Daphne Ang

Nicholas J Talley

Magnus Simrén

Pieter Janssen

Guy E Boeckxstaens

M.D Jan Tack
email: jan.tack@med.kuleuven.ac.be.

M Simren

ENDPOINTS USED IN FUNCTIONAL DYSPEPSIA DRUG THERAPY TRIALS

Keywords: Functional dyspepsia < Disease-based, Functional GI diseases < Disease-based, Stomach Functional dyspepsia, endpoints, clinical trials, patient reported outcomes, quality of life, questionnaires

published or not. The documents may come

INTRODUCTION

Functional dyspepsia (FD), is one of the most prevalent functional gastrointestinal disorders (FGIDs). Over the last 20 years, the definition of FD has undergone major changes from the 1988 working party 1 to the consecutive Rome consensus documents [START_REF] Talley | Functional dyspepsia: A classification with guidelines for diagnosis and management[END_REF][START_REF] Talley | Functional gastroduodenal disorders[END_REF][START_REF] Tack | Functional gastroduodenal disorders[END_REF] , in line with changing understanding of the pathophysiological basis of this disorder. Based on Rome III criteria [START_REF] Tack | Functional gastroduodenal disorders[END_REF] , FD is defined as the presence of symptoms thought to originate in the gastroduodenal region (early satiation, postprandial fullness, epigastric pain or burning), in the absence of any organic, systemic or metabolic disease that is likely to explain the symptoms. FD is further subdivided into 2 diagnostic categories of meal induced dyspeptic symptoms (postprandial distress syndrome [PDS], characterized by postprandial fullness and early satiation) and epigastric pain syndrome ([EPS], characterized by epigastric pain and burning). Whereas the previous Rome II definition [START_REF] Talley | Functional gastroduodenal disorders[END_REF] for FD excluded patients with predominant heartburn and was unclear on nonpredominant heartburn, the Rome III definition states that heartburn is not a gastroduodenal symptom, although it often occurs simultaneously with FD symptoms. [START_REF] Tack | Functional gastroduodenal disorders[END_REF] Similarly, although there is frequent overlap with the irritable bowel syndrome, the symptom pattern of both entities is distinct.

FD is one of the most important categories of the FGID, in view of its prevalence and impact on the general population. [START_REF] Drossman | Identification of subgroups of functional gastrointestinal disorders[END_REF][START_REF] Talley | Non-ulcer dyspepsia: Potential causes and pathophysiology[END_REF][START_REF] Talley | Onset and disappearance of gastrointestinal symptoms and functional gastrointestinal disorders[END_REF][START_REF] Shaib | The prevalence and risk factors of functional dyspepsia in a multiethnic population in the United States[END_REF] At present, there is no treatment with established efficacy for FD. 1 The Food and Drug Administration (PRO) before endorsing a clinical product. [START_REF]Patient reported outcome measures: use in medical product development to support labeling claims[END_REF] The Rome III committee [START_REF] Of | Design of treatment trials for functional gastrointestinal disorders[END_REF] has also provided guidelines for clinical trial design in FGIDs, with a similar emphasis on individual patient assessment and the use of validated outcome measures. The aim of the present study is to evaluate the currently available endpoints for FD drug development, in line with the Rome III definitions, the published FDA guidelines and Rome III clinical trials recommendations.

MATERIALS AND METHODS

Identification of relevant studies

To identify relevant studies, both computerized (Medline) and manual searches were performed, using the cited references of the retrieved articles.

MeSH and free-text terms for FD therapies were combined with the terms dyspepsia, clinical trials, symptom assessment, questionnaires, patient reported measures and randomized for searches conducted for the time period between January 1979 and December 2008. FD therapeutic trials were retrieved and studied, with emphasis on the method used for evaluating outcome measures. Article reference lists were examined for relevant papers.

Analysis of both full papers and abstracts was conducted, with particular emphasis on outcome measures. The literature search was performed independently by 2 of the authors, and their retrievals were merged.

Inclusion criteria

The following criteria were used to select trials for analysis: (i) randomized double blind controlled trials (RCT), (ii) parallel or single cross-over trial designs, (iii) adult patients with FD, (iv) baseline gastroscopy to exclude structural pathology; (v) comparison of therapy vs. active or placebo control;

(vi) clear description of the method of assessing outcome measures for FD symptoms, and (vi) articles in English.

Outcome measures

One of the main difficulties encountered with therapeutic trials in FGIDs, and FD in particular where efficacy has not been established for any treatment, is the lack of objectively measurable outcome measures. [START_REF] Veldhuyzen Van Zanten | A systematic overview (meta-analysis) of outcome measures in Helicobacter pylori gastritis trials and functional dyspepsia[END_REF][START_REF] Talley | A critique of therapeutic trials in Helicobacter pylori-positive functional dyspepsia[END_REF][START_REF] Veldhuyzen Van Zanten | Drug treatment of functional dyspepsia: a systematic analysis of trial methodology with recommendations for design of future trials[END_REF][START_REF] Veldhuyzen Van Zanten | Assessment of outcome in dyspepsia: has progress been made?[END_REF] In FD, symptom patterns do not correlate well with putative pathophysiological mechanisms such as gastric accommodation, sensitivity to distension and gastric emptying rates. [START_REF] Tack | Pathophysiology and treatment of functional dyspepsia[END_REF] In the absence of quantifiable surrogate markers for symptom improvement, evaluation of treatment response has to rely on patient's reporting of symptom intensities.

Several types of outcome measures have been used in FD clinical trials.

These can be broadly classified into global outcomes, generic instruments and disease specific instruments. [START_REF] Guyatt | Measuring quality of life in clinical trials: a taxonomy and review[END_REF] Global outcomes are measured either by a dichotomous binary type response (e.g. yes/no to symptom improvement )

or a scoring method which can either be a Likert scale (categorical) or a visual analogue scale (VAS). Likert scales allow easier interpretation for the physician compared to the VAS, with 5-point or 7-point scales providing greater sensitivity than 4-point scales. [START_REF] Talley | The irritable bowel syndrome: toward optimal design of controlled treatment trials[END_REF] The VAS and 7-point Likert scales exhibit comparable responsiveness, although the ease of administration and interpretation of the 7-point scale recommend its use in clinical trials. [START_REF] Guyatt | A comparison of Likert and Visual Analogue Scales for measuring change in function[END_REF] The Likert scale is often incorporated into global scales, such as the overall treatment effect (OTE), [START_REF] Jaeschke | Measurement of health status:ascertaining the minimal clinically important difference[END_REF] outcome, and is particularly suitable to show deterioration. Unlike generic instruments, disease specific instruments focus on a particular medical condition and are likely to be more useful in quantifying changes in quality of life in FD therapeutic trials. [START_REF] Guyatt | Responsiveness and validity in health status measurement: a clarification[END_REF] Disease specific instruments in FD can be unidimensional (evaluating gastrointestinal symptoms) or multidimensional (evaluating both gastrointestinal symptoms and other domains such as emotional or social functioning and impact of symptoms on daily activities).

Validity of outcome measures

In 1999, the Rome II Working Group emphasised individual patient assessment as a primary outcome, allowing for the integration of multiple symptoms into a single global endpoint for FGID studies. [START_REF] Veldhuyzen Van Zanten | Design of treatment trials for functionalgastrointestinal disorders[END_REF] An alternative method was the use of a disease specific questionnaire to evaluate relevant aspects of the patient's symptoms and disease related quality of life.

