controlled trial of ‘on-demand’ therapy for 6 months. Aliment Pharmacol Ther 2001; 15: 34754.
  • 17
    Metz DC, Inadomi JM, Howden CW, Van Zanten SJ, Bytzer P. On-demand therapy for gastroesophageal reflux disease. Am J Gastroenterol 2007; 102: 64253.
    Direct Link:
  • 18
    Verdu EF, Armstrong D, Idstrom JP, et al. Effect of curing Helicobacter pylori infection on intragastric pH during treatment with omeprazole. Gut 1995; 37: 7438.
  • 19
    Nastaskin I, Mehdikhani E, Conklin J, Park S, Pimentel M. Studying the overlap between IBS and GERD: a systematic review of the literature. Dig Dis Sci 2006; 51: 211320.
  • 20
    Wright CE, Ebrecht M, Mitchell R, Anggiansah A, Weinman J. The effect of psychological stress on symptom severity and perception in patients with gastro-oesophageal reflux. J Psychosom Res 2005; 59: 41524.
  • 21
    Husser D, Bollmann A, Kuhne C, Molling J, Klein HU. Evaluation of noncardiac chest pain: diagnostic approach, coping strategies and quality of life. Eur J Pain 2006; 10: 515.
  • 22
    Biertho L, Sanjeev D, Sebajang H, Antony M, Anvari M. The influence of psychological factors on the outcomes of laparoscopic Nissen fundoplication. Ann Surg Innov Res 2007; 1: 2.
  • 23
    Moher D, Schulz KF, Altman DG. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials. Ann Intern Med 2001; 134: 65762.
  • 24
    Piaggio G, Elbourne DR, Altman DG, Pocock SJ, Evans SJ. Reporting of noninferiority and equivalence randomized trials: an extension of the CONSORT statement. JAMA 2006; 295: 115260.
  • 25
    Hetzel DJ, Dent J, Reed WD, et al. Healing and relapse of severe peptic esophagitis after treatment with omeprazole. Gastroenterology 1988; 95: 90312.
  • 26
    Carlsson R, Galmiche JP, Dent J, Lundell L, Frison L. Prognostic factors influencing relapse of oesophagitis during maintenance therapy with antisecretory drugs: a meta-analysis of long-term omeprazole trials. Aliment Pharmacol Ther 1997; 11: 47382.
  • 27
    Hunfeld NGM, Geus WP, Kuipers EJ. Systematic review: Rebound acid hypersecretion after therapy with proton pump inhibitors. Aliment Pharmacol Ther 2007; 25: 3946.
  • 28
    Pignone M, Anderson GK, Binns K, Tilson HH, Weisman SM. Aspirin use among adults aged 40 and older in the United States: results of a national survey. Am J Prev Med 2007; 32: 4037.
  • 29
    Kim SL, Hunter JG, Wo JM, Davis LP, Waring JP. NSAIDs, aspirin, and esophageal strictures: are over-the-counter medications harmful to the esophagus? J Clin Gastroenterol 1999; 29: 324.
  • 30
    Lundell LR, Miettinen P, Myrvold HE, et al. Anti-reflux surgery compared with maintenance omeprazole for reflux esophagitis. Results after 12 years. Gastroenterology 2007; 4(Suppl. 2): A107.
  • 31
    Greenhalgh T. Assessing the methodological quality of published papers. BMJ 1997; 315: 3058.
  • 32
    Johnson DA, Fennerty MB. Heartburn Severity Underestimates Erosive Esophagitis Severity in Elderly Patients with Gastroesophageal Reflux Disease. Gastroenterology 2004; 126: 6604.
  • 33
    Bayer A, Tadd W. Unjustified exclusion of elderly people from studies submitted to research ethics committee for approval: descriptive study. BMJ 2000; 321: 9923.
  • 34
    European Medicines Agency. Note for Guidance on Studies in Support of Special Populations: Geriatrics (CPMP/ICH/379/95). 1994. Available at: http://www.emea.europa.eu (accessed 6 July 2007).
  • 35
    Sibbald B, Roberts C. Understanding controlled trials. Crossover trials. BMJ 1998; 316: 1719.
  • 36
    Lord SJ, Gebski VJ, Keech AC. Multiple analyses in clinical trials: sound science or data dredging? Med J Aust 2004; 181: 4524.
  • 37
    Food and Drug Administration. Guidance for Industry: E9 Statistical Principles for Clinical Trials. 1998. Available at: http://www.fda.gov (accessed 10 September 2007).
