- Email: [email protected]
White Paper AGA: Functional Dyspepsia
Accepted Manuscript White Paper AGA: Functional Dyspepsia Nimish B. Vakil, MD, AGAF, Colin W. Howden, MD, AGAF, Paul Moayyedi, MD AGAF, Jan Tack, MD
PII: DOI: Reference:
S1542-3565(17)30588-8 10.1016/j.cgh.2017.05.013 YJCGH 55241
To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 5 May 2017 Please cite this article as: Vakil NB, Howden CW, Moayyedi P, Tack J, White Paper AGA: Functional Dyspepsia, Clinical Gastroenterology and Hepatology (2017), doi: 10.1016/j.cgh.2017.05.013. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1 White Paper AGA: Functional Dyspepsia
Colin W. Howden MD, AGAF2
Jan Tack MD4
Affiliations: 1
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Paul Moayyedi MD AGAF3
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Nimish B. Vakil MD, AGAF1
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University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
2
University of Tennessee Health Science Center, Memphis, Tennessee 3
McMaster University, Hamilton ON Canada University of Leuven, Leuven Belgium
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4
Corresponding author Nimish Vakil MD Aurora Summit Hospital 36500 Aurora Drive Summit WI 53066 Tel: 262-434-5761 e-mail: [email protected]
ACCEPTED MANUSCRIPT 2 Funding Sources: None
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Key words: Dyspepsia, Functional Dyspepsia, patient reported outcome
Disclosures: 1
Otsuka, US World Meds and Actavis.
2
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Dr. Vakil is a consultant for AstraZeneca, Ironwood, Restech, Yuhan, Allergan,
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Dr. Howden is a consultant for Otsuka, Takeda, Ironwood, Allergan, Aralez,
Pfizer Consumer Health, SynteractHCR and US World Meds.
3
Dr. Moayyedi is a consultant for Allergan, Shire, and Salix Pharmaceuticals. He
4
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has received research funds from Allergan and Takeda.
Dr. Tack is a consultant to Abide Therapeutics, AlfaWassermann, Allergan,
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Christian Hansen, Danone, EA pharma, Genfit, Ironwood, Janssen, Kiowa Kirin, Menarini, Mylan, Novartis, Nutricia, Ono Pharma, Rhythm, Shionogi, Shire, SK
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Life Sciences, Takeda, Theravance, Tsumura, Yuhan; Zealand, Zeria. He has received research grants or support from Abide Therapeutics, Shire, Zeria. Speaker bureau: Abbott, Allergan, AstraZeneca, Janssen, Kiowa Kirin, Menarini, Mylan, Novartis, Shire, Takeda, Zeria.
ACCEPTED MANUSCRIPT 3
Dyspepsia is a widely prevalent disorder throughout the world with populationbased estimates varying according to the definition used. The prevalence
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declines as the definition becomes more restrictive with 7% (95% confidence interval 5 to 11%) of the general population having Rome III criteria dyspepsia.1 The majority of patients with dyspepsia have no organic pathology identified at
SC
esophagogastroduodenoscopy that could explain symptoms and thus fulfill the definition of functional dyspepsia (FD; previously called non-ulcer dyspepsia).2
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The Rome IV classification of FD largely coincides with that of Rome III and retains the two categories of epigastric pain syndrome (EPS) and post-prandial distress syndrome (PDS).3 EPS consists of bothersome epigastric pain or epigastric burning on 1 or more days per week in the preceding 3 months with at least a 6-month history. PDS consists of bothersome early satiety or postprandial
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fullness on 3 or more days per week in the preceding 3 months with at least a 6month history. FD is a global problem that significantly reduces quality of life.4
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The economic cost of dyspepsia is also substantial with time lost from work, reduced productivity at work and medical costs for care accounting for most of
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the costs.5
On Oct. 27-28, 2016, a meeting was held in Washington, DC, sponsored by the American Gastroenterological Association’s Center for Diagnostics and Therapeutics that included members of the Food and Drug Administration (FDA) and the pharmaceutical industry, experts in FD and representatives of patient organizations.