RESULTS

Description of studies

Amongst the therapeutic trials for FD, 117 studies were initially obtained. After excluding 31 studies which did not satisfy the inclusion criteria, 86 studies were selected for analysis of the outcome measures. 1 summarizes the types of endpoints used in the FD studies that were selected for the analysis.

A. Adequate relief or satisfactory relief (Binary Outcome) as a primary endpoint

Evaluating the relief of FD symptoms using a binary outcome approach (yes/no response) was first employed in a study which was designed to compare reflux episodes in FD patients who responded to omeprazole with non-responders. [START_REF] Farup | Patients with functional dyspepsia responding to omeprazole have a characteristic gastrooesophageal reflux pattern[END_REF] Responders were defined as patients who considered themselves to have achieved sufficient relief of symptoms at the end of study period. A significantly higher number of reflux episodes on 24 hour oesophageal pH measurement were detected in omeprazole responders.

Based on extensive experience from irritable bowel syndrome (IBS) studies, [START_REF] Camilleri | Improvement in pain and bowel function in female irritable bowel patients with alosetron, a 5-HT3 receptor antagonist[END_REF] The endpoint of adequate relief is responsive, reproducible and demonstrates good construct validity, [START_REF] Mangel | Personal view: adequate relief as a primary endpoint in irritable bowel syndrome[END_REF][START_REF] Camilleri | Primary endpoints for FGID trials: A review of binary and integrated symptom assessments[END_REF] and has been used in both IBS [START_REF] Camilleri | Improvement in pain and bowel function in female irritable bowel patients with alosetron, a 5-HT3 receptor antagonist[END_REF][START_REF] Camilleri | Efficacy and safety of alosetron in women with irritable bowel syndrome: a randomized, placebo-controlled trial[END_REF][START_REF] Camilleri | A randomized controlled clinical trial of the serotonin type 3 receptor antagonist alosetron in women with diarrhoea-predominant irritable bowel syndrome[END_REF][START_REF] Miner | Cilansetron in irritable bowel syndrome with diarrhoea predominance (IBS-D); efficacy and safety in a 3 month US study[END_REF][START_REF] Leventer | The potential dextofisopam for treatment of irritable bowel syndrome and the irritable bowel syndrome[END_REF][START_REF] Bradette | Cilansetron in irritable bowel syndrome with diarrhoea predominance (IBS-D): efficacy and safety in a 6 month global study[END_REF][START_REF] Coremans | Cilansetron, a novel 5-HT3 antagonist demonstrated efficacy in males with irritable bowel syndrome with diarrhoea-predominance (IBS-D)[END_REF][START_REF] Leventer | The safety and efficacy of dextofisopam in patients with diarrhoea-predominant or alternating irritable bowel syndrome[END_REF] and FD [START_REF] Talley | A dose ranging placebo controlled randomized trial of alosetron in patients with functional dyspepsia[END_REF][START_REF] Matsueda | Therapeutic Efficacy of Novel Agent(Z-338) in Functional Dyspepsia(FD)[END_REF][START_REF] Talley | A Novel Acetylcholine Esterase Inhibitor Acotiamide Hydrochloride (YM443) in Functional Dyspepsia: Efficacy in a Randomized, Double-Blind, Placebo-Controlled Dose Ranging Trial[END_REF] clinical trials. It allows the patient to integrate all relevant symptoms and normalises the assessment to the patient's own internal reference system. [START_REF] Mangel | Personal view: adequate relief as a primary endpoint in irritable bowel syndrome[END_REF][START_REF] Camilleri | Primary endpoints for FGID trials: A review of binary and integrated symptom assessments[END_REF] On the other hand, the endpoint does not reflect the magnitude of improvement needed to reach the endpoint (which depends in part on the baseline severity level) and does not detect worsening of symptoms [START_REF] Camilleri | Primary endpoints for FGID trials: A review of binary and integrated symptom assessments[END_REF] .

Adequate relief was used as a primary endpoint in a phase 2b RCT of alosetron for FD [START_REF] Talley | A dose ranging placebo controlled randomized trial of alosetron in patients with functional dyspepsia[END_REF] . During the 12 weeks of treatment with alosetron or placebo, patients responded yes or no to the weekly question: "In the past 7 days, have you had adequate relief of your upper abdominal pain or discomfort?" A 1 mg dose of alosetron showed benefit over placebo and 0. properties. [START_REF] Matsueda | Therapeutic Efficacy of Novel Agent(Z-338) in Functional Dyspepsia(FD)[END_REF] During the first 4 weeks of treatment, the number of subjects reporting adequate relief for more than 50% of time was significantly higher with acotiamide 300 mg t.i.d. compared to placebo. [START_REF] Talley | A Novel Acetylcholine Esterase Inhibitor Acotiamide Hydrochloride (YM443) in Functional Dyspepsia: Efficacy in a Randomized, Double-Blind, Placebo-Controlled Dose Ranging Trial[END_REF] This was associated with significant improvement of symptoms of bloating, postprandial nausea, and stomach pain before meals, and with significant improvement of several domains of the Short Form-36 quality of life scale and of the Short form Nepean Dyspepsia Index. [START_REF] Talley | A Novel Acetylcholine Esterase Inhibitor Acotiamide Hydrochloride (YM443) in Functional Dyspepsia: Efficacy in a Randomized, Double-Blind, Placebo-Controlled Dose Ranging Trial[END_REF] The satisfactory relief endpoint has a construct that is similar to adequate relief, although less extensive validation data are available in the literature for the former. [START_REF] Camilleri | Primary endpoints for FGID trials: A review of binary and integrated symptom assessments[END_REF] Using satisfactory relief as an endpoint, the beneficial effects of tegaserod in IBS have been demonstrated. [START_REF] Kellow | An Asia-Pacific, double-blind, placebo controlled, randomized study to evaluate the efficacy, safety, and tolerability of tegaserod on patients with irritable bowel syndrome[END_REF][START_REF] Nyhlin | A double-blind, placebo-controlled, randomized study to evaluate the efficacy, safety and tolerability of tegaserod in patients with irritable bowel syndrome[END_REF][START_REF] Muller-Lissner | Tegaserod is effective in the initial and re-treatment of irritable bowel syndrome with constipation[END_REF][START_REF] Tack | A randomized controlled trial assessing the efficacy and safety of repeated tegaserod therapy in women with irritable bowel syndrome with constipation[END_REF] The binary satisfactory relief endpoint was also used in two phase 3 studies with tegaserod in dysmotilitytype FD, and demonstrated significant efficacy in one of these. [START_REF] Vakil | Tegaserod treatment for functional dyspepsia dysmotility symptoms: results of two randomized, controlled trials[END_REF] In the trial that achieved a significantly higher proportion of days with satisfactory relief from tegaserod, patients also had significant improvement of overall and

B. Categorical (Likert) Scales

Likert scales have been widely used both in assessing individual and global symptom severity as well as symptom frequency in numerous FD trials. Veldhuyzen and colleagues [START_REF] Veldhuyzen Van Zanten | Can severity of symptoms be used as outcome measures in trials of non-ulcer dyspepsia and Helicobacter pylori associated gastritis?[END_REF] Likert scores have been employed in numerous studies to date (Table 1), including the BOND and OPERA studies [START_REF] Talley | Efficacy of omeprazole in functional dyspepsia: double-blind, randomized, placebo-controlled trials (the Bond and Opera studies)[END_REF] which utilised a 4-point Likert scale to evaluate the efficacy of omeprazole in FD. A 7-point Likert scale was used in 2 very similar multicentre, multinational, RCTs: the OCAY [START_REF] Blum | Lack of effect of treating Helicobacter pylori infection in patients with nonulcer dyspepsia. Omeprazole plus Clarithromycin and Amoxicillin Effect One Year after Treatment (OCAY) Study Group[END_REF] and ORCHID studies, [START_REF] Talley | Eradication of Helicobacter pylori in functional dyspepsia: Randomised double blind placebo controlled trial with 12 months' follow up. The Optimal Regimen Cures Helicobacter Induced Dyspepsia (ORCHID) Study group[END_REF] which compared the efficacy of Helicobacter pylori eradication therapy with that of either omeprazole (OCAY study) or placebo (ORCHID study) in relieving dyspeptic symptoms 12 months after eradication therapy.