  • 38
    Food and Drug Adminstration. E8 General Considerations for Clinical Trials. 1997. Available at: http://www.fda.gov (accessed 10 September 2007).
  • 39
    Altman D. Practical Statistics for Medical Research. London: Chapman and Hall, 1991: 456.
  • 40
    Greenhalgh T. How to read a paper. Statistics for the non-statistician. I: Different types of data need different statistical tests. BMJ 1997; 315: 3646.
  • 41
    Food and Drug Administration. Patient Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. 2006. Available at: http://www.fda.gov (accessed 24 July 2007).
  • 42
    European Medicines Agency. Reflection Paper on the Regulatory Guidance for the Use of Health-Related Quality of Life (HRQL) Measures in the Evaluation of Medicinal Products. 2005. Available at: http://emea.europe.eu (accessed 10 December 2007).
  • 43
    McColl E, Junghard O, Wiklund I, Revicki DA. Assessing symptoms in gastroesophageal reflux disease: How well do clinicians’ assessments agree with those of their patients? Am J Gastroenterol 2005; 100: 118.
    Direct Link:
  • 44
    McColl E. Best practice in symptom assessment: a review. Gut 2004; 53(Suppl. 4): iv4954.
  • 45
    Fallone CA, Guyatt GH, Armstrong D, et al. Do physicians correctly assess patient symptom severity in gastro-oesophageal reflux disease? Aliment Pharmacol Ther 2004; 20: 11619.
  • 46
    Veldhuyzen van Zanten S, Talley N, Bytzer P, Klein K, Whorwell P, Zinsmeister A. Rome II: the Functional Gastrointestinal Disorders 1999. In: Drossman, Carazziari, Talley, Thompson, Whitehead, and the Rome II International Working Teams, ed. Design of Treatment Trials for the Functional Gastrointestinal Disorders. MacLean, VA, USA: Degnon Associates, 2000: 577622.
  • 47
    Lauritsen K, Degl’ Innocenti A, Hendel L, et al. Symptom recording in a randomised clinical trial: paper diaries vs. electronic or telephone data capture. Control Clin Trials 2004; 25: 58597.
  • 48
    Hyland ME, Kenyon CA, Allen R, Howarth P. Diary keeping in asthma: comparison of written and electronic methods. BMJ 1993; 306: 4879.
  • 49
    Stone AA, Shiffman S, Schwartz JE, Broderick JE, Hufford MR. Patient compliance with paper and electronic diaries. Control Clin Trials 2003; 24: 18299.
  • 50
    Stanghellini V, Armstrong D, Monnikes H, Bardhan KD. Systematic review: Do we need a new gastro-oesophageal reflux disease questionnaire? Aliment Pharmacol Ther 2004; 19: 46379.
  • 51
    Revicki DA, Wood M, Wiklund I, Crawley J. Reliability and validity of the Gastrointestinal Symptom Rating Scale in patients with gastroesophageal reflux disease. Qual Life Res 1998; 7: 7583.
  • 52
    Allen CJ, Parameswaran K, Belda J, Anvari M. Reproducibility, validity, and responsiveness of a disease-specific symptom questionnaire for gastroesophageal reflux disease. Dis Esophagus 2000; 13: 26570.
  • 53
    Dimenas E, Glise H, Hallerback B, Hernqvist H, Svedlund J, Wiklund I. Quality of life in patients with upper gastrointestinal symptoms. An improved evaluation of treatment regimens? Scand J Gastroenterol 1993; 28: 6817.
  • 54
    Rothman M, Farup C, Stewart W, Helbers L, Zeldis J. Symptoms associated with gastroesophageal reflux disease: development of a questionnaire for use in clinical trials. Dig Dis Sci 2001; 46: 15409.
  • 55
    Williford WO, Krol WF, Spechler SJ. Development for and results of the use of a gastroesophageal reflux disease activity index as an outcome variable in a clinical trial. VA Cooperative Study Group on Gastroesophageal Reflux Disease (GERD). Control Clin Trials 1994; 15: 33548.
  • 56
    Shaw MJ, Talley NJ, Beebe TJ, et al. Initial validation of a diagnostic questionnaire for gastroesophageal reflux disease. Am J Gastroenterol 2001; 96: 527.