ACCEPTED MANUSCRIPT 4
Session 1: Present Status and Lessons from Current therapies The first session was devoted to a review of the present status of FD and its
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treatment. Dr. Paul Moayyedi presented data on currently available treatments
for FD using data from systematic reviews that were being updated. Despite the high prevalence of the disorder, there are no approved treatments for FD in the
SC
United States, Canada or the European Union. A number of approaches that are available in Western countries are not specifically approved for use in FD but
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may have efficacy in reducing symptoms. These include eradication of Helicobacter pylori (H. pylori), acid inhibition with proton pump inhibitors (PPIs), prokinetic drugs and tricyclic antidepressants (TCAs). H. pylori eradication has been evaluated in 22 randomized, controlled trials (RCTs) including 4896
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patients with functional dyspepsia of any symptom subtype. H. pylori eradication has modest efficacy with a relative risk reduction (RRR) of 0.91 (95% CI = 0.88 to 0.94) and a number needed to treat (NNT) of 12.5 (95% CI = 10 to 20) in
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reducing overall dyspepsia symptoms. It is important to point out that these trials demonstrate that antibiotic therapy has a modest impact on FD. This may be
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related to the eradication of H. pylori but also may be related to more general changes in the microbiome of the upper gastrointestinal tract.6 There were 15 RCTs with 5389 FD patients of any subtype (excluding those with predominant heartburn) that compared PPI therapy with placebo. The RRR was 0.83 (95% CI = 0.77 to 0.89) and the NNT was 8 (95% CI = 6 to 14). There were 3 RCTs that compared TCAs (amitriptyline or imipramine) with placebo in 339
ACCEPTED MANUSCRIPT 5 patients with FD. The RRR was 0.74 (95% CI = 0.61 to 0.91) with a NNT of 6 ( 95% CI = 4 to 13).7 There were 23 RCTs of prokinetic drugs compared to placebo in 8788 FD patients.8 The RRR was 0.92 (95% CI = 0.88 to 0.97) with a
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NNT of 12.5 (95% CI = 8 to 25) at improving overall FD symptoms. When
symptom improvement was used as the end-point in clinical trials, the results
were more robust than when complete absence of symptoms was used. These
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studies emphasize the unmet need for medications to treat patients with FD and
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the limited efficacy of currently available treatment.
Session 2: Trial design in functional dyspepsia
The second session was devoted to current trial design in FD. Dr. Colin Howden began by summarizing the trial design issues that are inherent to all trials in
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functional gastrointestinal disorders (FGIDs) and then defined trial design concerns that are specific to FD. All trials in FGIDs rely on a symptom-based definition and end-points. The symptom complex can have many underlying
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etiologies and the placebo response rate in these studies is generally high.9 FD trials have additional problems because PDS may overlap with gastroparesis and
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EPS may overlap with acid-peptic disorders such as GERD.10
The importance of defining a patient population or sub-population that meets the Rome criteria for FD was emphasized. Small changes in the criteria for recruitment into trials or a shift in the population (primary care versus specialist care) can alter the outcome of the study as illustrated by the favorable results
ACCEPTED MANUSCRIPT 6 seen with itopride in phase 2 studies but the subsequent lack of efficacy in phase 3 trials.11 This session emphasized that the Rome definition required “bothersome” symptoms as a requirement for the definition of the disorder with
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“bothersome” defined as severe enough to interfere with regular activities.3 Therefore an end-point based on the definition would require not only an
improvement in symptoms but a measure of how the bothersomeness of the
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symptoms was alleviated. The FDA defines clinical benefit as a favorable effect
on a meaningful aspect of how the patient feels, functions or survives as a result
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of treatment. Survival is not a meaningful endpoint in FD and therefore a robust measure of symptom improvement and the impact of symptom improvement on functioning is required.
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Entry criteria for FD trials can be too restrictive or too inclusive. Early trials on FD required a symptom diagnosis coupled with an endoscopy that showed no abnormalities, to allow patients to enter a trial. Concerns about overlapping
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conditions led to other trials that went to extraordinary measures to exclude GERD (by performing 48-hour wireless pH-metry and single-blind run-in PPI
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treatment) and to exclude gastroparesis (with gastric emptying studies). There was concern about overlap between FD and other FGIDs such as irritable bowel syndrome (IBS). Excluding patients with all overlapping conditions has led to difficulty enrolling patients in FD trials and the generalizability of the results may be called into question because the resulting, narrowly defined patient populations do not resemble those patients typically seen in routine clinical
ACCEPTED MANUSCRIPT 7 practice.9
The recommendations of this session were to exclude patients with known
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causes of dyspeptic symptoms such as those with endoscopic abnormalities, those with H. pylori infection and those consuming non-steroidal anti-
inflammatory drugs (NSAIDs) on a regular basis. Patients with predominant
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heartburn should likewise be excluded. The role of gastric emptying studies was discussed as a means of excluding underlying gastroparesis as a cause of
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dyspeptic symptoms. Standardized criteria for the performance of a gastric emptying scintigraphy study have been developed. The FDA has recently approved a new gastric emptying breath test making measurement of gastric emptying accessible in small clinic settings. The consensus was that, while
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gastric emptying studies were important to understand the pathogenesis of symptoms in FD, they should not be an entry criterion for FD trials.