Using a stringent definition of treatment success (absence of symptoms or the presence of only minimal symptoms (Likert score 1 or 2) during the seven days preceding the final visit) no significant symptomatic benefit of Helicobacter pylori eradication therapy in FD was found. [START_REF] Blum | Lack of effect of treating Helicobacter pylori infection in patients with nonulcer dyspepsia. Omeprazole plus Clarithromycin and Amoxicillin Effect One Year after Treatment (OCAY) Study Group[END_REF][START_REF] Talley | Eradication of Helicobacter pylori in functional dyspepsia: Randomised double blind placebo controlled trial with 12 months' follow up. The Optimal Regimen Cures Helicobacter Induced Dyspepsia (ORCHID) Study group[END_REF] In addition, Likert scales have been used for global evaluation. Using a Likerttype scale with 5 grades (symptom-free, markedly improved, moderately improved, not changed, and deteriorated) to measure patients' global assessment of efficacy, a statistically significant benefit was found in a Phase IIb trial for itopride over placebo in the number of patients who reported being symptom-free or with marked improvement. [START_REF] Holtmann | A placebocontrolled trial of itopride in functional dyspepsia[END_REF] However, this effect was not seen when the same global patient assessment of efficacy was evaluated in 2 phase III trials. [START_REF] Talley | randomized, doubleblind, placebo-controlled trials[END_REF] Another method of assessing global outcome is the "overall treatment effect" (OTE) approach. [START_REF] Guyatt | A comparison of Likert and Visual Analogue Scales for measuring change in function[END_REF] At intervals during or at the completion of treatment, the patient is asked to decide whether symptoms have remained the same, improved or deteriorated compared to pre-treatment phase, by means of a Likert scale. The advantage of this endpoint is that it closely resembles the way physicians evaluate treatment benefit in clinical practice, but the main disadvantage is the inherent recall of pre-treatment symptom severity which may lead to bias. OTE was used as a secondary outcome measure in the OCAY study, and in a number of studies of acid suppression in FD. [START_REF] Blum | Lack of effect of treating Helicobacter pylori infection in patients with nonulcer dyspepsia. Omeprazole plus Clarithromycin and Amoxicillin Effect One Year after Treatment (OCAY) Study Group[END_REF][START_REF] Veldhuyzen Van Zanten | A randomized trial comparing omeprazole, ranitidine, cisapride, or placebo in Helicobacter pylori negative, primary care patients with dyspepsia:The CADET-HN study[END_REF][START_REF] Chiba | Treating Helicobacter pylori infection in primary care patients with uninvestigated dyspepsia: The Canadian adult dyspepsia empiric treatment-Helicobacter pylori positive (CADET-HP) randomised controlled trial[END_REF][START_REF] Armstrong | Heartburn-dominant, uninvestigated dyspepsia: A comparison of 'PPI-Start' and 'H2-RA-Start' management strategies in primary care. The CADET-HR Study[END_REF][START_REF] Veldhuyzen Van Zanten | Esomeprazole 40 mg once a day in patients with functional dyspepsia: The Randomized, Placebo-Controlled "ENTER" Trial[END_REF] Overall treatment evaluation was used most recently in the tegaserod FD studies, where a weekly global assessment of change was rated on a 7-point Likert scale, and this endpoint generated the most consistent improvements with tegaserod over placebo. [START_REF] Vakil | Tegaserod treatment for functional dyspepsia dysmotility symptoms: results of two randomized, controlled trials[END_REF] OTE was also used in the U.S. and Japanese Acotiamide trials as a secondary or primary endpoint respectively. [START_REF] Talley | A Novel Acetylcholine Esterase Inhibitor Acotiamide Hydrochloride (YM443) in Functional Dyspepsia: Efficacy in a Randomized, Double-Blind, Placebo-Controlled Dose Ranging Trial[END_REF]98 In the U.S. study, benefit using the OTE paralleled the adequate relief outcome result, with significance during the first 4 to 6 weeks. [START_REF] Talley | A Novel Acetylcholine Esterase Inhibitor Acotiamide Hydrochloride (YM443) in Functional Dyspepsia: Efficacy in a Randomized, Double-Blind, Placebo-Controlled Dose Ranging Trial[END_REF] In the Japanese study, significant benefit was found using the OTE for the 100 mg dose in mealrelated FD symptoms, and this was associated with a higher rate of disappearance of postprandial fullness and upper abdominal bloating. 98 VAS scores, which may be more difficult to interpret in terms of magnitude of response, have been used in only a few, mainly less recent studies. that it is not specific for dyspepsia. In addition, it measures only the severity of GI related symptoms and not their impact on quality of life. The GSRS has been used as a primary outcome measure in a study evaluating the efficacy of rebamipide 112 and as a secondary outcome measure in various studies. 88,94- 97,113,114 C.3. Leeds Dyspepsia Questionnaire (LDQ)

The LDQ 115 is administered by an investigator during an interview, and evaluates the frequency and severity of 8 symptoms (epigastric pain, retrosternal pain, regurgitation, nausea, vomiting, belching, early satiety and dysphagia) The scoring system uses the frequency of the first 5 symptoms to determine the presence of dyspepsia, whilst all 8 symptoms are used to access severity of dyspepsia on a scale of 0 (absent) to 5 (most severe). The severity of dyspepsia is assessed as a summary score (range 0-40). The LDQ was shown to be reliable, valid and responsive to change in both primary and secondary care populations in the U.K. Several potential drawbacks of the LDQ include the administration of the questionnaire by a researcher, inclusion of GERD and nausea symptoms, and a complex scoring system.

The psychometric properties of the LDQ were evaluated in 99 primary care patients and 215 hospital referral patients. Physician diagnosis was the gold standard used to validate the ability of the LDQ to detect dyspepsia. The sensitivity and specificity of the LDQ at the primary care setting were 80% and 79%, respectively. In the hospital setting, the LDQ showed a sensitivity of The GDSS 134 provides a tool for the global evaluation of dyspepsia during the preceding six months, and was shown to be reliable, valid and responsive. It were referred. Test-retest reliability yielded an intraclass coefficient value of 0.69. However, responsiveness was not assessed.

The Gastrointestinal Symptom Score (GIS) is a 10-item questionnaire developed for the study of FD. 138 It was developed based on patient focus groups, and validated by comparison with the Nepean Dyspepsia Index.

