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.


  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.


  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 (, 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.


  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.


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

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.