    Direct Link:
  • 57
    Ducrotte P, Zerbib F. ReQuest: a new questionnaire for the simultaneous evaluation of symptoms and well-being in patients with gastro-oesophageal reflux. Digestion 2007; 75(Suppl. 1): 7986.
  • 58
    Atkinson MJ, Sinha A, Hass SL, et al. Validation of a general measure of treatment satisfaction, the Treatment Satisfaction Questionnaire for Medication (TSQM), using a national panel study of chronic disease. Health Qual Life Outcomes 2004; 2: 12.
  • 59
    Atkinson MJ, Kumar R, Cappelleri JC, Hass SL. Hierarchical construct validity of the treatment satisfaction questionnaire for medication (TSQM version II) among outpatient pharmacy consumers. Value Health 2005; 8(Suppl. 1): S924.
  • 60
    Wyrwich KW, Tardino VM. A blueprint for symptom scales and responses: measurement and reporting. Gut 2004; 53(Suppl. 4): iv458.
  • 61
    Bytzer P. Information bias in endoscopic assessment. Am J Gastroenterol 2007; 102: 15857.
    Direct Link:
  • 62
    Junghard O, Carlsson R, Lind T. Sufficient control of heartburn in endoscopy-negative gastro-oesophageal reflux disease trials. Scand J Gastroenterol 2003; 38: 11979.
  • 63
    Fraser A, Delaney B, Moayyedi P. Symptom-based outcome measures for dyspepsia and GERD trials: a systematic review. Am J Gastroenterol 2005; 100: 44252.
    Direct Link:
  • 64
    Veldhuyzen van Zanten SJ, Chiba N, Armstrong D, et al. Validation of a 7-point Global Overall Symptom scale to measure the severity of dyspepsia symptoms in clinical trials. Aliment Pharmacol Ther 2006; 23: 5219.
  • 65
    Talley NJ, Fullerton S, Junghard O, Wiklund I. Quality of life in patients with endoscopy-negative heartburn: reliability and sensitivity of disease-specific instruments. Am J Gastroenterol 2001; 96: 19982004.
    Direct Link:
  • 66
    Sharma N, Donnellan C, Preston C, Delaney B, Duckett G, Moayyedi P. A systematic review of symptomatic outcomes used in oesophagitis drug therapy trials. Gut 2004; 53(Suppl. 4): iv5865.
  • 67
    Irvine EJ, Whitehead WE, Chey WD, et al. Design of treatment trials for functional gastrointestinal disorders. Gastroenterology 2006; 130: 153851.
  • 68
    Veldhuyzen van Zanten SJ, Talley NJ, Bytzer P, Klein KB, Whorwell PJ, Zinsmeister AR. Design of treatment trials for functional gastrointestinal disorders. Gut 1999; 45(Suppl. 2): II6977.
  • 69
    Mangel AW, Hahn BA, Heath AT, et al. Adequate relief as an endpoint in clinical trials in irritable bowel syndrome. J Int Med Res 1998; 26: 7681.
  • 70
    Muller-Lissner S, Koch G, Talley NJ, et al. Subject’s Global Assessment of Relief: an appropriate method to assess the impact of treatment on irritable bowel syndrome-related symptoms in clinical trials. J Clin Epidemiol 2003; 56: 3106.
  • 71
    Whitehead WE, Palsson OS, Levy RL, Feld AD, VonKorff M, Turner M. Reports of “satisfactory relief” by IBS patients receiving usual medical care are confounded by baseline symptom severity and do not accurately reflect symptom improvement. Am J Gastroenterol 2006; 101: 105765.
    Direct Link:
  • 72
    Talley NJ, Venables TL, Green JR, et al. Esomeprazole 40 mg and 20 mg is efficacious in the long-term management of patients with endoscopy-negative gastro-oesophageal reflux disease: a placebo-controlled trial of on-demand therapy for 6 months. Eur J Gastroenterol Hepatol 2002; 14: 85763.
  • 73
    Lind T, Havelund T, Lundell L, et al. On demand therapy with omeprazole for the long-term management of patients with heartburn without oesophagitis--a placebo-controlled randomized trial. Aliment Pharmacol Ther 1999; 13: 90714.
  • 74
    Zacny J, Zamakhshary M, Sketris I, Van Zanten SV. Systematic review: the efficacy of intermittent and on-demand therapy with histamine H2-receptor antagonists or proton pump inhibitors for gastro-oesophageal reflux disease patients. Aliment Pharmacol Ther 2005; 21: 1299312.