However, the questionnaire includes typical GERD symptoms like heartburn, regurgitation and retrosternal discomfort. The GIS has been used in studies of herbal medicines in FD. 139-141

Quality of life measures

Quality of life (QOL) measures can be assessed either by generic instruments or by disease specific measures. The Short Form of General Health Questionnaire (SF-36) 142 is a generic instrument that has been widely used in various disorders. To evaluate more specifically QOL in specific disorders, such as in functional gastrointestinal disorders, questionnaires that are available include the Nepean Dyspepsia Index (NDI) [121][122][123][124][125][126] for FD, the PAGI-QOL for upper GI disorders 130 and the IBS-QOL 143 for IBS. Although these quality of life measures have been strongly recommended as secondary outcome measures, they are not utilised as primary outcome measures as they are regarded by regulatory agencies as being insufficiently responsive to treatment, although this may not necessarily be correct.

DISCUSSION

Evaluating the therapeutic efficacy of drugs in FD remains challenging due to the variable intensity of symptoms in one individual and the high placebo response rates. [START_REF] Veldhuyzen Van Zanten | Drug treatment of functional dyspepsia: a systematic analysis of trial methodology with recommendations for design of future trials[END_REF][145][146][147][148][149] The choice of the endpoint for a clinical trial is a key factor in assessing therapeutic efficacy. However, there is a lack of consensus on the best method to measure clinical outcome in FD drug trials. [START_REF] Veldhuyzen Van Zanten | Drug treatment of functional dyspepsia: a systematic analysis of trial methodology with recommendations for design of future trials[END_REF][START_REF] Veldhuyzen Van Zanten | Assessment of outcome in dyspepsia: has progress been made?[END_REF] In this setting, the most recent mandate emphasises the use of PRO in symptom reporting. [START_REF]Patient reported outcome measures: use in medical product development to support labeling claims[END_REF] , The dichotomous endpoint of adequate or satisfactory relief has seen increasing use as primary endpoint in recent trials, while alternative outcome measures such as integrative questionnaires are also considered potentially acceptable, but these views seem largely driven by experience with IBS trials. [START_REF] Camilleri | Improvement in pain and bowel function in female irritable bowel patients with alosetron, a 5-HT3 receptor antagonist[END_REF][START_REF] Camilleri | Efficacy and safety of alosetron in women with irritable bowel syndrome: a randomized, placebo-controlled trial[END_REF][START_REF] Camilleri | A randomized controlled clinical trial of the serotonin type 3 receptor antagonist alosetron in women with diarrhoea-predominant irritable bowel syndrome[END_REF][START_REF] Miner | Cilansetron in irritable bowel syndrome with diarrhoea predominance (IBS-D); efficacy and safety in a 3 month US study[END_REF][START_REF] Leventer | The potential dextofisopam for treatment of irritable bowel syndrome and the irritable bowel syndrome[END_REF][START_REF] Bradette | Cilansetron in irritable bowel syndrome with diarrhoea predominance (IBS-D): efficacy and safety in a 6 month global study[END_REF][START_REF] Coremans | Cilansetron, a novel 5-HT3 antagonist demonstrated efficacy in males with irritable bowel syndrome with diarrhoea-predominance (IBS-D)[END_REF][START_REF] Leventer | The safety and efficacy of dextofisopam in patients with diarrhoea-predominant or alternating irritable bowel syndrome[END_REF][START_REF] Kellow | An Asia-Pacific, double-blind, placebo controlled, randomized study to evaluate the efficacy, safety, and tolerability of tegaserod on patients with irritable bowel syndrome[END_REF][START_REF] Nyhlin | A double-blind, placebo-controlled, randomized study to evaluate the efficacy, safety and tolerability of tegaserod in patients with irritable bowel syndrome[END_REF][START_REF] Muller-Lissner | Tegaserod is effective in the initial and re-treatment of irritable bowel syndrome with constipation[END_REF][START_REF] Tack | A randomized controlled trial assessing the efficacy and safety of repeated tegaserod therapy in women with irritable bowel syndrome with constipation[END_REF] Achieving the adequate relief endpoint in clinical drug trials was instrumental in obtaining FDA approval initially for ranitidine for the treatment of heartburn, 151 for alosetron in IBS [START_REF] Camilleri | Improvement in pain and bowel function in female irritable bowel patients with alosetron, a 5-HT3 receptor antagonist[END_REF][START_REF] Camilleri | Efficacy and safety of alosetron in women with irritable bowel syndrome: a randomized, placebo-controlled trial[END_REF][START_REF] Camilleri | A randomized controlled clinical trial of the serotonin type 3 receptor antagonist alosetron in women with diarrhoea-predominant irritable bowel syndrome[END_REF] , and subsequently for tegaserod in IBS (using satisfactory relief). [START_REF] Kellow | An Asia-Pacific, double-blind, placebo controlled, randomized study to evaluate the efficacy, safety, and tolerability of tegaserod on patients with irritable bowel syndrome[END_REF][START_REF] Nyhlin | A double-blind, placebo-controlled, randomized study to evaluate the efficacy, safety and tolerability of tegaserod in patients with irritable bowel syndrome[END_REF][START_REF] Muller-Lissner | Tegaserod is effective in the initial and re-treatment of irritable bowel syndrome with constipation[END_REF][START_REF] Tack | A randomized controlled trial assessing the efficacy and safety of repeated tegaserod therapy in women with irritable bowel syndrome with constipation[END_REF] Evidence supporting responsiveness of the adequate or satisfactory relief endpoints was documented mainly in IBS trials, where the binary endpoint correlated with other standard measures of treatment efficacy. [START_REF] Camilleri | Improvement in pain and bowel function in female irritable bowel patients with alosetron, a 5-HT3 receptor antagonist[END_REF][START_REF] Camilleri | Efficacy and safety of alosetron in women with irritable bowel syndrome: a randomized, placebo-controlled trial[END_REF][START_REF] Camilleri | A randomized controlled clinical trial of the serotonin type 3 receptor antagonist alosetron in women with diarrhoea-predominant irritable bowel syndrome[END_REF][START_REF] Miner | Cilansetron in irritable bowel syndrome with diarrhoea predominance (IBS-D); efficacy and safety in a 3 month US study[END_REF][START_REF] Leventer | The potential dextofisopam for treatment of irritable bowel syndrome and the irritable bowel syndrome[END_REF][START_REF] Bradette | Cilansetron in irritable bowel syndrome with diarrhoea predominance (IBS-D): efficacy and safety in a 6 month global study[END_REF][START_REF] Coremans | Cilansetron, a novel 5-HT3 antagonist demonstrated efficacy in males with irritable bowel syndrome with diarrhoea-predominance (IBS-D)[END_REF][START_REF] Leventer | The safety and efficacy of dextofisopam in patients with diarrhoea-predominant or alternating irritable bowel syndrome[END_REF][START_REF] Kellow | An Asia-Pacific, double-blind, placebo controlled, randomized study to evaluate the efficacy, safety, and tolerability of tegaserod on patients with irritable bowel syndrome[END_REF][START_REF] Nyhlin | A double-blind, placebo-controlled, randomized study to evaluate the efficacy, safety and tolerability of tegaserod in patients with irritable bowel syndrome[END_REF][START_REF] Muller-Lissner | Tegaserod is effective in the initial and re-treatment of irritable bowel syndrome with constipation[END_REF][START_REF] Tack | A randomized controlled trial assessing the efficacy and safety of repeated tegaserod therapy in women with irritable bowel syndrome with constipation[END_REF]152,153 On the other hand, limitations of the binary endpoints include the lack of sensitivity and validation, inability to detect worsening of symptoms (unlike the OTE), lack of information on the magnitude of improvement needed to reach adequate relief, the potential for failure to report adequate relief in subsequent weeks once achieved, the influence of baseline severity of symptoms and response outcomes and variable interpretation of the adequate relief construct. [START_REF] Camilleri | Primary endpoints for FGID trials: A review of binary and integrated symptom assessments[END_REF] Based on an observational IBS study in a health maintenance organization setting, it has been suggested that patients with mild symptoms at baseline are more likely to achieve satisfactory relief compared to those with severe symptoms at baseline. 154 Contrary to this suggestion, the greatest improvement in percentage of days that FD patients reported satisfactory relief of symptoms occurred in those who had severe baseline symptoms compared with those who had mild symptoms (p<0.05). [START_REF] Vakil | Tegaserod treatment for functional dyspepsia dysmotility symptoms: results of two randomized, controlled trials[END_REF] Hence, the use of binary relief endpoints in FD deserves additional validation studies. Compared to questionnaires that use specific FD symptoms, the binary or overall treatment evaluation question may be more suitable to capture an overall treatment impact in functional disorders, especially as this approach has the potential to also contain changes in associated more global symptoms (e.g.