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In the ensuing discussion, it became clear that while the Rome criteria for diagnosis were necessary to define the disorder, the pharmacological properties
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of the investigational drug and the population likely to benefit should determine the inclusion criteria. Therefore the Rome criteria will determine the general criteria for trial inclusion but the specific properties of the drug will determine the subgroups of FD to be studied.
Session 3: End-points in functional dyspepsia trials
ACCEPTED MANUSCRIPT 8 In this session, Dr. Nimish Vakil presented information on the evolution of endpoints in clinical trials of FD. Inclusion criteria for clinical trials in FD inevitably influence trial results and outcome measures. Concepts on inclusion criteria for
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trials in FD were evaluated further. Phase 3 studies for tegaserod in FD
demonstrated that attempts to identify a cohort of patients with “pure” dyspepsia by excluding patients meeting the criteria for IBS or GERD led to a very small
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cohort of eligible patients (11%).12 Overlapping conditions have a significant
effect on the troublesomeness of symptoms as defined by the Rome criteria.
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Patients with two or more disorders have substantially more disruption to their lives than patients who meet the criteria for just one disorder.13 Therefore, patients with overlapping disorders may be more in need of treatment than those with just one disorder.
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The relevance of objective testing as an end-point in FD was discussed. The two potential objective tests that were considered were gastric emptying studies and the nutrient /saline load test. While both tests were felt to be useful in
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understanding the pathogenesis of dyspeptic symptoms, neither test is validated sufficiently as an end-point for dyspepsia trials. There was general agreement
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that no biomarker or diagnostic test is suitable as an end-point for clinical trials in FD at this time. As a syndrome defined by a collection of symptoms, the most appropriate end-point is based on improvement of symptoms. Composite endpoints have been used in the past.14 They evaluate various quantitative measures of symptoms and the number of days without symptoms. However,
ACCEPTED MANUSCRIPT 9 guidance from the FDA has changed our approach to the measurement of symptoms. Criteria for the development of a validated symptom assessment tool that obtains
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information regarding symptoms and bothersomeness directly from the patient were discussed. Based on the FDA’s guidance, the patient-reported outcome (PRO) measure requires the development of a conceptual framework of the
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relevant symptoms of the syndrome based on literature search and expert
review.15 The conceptual framework is adjusted based on patient interview and
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focus groups. A draft instrument is then developed and is tested in patients with the disorder to measure validity of the construct, the ability to respond to change and its reliability from test to re-test. Based on this information, the instrument is modified for use in clinical trials. A validated PRO measure is not yet available for
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FD but is an urgent need for future studies.
Session 4: The development of the Functional Dyspepsia Diary
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In March 2009, the Critical Path Institute (C-Path) in cooperation with the FDA and 27 pharmaceutical firms with representatives of government agencies (FDA,
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NIH), clinical consultants, academic researchers, patients, and clinical research organizations developed a consortium for the development and testing of PRO instruments. Ms. Robyn Carlson of Allergan Pharmaceuticals presented preliminary data on their efforts in developing a validated PRO instrument for use in FD trials. The group has developed the conceptual framework and is developing endpoints for EPS, PDS and the overlap of EPS with PDS. The most
ACCEPTED MANUSCRIPT 10 commonly reported symptoms by patients were bloating, stomach pain, early satiety, nausea, and burping. Seven items were included in the draft questionnaire: stomach pain, upper abdominal burning, nausea, bloating,
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postprandial fullness, early satiety, and burping/belching. Assessment of
measurement properties is in progress; appropriate further steps will be to modify the instrument and then to finalize it for initial use. This is a significant
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development in FD as a validated publicly available instrument will soon be
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available for dyspepsia trials.