  • 75
    Dent J, Armstrong D, Delaney B, Moayyedi P, Talley NJ, Vakil N. Symptom evaluation in reflux disease: workshop background, processes, terminology, recommendations, and discussion outputs. Gut 2004; 53: iv124.
  • 76
    Coyne KS, Wiklund I, Schmier J, Halling K, Degl’ Innocenti A, Revicki D. Development and validation of a disease-specific treatment satisfaction questionnaire for gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2003; 18: 90715.
  • 77
    Holloway RH, Dent J, Narielvala F, Mackinnon AM. Relation between oesophageal acid exposure and healing of oesophagitis with omeprazole in patients with severe reflux oesophagitis. Gut 1996; 38: 64954.
  • 78
    Wiklund I, Carlsson J, Vakil N. Gastroesophageal reflux symptoms and well-being in a random sample of the general population of a Swedish community. Am J Gastroenterol 2006; 101: 1828.
    Direct Link:
  • 79
    Ronkainen J, Aro P, Storskrubb T, et al. Gastro-oesophageal reflux symptoms and health-related quality of life in the adult general population – the Kalixanda study. Aliment Pharmacol Ther 2006; 23: 172533.
  • 80
    Van Zanten SV, Armstrong D, Barkun A, Junghard O, White RJ, Wiklund IK. Symptom overlap in patients with upper gastrointestinal complaints in the Canadian confirmatory acid suppression test (CAST) study: further psychometric validation of the reflux disease questionnaire. Aliment Pharmacol Ther 2007; 25: 108797.
  • 81
    Monnikes H, Bardhan KD, Stanghellini V, Berghofer P, Bethke TD, Armstrong D. Evaluation of GERD symptoms during therapy: Part II. Psychometric evaluation and validation of the new questionnaire ReQuestTM in erosive GERD. Digestion 2004; 69: 23844.
  • 82
    Armstrong D, Monnikes H, Bardhan KD, Stanghellini V. The construction of a new evaluative GERD questionnaire – methods and state of the art. Digestion 2004; 70: 718.
  • 83
    Bardhan KD, Stanghellini V, Armstrong D, Berghofer P, Gatz G, Monnikes H. Evaluation of GERD symptoms during therapy: Part I. Development of the new GERD Questionnaire ReQuestTM. Digestion 2004; 69: 22937.
  • 84
    Donnellan C, Sharma N, Preston C, Moayyedi P. Medical treatments for the maintenance therapy of reflux oesophagitis and endoscopic negative reflux disease. Cochrane Database Syst Rev 2005; 2: CD003245.
  • 85
    Thjodleifsson B, Rindi G, Fiocca R, et al. A randomized, double-blind trial of the efficacy and safety of 10 or 20 mg rabeprazole compared with 20 mg omeprazole in the maintenance of gastro-oesophageal reflux disease over 5 years. Aliment Pharmacol Ther 2003; 17: 34351.
  • 86
    Shaker R, Castell DO, Schoenfeld PS, Spechler SJ. Nighttime heartburn is an under-appreciated clinical problem that impacts sleep and daytime function: the results of a Gallup survey conducted on behalf of the American Gastroenterological Association. Am J Gastroenterol 2003; 98: 148793.
    Direct Link:
  • 87
    Dubois RW, Aguilar D, Fass R, et al. Consequences of frequent nocturnal gastro-oesophageal reflux disease among employed adults: symptom severity, quality of life and work productivity. Aliment Pharmacol Ther 2007; 25: 487500.
  • 88
    Cremonini F, Wise J, Moayyedi P, Talley NJ. Diagnostic and therapeutic use of proton pump inhibitors in non-cardiac chest pain: a metaanalysis. Am J Gastroenterol 2005; 100: 122632.
    Direct Link:
  • 89
    Achem SR, Kolts BE, MacMath T, et al. Effects of omeprazole versus placebo in treatment of noncardiac chest pain and gastroesophageal reflux. Dig Dis Sci 1997; 42: 213845.
  • 90
    Bautista J, Fullerton H, Briseno M, Cui H, Fass R. The effect of an empirical trial of high-dose lansoprazole on symptom response of patients with non-cardiac chest pain - A randomized, double-blind, placebo-controlled, crossover trial. Aliment Pharmacol Ther 2004; 19: 112330.