fatigue).

In addressing the use of an acceptable alternative outcome measure, a questionnaire should undergo appropriate psychometric validation in accordance with the FDA guidance regulations and Rome III guidelines on clinical trials. [START_REF]Patient reported outcome measures: use in medical product development to support labeling claims[END_REF][START_REF] Of | Design of treatment trials for functional gastrointestinal disorders[END_REF] In our opinion, existing questionnaires present some methodological flaws, mainly due to the failure to satisfy the psychometric property of content validity. In the light of the Rome III criteria [START_REF] Tack | Functional gastroduodenal disorders[END_REF] , none of the existing questionnaires are sufficiently validated to be recommended non-FD symptoms can be narrowed down to evaluate only the cardinal symptoms according to Rome III. Such an approach was used in the itopride phase 2 and 3 studies, which used 2 FD-specific questions (severity of epigastric pain and of postprandial fullness) from the LDQ as co-primary endpoint, whereas the full LDQ score was a secondary endpoint. [START_REF] Holtmann | A placebocontrolled trial of itopride in functional dyspepsia[END_REF][START_REF] Talley | randomized, doubleblind, placebo-controlled trials[END_REF] The most valuable questionnaires are probably the ones that used patient focus groups to identify relevant symptoms, such as the DSSI, PAGI-SYM or GIS questionnaires. 117,121,130,138 Another possibility is to incorporate the OTE with the binary endpoints of adequate or satisfactory relief, for which there is extensive experience from IBS trials [START_REF] Camilleri | Improvement in pain and bowel function in female irritable bowel patients with alosetron, a 5-HT3 receptor antagonist[END_REF][START_REF] Camilleri | Efficacy and safety of alosetron in women with irritable bowel syndrome: a randomized, placebo-controlled trial[END_REF][START_REF] Camilleri | A randomized controlled clinical trial of the serotonin type 3 receptor antagonist alosetron in women with diarrhoea-predominant irritable bowel syndrome[END_REF][START_REF] Miner | Cilansetron in irritable bowel syndrome with diarrhoea predominance (IBS-D); efficacy and safety in a 3 month US study[END_REF][START_REF] Leventer | The potential dextofisopam for treatment of irritable bowel syndrome and the irritable bowel syndrome[END_REF][START_REF] Bradette | Cilansetron in irritable bowel syndrome with diarrhoea predominance (IBS-D): efficacy and safety in a 6 month global study[END_REF][START_REF] Coremans | Cilansetron, a novel 5-HT3 antagonist demonstrated efficacy in males with irritable bowel syndrome with diarrhoea-predominance (IBS-D)[END_REF][START_REF] Leventer | The safety and efficacy of dextofisopam in patients with diarrhoea-predominant or alternating irritable bowel syndrome[END_REF][START_REF] Kellow | An Asia-Pacific, double-blind, placebo controlled, randomized study to evaluate the efficacy, safety, and tolerability of tegaserod on patients with irritable bowel syndrome[END_REF][START_REF] Nyhlin | A double-blind, placebo-controlled, randomized study to evaluate the efficacy, safety and tolerability of tegaserod in patients with irritable bowel syndrome[END_REF][START_REF] Muller-Lissner | Tegaserod is effective in the initial and re-treatment of irritable bowel syndrome with constipation[END_REF][START_REF] Tack | A randomized controlled trial assessing the efficacy and safety of repeated tegaserod therapy in women with irritable bowel syndrome with constipation[END_REF] and emerging experience from FD trials. [START_REF] Farup | Patients with functional dyspepsia responding to omeprazole have a characteristic gastrooesophageal reflux pattern[END_REF][START_REF] Talley | A dose ranging placebo controlled randomized trial of alosetron in patients with functional dyspepsia[END_REF][START_REF] Matsueda | Therapeutic Efficacy of Novel Agent(Z-338) in Functional Dyspepsia(FD)[END_REF][START_REF] Talley | A Novel Acetylcholine Esterase Inhibitor Acotiamide Hydrochloride (YM443) in Functional Dyspepsia: Efficacy in a Randomized, Double-Blind, Placebo-Controlled Dose Ranging Trial[END_REF][START_REF] Vakil | Tegaserod treatment for functional dyspepsia dysmotility symptoms: results of two randomized, controlled trials[END_REF] The OTE was extensively used in the OCAY, CADET and ENTER trials [START_REF] Blum | Lack of effect of treating Helicobacter pylori infection in patients with nonulcer dyspepsia. Omeprazole plus Clarithromycin and Amoxicillin Effect One Year after Treatment (OCAY) Study Group[END_REF][START_REF] Veldhuyzen Van Zanten | A randomized trial comparing omeprazole, ranitidine, cisapride, or placebo in Helicobacter pylori negative, primary care patients with dyspepsia:The CADET-HN study[END_REF][START_REF] Chiba | Treating Helicobacter pylori infection in primary care patients with uninvestigated dyspepsia: The Canadian adult dyspepsia empiric treatment-Helicobacter pylori positive (CADET-HP) randomised controlled trial[END_REF][START_REF] Armstrong | Heartburn-dominant, uninvestigated dyspepsia: A comparison of 'PPI-Start' and 'H2-RA-Start' management strategies in primary care. The CADET-HR Study[END_REF][START_REF] Veldhuyzen Van Zanten | Esomeprazole 40 mg once a day in patients with functional dyspepsia: The Randomized, Placebo-Controlled "ENTER" Trial[END_REF] and most recently in the tegaserod and acotiamide studies. [START_REF] Talley | A Novel Acetylcholine Esterase Inhibitor Acotiamide Hydrochloride (YM443) in Functional Dyspepsia: Efficacy in a Randomized, Double-Blind, Placebo-Controlled Dose Ranging Trial[END_REF][START_REF] Vakil | Tegaserod treatment for functional dyspepsia dysmotility symptoms: results of two randomized, controlled trials[END_REF] The subjective nature of the global outcome approach or OTE allows the individual to integrate all aspects of his condition into a single treatment outcome. Although the OTE is particularly suitable to show deterioration, it is prone to recall bias as it compares current symptoms to pre-treatment severity. Nevertheless, using both the OTE and binary outcome to evaluate treatment efficacy would provide valuable information both from a global perspective as well as in assessing symptom improvement and/or deterioration.

Similar to other FGIDs, the magnitude of the placebo response is a major concern in the evaluation of efficacy of drugs in FD. The available recent studies do not show a major difference in responder rate when comparing binary endpoints to OTE responses or to responder rates on composite questionnaires like the LDQ or DSSI, provided the cut-off level for response was adequately chosen. [START_REF] Talley | A Novel Acetylcholine Esterase Inhibitor Acotiamide Hydrochloride (YM443) in Functional Dyspepsia: Efficacy in a Randomized, Double-Blind, Placebo-Controlled Dose Ranging Trial[END_REF][START_REF] Vakil | Tegaserod treatment for functional dyspepsia dysmotility symptoms: results of two randomized, controlled trials[END_REF][START_REF] Talley | randomized, doubleblind, placebo-controlled trials[END_REF] Indeed, these studies illustrate how the magnitude of the placebo effect depends on the level of improvement used to define a responder. For instance, in the itopride phase 3 trials, an improvement of 1 point on the LDQ had a placebo response of 70 to 75%; when a 2 point improvement was chosen as response definition, the placebo response was 45 to 55%, quite similar to the placebo response on a global patient assessment of efficacy. [START_REF] Talley | randomized, doubleblind, placebo-controlled trials[END_REF] Similarly, requiring a 50% weekly response rate over a 75% weekly response rate is associated with a higher placebo rate. [START_REF] Talley | A Novel Acetylcholine Esterase Inhibitor Acotiamide Hydrochloride (YM443) in Functional Dyspepsia: Efficacy in a Randomized, Double-Blind, Placebo-Controlled Dose Ranging Trial[END_REF][START_REF] Vakil | Tegaserod treatment for functional dyspepsia dysmotility symptoms: results of two randomized, controlled trials[END_REF] In addition, the tegaserod phase 3 studies showed a high placebo response rate, and a low therapeutic gain of active drug over placebo, when patients with mild symptoms were considered, while a bigger therapeutic gain over placebo was obtained in those with moderate or severe symptoms. [START_REF] Vakil | Tegaserod treatment for functional dyspepsia dysmotility symptoms: results of two randomized, controlled trials[END_REF] Hence, in order to minimize the placebo effect, inclusion of patients with at least moderate symptom severity, and the choice of a high enough threshold for response definition is recommended.

Some studies in FD have used elimination of symptoms, usually measured on Likert scales, as an endpoint. 98,114,135 Although it is clear that becoming asymptomatic is clinically relevant, the proportion of patients with functional gastrointestinal disorders in whom this can be achieved by a pharmacological intervention (and by the comparator placebo arm) is likely to be low. Placebo responses are indeed low when this endpoint is considered. 98,114,135 Elimination of symptoms, therefore, probably sets a very high threshold for response and focusing on this endpoint induces a risk of disregarding clinically relevant degrees of symptom improvement in FD and other FGIDs.

International consensus guidelines, as well as FDA guidance, therefore focus on identifying and recognizing significant symptom improvement using validated scales, [START_REF]Patient reported outcome measures: use in medical product development to support labeling claims[END_REF][START_REF] Of | Design of treatment trials for functional gastrointestinal disorders[END_REF][START_REF] Veldhuyzen Van Zanten | A systematic overview (meta-analysis) of outcome measures in Helicobacter pylori gastritis trials and functional dyspepsia[END_REF][START_REF] Talley | A critique of therapeutic trials in Helicobacter pylori-positive functional dyspepsia[END_REF][START_REF] Veldhuyzen Van Zanten | Drug treatment of functional dyspepsia: a systematic analysis of trial methodology with recommendations for design of future trials[END_REF] rather than symptom elimination which can still be considered a useful secondary outcome variable.

No regulatory guideline exists on which magnitude of an active drug response rate over placebo is needed to be considered clinically relevant. This was also not specifically addressed by the Rome III working committee on design of treatment trials in functional disorders. [START_REF] Of | Design of treatment trials for functional gastrointestinal disorders[END_REF] I would like to see some further mention of the high placebo response rates in FD (the authors mention this briefly in the Discussion) and the challenge in ascertaining a significant difference between placebo and active management in disease specific measures and overall improvement. How much of a difference is worthwhile? Many researchers are of the view that in functional disorders improvements in specific symptoms are not as important as an overall improvement in well being. Specific symptoms measures may be the wrong trading currency in functional problems, which, by their nature are likely to be part of a global disorder (e.g. tiredness included).

Response: We added a paragraph on the placebo response; the available data show an influence of threshold level choice, but not of the type of endpoint chosen (binary vs overall vs composite). We also, briefly, addressed the (lack of data and consensus on) minimally relevant margin over placebo. We also added a statement on the limitations of addressing only specific FD symptoms in assessment of therapeutic benefit.

.

(

  FDA) guidance released in February 2006 provides recommendations for the instruments to assess treatment outcomes, and describes the proper development and psychometric validation of patient reported outcomes

  measured on a Likert scale, and a significantly better global assessment of change in dyspepsia symptoms.

used a 5 -

 5 point Likert scale (0=no problem, 4=very severe problem) to score the severity of 8 gastrointestinal symptoms (epigastric pain, burping, heartburn, bloating, flatulence, sour taste, nausea and halitosis). A validation study was performed in non ulcer dyspepsia (NUD) and Helicobacter pylori associated gastritis (HPAG). Its reproducibility was demonstrated by comparing symptom scores in the 2 groups of patients before treatment, and responsiveness was demonstrated in both NUD and HPAG patients, where cumulative scores were significantly reduced after therapy. However, the validity of this scale as a measure of improvement was only assessed by comparing changes in symptom scores with changes in the patients' overall health status (deteriorated, stayed the same or improved during the trial) rather than against an established questionnaire. In addition, it combined FD symptoms with symptoms suggestive of GERD, nausea and intestinal dysfunction. Finally, the cumulative symptom score attributed equal weight to all symptoms, although some of them may be related. Nevertheless, the results from this study support the applicability of a Likert-scale in measuring the severity of FD symptoms.