  • 91
    Fass R, Fennerty MB, Ofman JJ, et al. The clinical and economic value of a short course of omeprazole in patients with noncardiac chest pain. Gastroenterology 1998; 115: 429.
  • 92
    Pandak WM, Arezo S, Everett S, et al. Short course of omeprazole: a better first diagnostic approach to noncardiac chest pain than endoscopy, manometry, or 24-hour esophageal pH monitoring. J Clin Gastroenterol 2002; 35: 30714.
  • 93
    Xia HH, Lai KC, Lam SK, et al. Symptomatic response to lansoprazole predicts abnormal acid reflux in endoscopy-negative patients with non-cardiac chest pain. Aliment Pharmacol Ther 2003; 17: 36977.
  • 94
    Dickman R, Emmons S, Cui H, et al. The effect of a therapeutic trial of high-dose rabeprazole on symptom response of patients with non-cardiac chest pain: a randomized, double-blind, placebo-controlled, crossover trial. Aliment Pharmacol Ther 2005; 22: 54755.
  • 95
    Khan M, Santana J, Donnellan C, Preston C, Moayyedi P. Medical treatments in the short term management of reflux oesophagitis. Cochrane Database Syst Rev 2007; 2: CD003244.
  • 96
    Armstrong D, Bennett JR, Blum AL, et al. The endoscopic assessment of esophagitis: a progress report on observer agreement. Gastroenterology 1996; 111: 8592.
  • 97
    Lundell LR, Dent J, Bennett JR, et al. Endoscopic assessment of oesophagitis: clinical and functional correlates and further validation of the Los Angeles classification. Gut 1999; 45: 17280.
  • 98
    Pandolfino JE, Vakil NB, Kahrilas PJ. Comparison of inter- and intraobserver consistency for grading of esophagitis by expert and trainee endoscopists. Gastrointest Endosc 2002; 56: 63943.
  • 99
    Sharma P, Wani S, Bansal A, et al. A feasibility trial of narrow band imaging endoscopy in patients with gastroesophageal reflux disease. Gastroenterology 2007; 133: 45464; quiz 674.
  • 100
    Kiesslich R, Kanzler S, Vieth M, et al. Minimal change esophagitis: prospective comparison of endoscopic and histological markers between patients with non-erosive reflux disease and normal controls using magnifying endoscopy. Dig Dis 2004; 22: 2217.
  • 101
    Van Pinxteren B, Numans ME, Bonis PA, Lau J. Short-term treatment with proton pump inhibitors, H2-receptor antagonists and prokinetics for gastro-oesophageal reflux disease-like symptoms and endoscopy negative reflux disease. Cochrane Database Syst Rev 2006; 3: CD002095.
  • 102
    Revicki DA, Wood M, Maton PN, Sorensen S. The impact of gastroesophageal reflux disease on health-related quality of life. Am J Med 1998; 104: 2528.
  • 103
    Sonnenberg A, El-Serag HB. Clinical epidemiology and natural history of gastroesophageal reflux disease. Yale J Biol Med 1999; 72: 8192.
  • 104
    Furuta GT, Straumann A. Review article: the pathogenesis and management of eosinophilic oesophagitis. Aliment Pharmacol Ther 2006; 24: 17382.
  • 105
    Desai TK, Stecevic V, Chang CH, Goldstein NS, Badizadegan K, Furuta GT. Association of eosinophilic inflammation with esophageal food impaction in adults. Gastrointest Endosc 2005; 61: 795801.
  • 106
    Potter JW, Saeian K, Staff D, et al. Eosinophilic esophagitis in adults: an emerging problem with unique esophageal features. Gastrointest Endosc 2004; 59: 35561.
  • 107
    Gonsalves N, Policarpio-Nicolas M, Zhang Q, Rao MS, Hirano I. Histopathologic variability and endoscopic correlates in adults with eosinophilic esophagitis. Gastrointest Endosc 2006; 64: 3139.
  • 108
    Sharma P, McQuaid K, Dent J, et al. A critical review of the diagnosis and management of Barrett’s esophagus: The AGA Chicago Workshop. Gastroenterology 2004; 127: 31030.
  • 109
    Sampliner RE. Updated guidelines for the diagnosis, surveillance, and therapy of Barrett’s esophagus. Am J Gastroenterol 2002; 97: 188895.
    Direct Link:
  • 110
    Ofman JJ, Shaheen NJ, Desai AA, Moody B, Bozymski EM, Weinstein WM. The quality of care in Barrett’s esophagus: endoscopist and pathologist practices. Am J Gastroenterol 2001; 96: 87681.
    Direct Link:
  • 111
    Sharma P, Dent J, Armstrong D, et al. The development and validation of an endoscopic grading system for Barrett’s esophagus: the Prague C & M criteria. Gastroenterology 2006; 131: 13929.
  • 112
    Dekel R, Wakelin DE, Wendel C, et al. Progression or regression of Barrett’s esophagus--is it all in the eye of the beholder? Am J Gastroenterol 2003; 98: 26125.
  • 113
    Reid BJ, Levine DS, Longton G, Blount PL, Rabinovitch PS. Predictors of progression to cancer in Barrett’s esophagus: baseline histology and flow cytometry identify low- and high-risk patient subsets. Am J Gastroenterol 2000; 95: 166976.
  • 114
    Weston AP, Sharma P, Topalovski M, Richards R, Cherian R, Dixon A. Long-term follow-up of Barrett’s high-grade dysplasia. Am J Gastroenterol 2000; 95: 188893.
    Direct Link:
  • 115
    Nigro JJ, Hagen JA, DeMeester TR, et al. Occult esophageal adenocarcinoma: extent of disease and implications for effective therapy. Ann Surg 1999; 230: 4338; discussion 438–40.
  • 116
    Kara MA, Peters FP, Rosmolen WD, et al. High-resolution endoscopy plus chromoendoscopy or narrow-band imaging in Barrett’s esophagus: a prospective randomized crossover study. Endoscopy 2005; 37: 92936.
  • 117
    Chang AB, Lasserson TJ, Kiljander TO, Connor FL, Gaffney JT, Garske LA. Systematic review and meta-analysis of randomised controlled trials of gastro-oesophageal reflux interventions for chronic cough associated with gastro-oesophageal reflux. BMJ 2006; 332: 114.
  • 118
    Blondeau K, Dupont LJ, Mertens V, Tack J, Sifrim D. Improved diagnosis of gastro-oesophageal reflux in patients with unexplained chronic cough. Aliment Pharmacol Ther 2007; 25: 72332.
  • 119
    Raj AA, Birring SS. Clinical assessment of chronic cough severity. Pulm Pharmacol Ther 2007; 20: 3347.
  • 120
    Qadeer MA, Phillips CO, Lopez AR, et al. Proton pump inhibitor therapy for suspected GERD-related chronic laryngitis: a meta-analysis of randomized controlled trials. Am J Gastroenterol 2006; 101: 264654.
  • 121
    Gatta L, Vaira D, Sorrenti G, Zucchini S, Sama C, Vakil N. Meta-analysis: the efficacy of proton pump inhibitors for laryngeal symptoms attributed to gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2007; 25: 38592.
  • 122
    Vaezi MF, Lopez R, Hicks DM, Abelson TI, Milstein C. What is the optimal initial therapy duration for patients with suspected GERD-related laryngitis? Gastroenterology 2006; 130: A140.
  • 123
    Food and Drug Administration. Patient Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. 2006. Available at: http://www.fda.gov (accessed 24 June 2007).
  • 124
    Park W, Hicks DM, Khandwala F, et al. Laryngopharyngeal reflux: prospective cohort study evaluating optimal dose of proton-pump inhibitor therapy and pretherapy predictors of response. Laryngoscope 2005; 115: 12308.
  • 125
    Hicks DM, Ours TM, Abelson TI, Vaezi MF, Richter JE. The prevalence of hypopharynx findings associated with gastroesophageal reflux in normal volunteers. J Voice 2002; 16: 56479.
  • 126
    Vavricka SR, Storck CA, Wildi SM, et al. Limited diagnostic value of laryngopharyngeal lesions in patients with gastroesophageal reflux during routine upper gastrointestinal endoscopy. Am J Gastroenterol 2007; 102: 71622.
    Direct Link:
  • 127
    Falk GW. Laryngopharyngeal reflux: beauty is in the eye of the beholder. Gastroenterology 2007; 133: 137981.
  • 128