  records frequency of symptoms (maximum score,5); effect on daily activities(2); the number of days off work because of dyspepsia(2), frequency of medical consultations(2); home visits by a general practitioner (2); clinical investigations performed (2); use of over the counter medications (2) and prescription medications(3). Scores range from 0-20, and are significantly lower in healthy volunteers (mean score 1.16) compared to patients with duodenal ulcer (11.1) or FD(10.5). The coefficient of variation was 2% and 8% for intra-and inter-observer assessment respectively. Following eradication of Helicobacter pylori in duodenal ulcer, the score changed from 11.4 to 1.3, compared with an average change of 10.5 to 8.5 in patients with persistent Helicobacter pylori infection, confirming responsiveness of the GDSS. A score of 0 or 1 on the GDSS corresponds to complete resolution of of the GDSS are administration by an investigator, and lack of standardized definition of dyspepsia for the investigator to adhere to. The GDSS was utilised by McColl et al 135 in a trial evaluating the efficacy of Helicobacter pylori eradication therapy in non ulcer dyspepsia. A Spanish translation of the GDSS and a Likert-scale symptomatic test were evaluated for responsiveness to treatment, validity and reproducibility by means of phone interview. 136 Both the GDSS and Likert-scales were valid (higher scores in patients undergoing endoscopy than in healthy controls); had adequate response after subjects completed Helicobacter pylori eradication therapy, and showed low intraobserver variation whether the interviews were conducted by phone or by a combination of phone and clinical interview. The GDSS was superior to the Likert-scale in remaining reproducible even when conducted by different observers. D.5. Other disease specific multidimensional instruments.The Clinical Dyspepsia Questionnaire is a condition specific self-administered measure of dyspepsia and peptic-ulcer related symptoms. It assesses the frequency and severity of symptoms and their impact on QOL.137 Patient scores on this questionnaire reviewed only small to moderate correlations (0.20 to 0.66) with the SF-36 quality of life survey, but further validity tests showed significant correlations with general practitioner perceptions of symptom severity, family history of peptic ulcer disease and whether patients

  et al.,32 unequivocally as the primary outcome measure for FD trials. Central to the problem of previously validated questionnaires was the inclusion of many symptoms which are not considered cardinal FD symptoms according to current criteria[START_REF] Tack | Functional gastroduodenal disorders[END_REF] . An adequate and valid questionnaire, i.e. one that incorporates all the psychometric validation standards, in particular incorporating the Rome III criteria for FD, would facilitate future therapeutic trials in FD.The absence of a validated instrument for the evaluation of treatment efficacy in FD according to Rome III criteria and the lack of robust psychometric validation data for the binary outcome measure in FD trials should not impair ongoing or planned drug development in this area. One plausible solution is to build upon the heritage of current instruments to serve as a useful framework in designing a new questionnaire. Existing questionnaires that include many

  99% whilst the specificity was 53%. Based on ĸ statistics, there was moderate to substantial agreement between the LDQ and physician assessment. Testretest reliability was evaluated in 107 patients by a research nurse during two clinic visits within 4-7 days, yielding a k statistic of 0.83 and internal consistency by Cronbach's α of 0.68. A similar high k statistic of 0.90 was achieved when two different researchers administered the LDQ to 42 patients within 30 minutes. Responsiveness to change was also detected, with the median LDQ score decreasing from 22.5 to 4.5 one month after receiving appropriate therapy. However, this was only assessed in 12 patients with relatively severe symptoms. The LDQ has been used in phase 2 and 3 studies of itopride.[START_REF] Holtmann | A placebocontrolled trial of itopride in functional dyspepsia[END_REF][START_REF] Talley | randomized, doubleblind, placebo-controlled trials[END_REF] The short-Form Leeds Dyspepsia Questionnaire (SF-Comparison of the summed total scores for patients in the primary care and secondary care setting yielded statistically significant differences, further confirmed the validity of the SF-LDQ. The SF-LDQ'sThe DSSI 117 is a 20-item self administered questionnaire divided into 3 subscales (reflux-like, ulcer-like and dysmotility-like symptoms), quantifying the severity of dyspepsia symptoms over the past 2 weeks. The items were derived from patient focus group interviews. One global item is included at the conclusion of the questionnaire to access the patient's overall impression of dyspepsia severity. The severity questions are graded on a 5-point Likert scale ranging from 0 (absent) to 4 (very severe). Subscale internal consistency levels were high (Cronbach α 0.84-0.89) and reproducible (ICC 0.90-0.92). The DSSI correlated well with the patients' symptom diary and

	Dyspepsia Endpoints Dyspepsia Endpoints Dyspepsia Endpoints Dyspepsia Endpoints Dyspepsia Endpoints Dyspepsia Endpoints Dyspepsia Endpoints	Ang et al., 19 Ang et al., 20 Ang et al., 21 Ang et al., 23 Ang et al., 24 Ang et al., 25 Ang et al., 26
	symptoms that were self administered, but only the 12 most discriminating upper abdominal pain, nausea and upper abdominal bloating are accessed for one study 127 employed both the short and long versions of the NDI, but only IBS. The SODA was used as a secondary outcome measure in the ENTER
	symptoms (epigastric pain, upper abdominal bloating, upper abdominal dull intensity, duration and frequency; whilst vomiting and early satiety are D. Disease specific instruments (multidimensional) the results of the long version were presented. trial. 97 The PAGI-QOL questionnaire consists of 30 items in five subscales: daily
	ache, epigastric pain before meals, epigastric pain when anxious, vomiting, accessed for frequency. Internal consistency of this questionnaire, as activities (10 items), clothing (2 items), diet and food (7 items), relationships (3
	nausea, belching, acid regurgitation, heartburn, feeling of acidity in the measured by Cronbach's alpha was 0.82. It was shown to be reproducible D.1. Nepean Dyspepsia Index (NDI) D.2. Severity of Dyspepsia Assessment (SODA) D.3. Patient assessment of upper gastrointestinal symptom severity index and items) and psychological distress (8 items). Patients accord a score to each
	stomach and loss of appetite) were selected. Symptoms are graded on a 5 when submitted to the test-retest procedure, both by the same interviewer quality of life (PAGI-SYM and PAGI-QOL) Questionnaires. item from 0 (absent) to 5 (severely impaired). It has been validated for
	point Likert scale, ranging from 1(no symptoms) to 5 (incapacitating (ICC 0.86) and by different interviewers (ICC 0.87). Its responsiveness was The NDI 121,122 was developed primarily as a disease specific quality of life The SODA 128 is a multidimensional outcome measure for dyspepsia related evaluating quality of life in FD, gastro-oesophageal reflux disease and
	symptoms resulting in an inability to perform daily activities and/or requiring demonstrated by a statistically significant reduction in the mean score measure. From an initial 42-items to measure the impact of dyspepsia on a health that consists of 17 questions incorporating 3 dimensions of pain The PAGI-SYM  questionnaire has been developed and validated for the gastroparesis by comparing it with the OTE. 133
	F o r F o r F o r days off work). A cut-off score of ≥16 was shown to have a sensitivity of 0.82 and specificity of 0.83 for identification of dyspeptic symptoms. There was good test-retest reliability and internal consistency, with an intraclass F o r obtained after treatment compared with baseline. In addition, the PADYQ demonstrated content, discriminant and criterion validity. However, the questionnaire focuses on the pain spectrum of FD, and does not address F o r patient's overall quality of life, it was shortened to 25-items centred around 4 F o r intensity (6 items); 7 non-pain symptoms (belching, heartburn, bloating, passing gas, sour taste, nausea and bad breath) and satisfaction scales (4 items). In this self administered questionnaire, patients are asked to assess F o r evaluation of symptom severity and treatment responsiveness in upper gastrointestinal disorders such as FD, gastroparesis and GERD. 130 It is composed of 20 items in 6 subscales: heartburn/regurgitation (7 items), F r o D.4. Glasgow Dyspepsia Severity Score (GDSS)
	P P P correlation coefficient of 0.89 and Cronbach's alpha coefficient of 0.90. P symptoms such as postprandial fullness and epigastric burning. P P the preceding 7 days. Reliability was good (Cronbach's α were 0.97, 0.90 and P P
	e e e e e e 0.92 for pain intensity, non-pain symptoms and satisfaction scales e e
	e r e r e r e r e r e r respectively) and mean change scores discriminated between patients who e r e r
	R e v i e w R e v i e w R e v i e w of GERD symptoms. This scoring system has been used in a study evaluating R e v i e w R e v i e w United States. 124 The NDI has been translated and validated in several R e v i e w reported improvement compared with those who were unchanged. The psychometric properties of SODA were further evaluated in a large study of arthritis patients receiving NSAIDS or celecoxib, confirming good internal consistency. 129 Responsiveness as evaluated by receiver operating characteristic (ROC) curves was high for pain intensity scale (area under the curve (AUC)=0.78); R e v i e w R questionnaire has good internal consistency, reliability and reproducibility over e 2 weeks, and adequate content and construct validity in samples of subjects with upper gastrointestinal disorders. 130 Responsiveness has been evaluated v i e in an 8-week study in GERD and FD, using OTE as a comparator. 131 The questionnaire has also been translated and validated in many different cultural w
	the efficacy of 4 weeks of lansoprazole treatment in patients who fulfilled languages, including Arabic. 125 The NDI was further shortened to 10 quality-non-pain symptoms (AUC =0.74) and satisfaction scales (AUC=0.75). and linguistic settings. Disadvantages of the PAGI-SYM questionnaire are the
	Rome II criteria for FD with a baseline score ≥16. 119 of-life items in 5 domains 126 . This short form NDI was validated in a large However, reproducibility was low, with ICC values of 0.49, 0.61 and 0.45 for equal weighting of different symptoms when making up total or subscales,
	responsiveness to change was significant in 37 patients who received multicentre trial in Europe and the United States. The short form NDI pain intensity, non-pain symptoms and satisfaction scales respectively. and the inclusion of a broad range of symptoms that are not specific for FD.
	treatment of known effectiveness. The Porto Alegre Dyspeptic Symptoms Questionnaire (PADYQ) 120 is an demonstrated adequate internal consistency (Cronbach α 0.71-0.76), Notably, SODA assesses the severity but not the frequency of symptoms, and However, subscales were proposed for use in specific disorders. 131 The
	investigator administered unidimensional 11-item instrument which evaluates correlated with the original long version and was highly responsive. To date, it includes a broad range of symptoms that are also suggestive for GERD or PAGI-SYM has been used in a study evaluating the 5-HT1A agonist R137696
	C.4. Dyspepsia Symptom Severity Index (DSSI) Hong Kong Dyspepsia Index 118 originally contained 24 gastrointestinal 5 symptoms of NUD as defined by the Rome I consensus. The symptoms of in FD, where no efficacy was demonstrated. 132