    Larrain A, Carrasco E, Galleguillos F, Sepulveda R, Pope CE, II. Medical and surgical treatment of nonallergic asthma associated with gastroesophageal reflux. Chest 1991; 99: 13305.
  • 129
    Sontag SJ, O’Connell S, Khandelwal S, et al. Asthmatics with gastroesophageal reflux: long term results of a randomized trial of medical and surgical antireflux therapies. Am J Gastroenterol 2003; 98: 98799.
  • 130
    Field SK, Gelfand GA, McFadden SD. The effects of antireflux surgery on asthmatics with gastroesophageal reflux. Chest 1999; 116: 76674.
  • 131
    Kiljander TO, Harding SM, Field SK, et al. Effects of esomeprazole 40 mg twice daily on asthma: a randomized placebo-controlled trial. Am J Respir Crit Care Med 2006; 173: 10917.
  • 132
    Field SK, Sutherland LR. Does medical antireflux therapy improve asthma in asthmatics with gastroesophageal reflux?: a critical review of the literature. Chest 1998; 114: 27583.
  • 133
    Littner MR, Leung FW, Ballard ED II, Huang B, Samra NK. Effects of 24 weeks of lansoprazole therapy on asthma symptoms, exacerbations, quality of life, and pulmonary function in adult asthmatic patients with acid reflux symptoms. Chest 2005; 128: 112835.
  • 134
    Munoz JV, Herreros B, Sanchiz V, et al. Dental and periodontal lesions in patients with gastro-oesophageal reflux disease. Dig Liver Dis 2003; 35: 4617.
  • 135
    Bohmer CJ, Klinkenberg-Knol EC, Niezen-de Boer MC, Meuwissen PR, Meuwissen SG. Dental erosions and gastro-oesophageal reflux disease in institutionalized intellectually disabled individuals. Oral Dis 1997; 3: 2725.
  • 136
    Schroeder PL, Filler SJ, Ramirez B, Lazarchik DA, Vaezi MF, Richter JE. Dental erosion and acid reflux disease. Ann Intern Med 1995; 122: 80915.
  • 137
    Weaver EM. Association between gastroesophageal reflux and sinusitis, otitis media, and laryngeal malignancy: a systematic review of the evidence. Am J Med 2003; 115(Suppl. 3A): 81S9S.
  • 138
    Groen JN, Smout AJ. Supra-oesophageal manifestations of gastro-oesophageal reflux disease. Eur J Gastroenterol Hepatol 2003; 15: 133950.
  • 139
    El-Serag HB, Sonnenberg A. Comorbid occurrence of laryngeal or pulmonary disease with esophagitis in United States military veterans. Gastroenterology 1997; 113: 75560.

Supporting Information

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results and discussion
  6. Acknowledgements
  7. References
  8. Supporting Information

Appendix S1.  List of statements that were rejected (voting results and subtext provided in online supplement).

23. There should be a defined period of baseline observation without treatment in placebo-controlled trials.

38. Frequency, rather than intensity, of a specific symptom is a more reliable measure of the burden from a specific symptom.

43. Validated reproducible instruments and scales that measure symptoms and response to therapy are currently not available for many GERD symptoms.

66. Double-blind studies are needed that test on-demand therapy in patients with Los Angeles (LA) grade A or B esophagitis.

76. Trials in suspected reflux chest pain syndrome should have a medical treatment phase of at least 3 months.

90. Trials of medical therapy in suspected reflux cough syndrome should have a treatment phase of at least 4 weeks.

95. Only a minority of patients suspected to have reflux laryngitis syndrome has troublesome heartburn.

Please note: Blackwell Publishing are not responsible for the content or functionality of any supplementary materials supplied by the authors. Any queries (other than missing material) should be directed to the corresponding author for the article.

FilenameFormatSizeDescription
APT_3700_sm_AppendixS1.doc53KSupporting info item

Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.