LDQ)

116

was developed to be self completed and a shorter version of the original LDQ. The SF-LDQ assesses the frequency and severity over the preceding 2 months of 4 symptoms (indigestion, heartburn, regurgitation and nausea). In the validation study involving both primary and secondary care patients, Cronbach's α coefficient was 0.90, demonstrating a high level of internal consistency. Pearson's correlation coefficient for test-retest reliability 2 days apart was 0.93. Validity was demonstrated by comparison with general practitioners' diagnosis. discriminated between patients and age-matched controls. However, despite its validity and reliability, its responsiveness was not assessed. Inclusion of GERD and nausea symptoms is another drawback. The DSSI was used in the Acotiamide U.S. Phase 2 program as a secondary endpoint.

[START_REF] Talley | A Novel Acetylcholine Esterase Inhibitor Acotiamide Hydrochloride (YM443) in Functional Dyspepsia: Efficacy in a Randomized, Double-Blind, Placebo-Controlled Dose Ranging Trial[END_REF]

Significant improvements in symptoms of bloating, postprandial nausea, and stomach pain before meals with the 300 mg dose t.i.d., were associated with significantly higher response rates on the adequate relief and OTE endpoints, and with significant improvement of several domains of the Short Form-36 quality of life scale and of the Short form Nepean Dyspepsia Index during the first weeks of the study.

[START_REF] Talley | A Novel Acetylcholine Esterase Inhibitor Acotiamide Hydrochloride (YM443) in Functional Dyspepsia: Efficacy in a Randomized, Double-Blind, Placebo-Controlled Dose Ranging Trial[END_REF]

C.5. Other uni-dimensional dyspepsia symptom questionnaires.

The only dyspepsia questionnaire to be validated in a Chinese population, the Dyspepsia scores correlated negatively with all aspects of the SF-36 quality of life scale with the exception of physical functioning, lending support for its construct validity. It was also able to discriminate between patients who reported a subjective improvement in symptoms and those who reported no change or worsening. Although it assesses disease severity, this questionnaire does not measure frequency of dyspeptic symptoms, excludes some key meal-related symptoms (e.g. early satiety) and includes a number subscales: (i) interference with activities of daily living (13 items); (ii) lack of control over the illness (7 items); (iii) disturbance of eating or drinking (3 items) and (iv) sleep disturbance (2 items). A separate symptom checklist measures the frequency, severity and bothersomeness of 15 common upper gastrointestinal symptoms over a 2-week period. An expert panel documented high internal consistency for the quality of life part of the NDI (Cronbach α 0.81-0.96) as well as good discriminative and convergent validity. The NDI was used as a secondary outcome measure in phase 2 and 3 itopride studies, in tegaserod phase 2 and 3 studies and in the Acotiamide U.S. Phase 2.

[START_REF] Talley | A Novel Acetylcholine Esterase Inhibitor Acotiamide Hydrochloride (YM443) in Functional Dyspepsia: Efficacy in a Randomized, Double-Blind, Placebo-Controlled Dose Ranging Trial[END_REF][START_REF] Vakil | Tegaserod treatment for functional dyspepsia dysmotility symptoms: results of two randomized, controlled trials[END_REF][START_REF] Holtmann | A placebocontrolled trial of itopride in functional dyspepsia[END_REF][START_REF] Talley | randomized, doubleblind, placebo-controlled trials[END_REF]123

Test retest reliability was evaluated in a multi-center study in the nausea/vomiting (3 items), postprandial fullness/early satiety (4 items), bloating (2 items), upper abdominal pain (2 items), and lower abdominal pain (2 items). Each item is scored from 0 (none) to 5 (very severe). The items were derived from patient focus groups and expert opinion. The PAGI-SYM

Table 1 .

 1 clinically relevant for functional disorders and for the irritable bowel syndrome in particular.155 It seems reasonable to assume that the same magnitude of margin over placebo could also be considered clinically relevant in FD.In conclusion, there are emerging data on the use of binary outcome measures in FD clinical trials, although further validation is required. Most existing questionnaires do not sufficiently fulfil psychometric validation criteria, in view of the latest consensus definitions of FD by Rome III criteria. Hence, evaluating and comparing the various options will need to go hand in hand with the analysis of recent, ongoing or future pharmaceutical trials for the treatment of FD, and optimization of potential endpoints that could be derived from existing instruments.Pieter Janssen is a research fellow of the FWO Flanders. This work was supported by a Methusalem grant to Jan Tack, M.D., Ph.D. Summary of included trials and outcome measures employed.

	F o r
	P
	e
	e r
	Grant support:	R
		e
		v i e
		w

However, a group of experts proposed a minimal range of efficacy of 10 to 15% over placebo to be