Session 5: Evolution in pathophysiology, diagnosis and treatment of functional dyspepsia
In this session, Professor Jan Tack provided a view from Europe and discussed
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new potential markers for trials in FD. Using the principles elucidated by the PRO guidance from the FDA, the Leuven Post prandial distress Score has been developed for use in trials of PDS and received support from the European
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Medicines Agency.16,17 This PRO was developed independently from the Functional Dyspepsia Diary, and focuses on the PDS subgroup only. Recent
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studies have shown that providing pictograms may help patients understand symptom concepts in a way that words do not.18 New short-term markers were discussed such as a cumulative symptom score after a meal and nutrient volume tolerance. 22 19These offer insights into the pathophysiology of FD and one or more of them may be a potential marker of efficacy in FD trials.
ACCEPTED MANUSCRIPT 11 Putative mechanisms for meal-related dyspeptic symptoms include delayed gastric emptying, impaired accommodation and hypersensitivity to distention. Data were presented that suggest that patients with PDS either alone or
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overlapping with EPS have symptoms soon after ingesting a meal in contrast to patients with EPS. These observations are in support of the subdivision of FD in EPS and PDS as proposed in the Rome IV consensus.3 Clinical trials are
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underway looking at sub-groups of patients with FD. Amisulpride is being tested in a sub-group of PDS patients with delayed gastric emptying and prucalopride is
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being studied in patients with PDS and normal emptying. These novel studies show an exploration of subgroups of dyspeptic symptoms for whom targeted therapy may be easier to develop, than for the diverse group of dyspeptic patients.
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Impaired accommodation has been shown to be a potential cause of symptoms in FD. Relaxation of the proximal stomach (including the fundus) is important to accommodate a meal. There are limited measures that can be used to measure
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accommodation in large clinical trials. Barostat or scintigraphic studies of accommodation are not practical in large trials.20,21 The nutrient drink test has
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been proposed as an alternative. In this test a defined nutrient meal is ingested over a period of time until dyspeptic symptoms develop or the patient reports feeling full. Response to treatment can be measured by repeating the test after treatment.22,23 More recently, intragastric pressure measurement during a nutrient meal change has been proposed as a minimally invasive test of nutrient
ACCEPTED MANUSCRIPT 12 tolerance and accommodation in FD.24 The test needs further validation but could be an objective measure of outcome in the future.
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Discussion
Most of the discussion after the presentations focused on two main issues,
namely the inclusion or exclusion of H. pylori-infected patients in FD trials, and
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the utility of gastric emptying studies as inclusion criteria and end-points in FD trials.
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There was broad agreement that H. pylori infection is not a major cause for FD in western countries but may be a common cause for dyspepsia in other countries. Excluding H. pylori-infected patients seems reasonable in FD trials but should not be mandatory, particularly in Western countries where the infection is a relatively
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rare..
There was agreement that gastric emptying and nutrient load tests may have a role in understanding the pathophysiology of FD but they are not recommended
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as a therapeutic end-point at this time.
There was agreement that patients with overlapping syndromes should be
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included but criteria for inclusion of overlapping IBS and GERD need to be developed. Indeed, in general it is advisable not to restrict patients entering into FD trials on the basis of symptom subtype or result of gastric emptying test but it is important to carefully phenotype the patients entering the trial so that hypothesis generating subgroup analyses can be performed. The presentation of a validated PRO instrument in FD is anticipated.
ACCEPTED MANUSCRIPT 13
1
Ford AC, Marwaha A, Sood R, Moayyedi P. Global prevalence of, and risk factors for,
uninvestigated dyspepsia: a meta-analysis. Gut 2015; 64: 1049-57. Ford AC, Marwaha A, Lim A, Moayyedi P. What is the prevalence of clinically
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2
significant endoscopic finding in subjects with dyspepsia? Systematic review and metaanalysis. Clin Gastroenterol Hepatol. 2010; 8: 830-37) 3
Stanghelini V, Chan F K L, Hasler W L, Malagelada J R, Suzuki H, Tack J, Talley N J.
4
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Gastroduodenal disorders. Gastroenterology 2016; 150: 1380 - 1392
Ford AC. Forman D. Bailey AG. Axon AT. Moayyedi P. Initial poor quality of life and
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new onset of dyspepsia: results from a longitudinal 10-year follow-up study. Gut 2007; 56: 321-7 5
Moayyedi P, Mason J. Clinical and economic consequences of dyspepsia in the
community. Gut 2002; 50 (suppl 4: 10-12). 6
Moayyedi P. Helicobacter pylori eradication for functional dyspepsia. What are we
7
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treating? Arch Intern Med 2011; 171: 1936-8 Ford A, Luthra P, Tack J, Boeckstaens G, Moayeddi P, Talley N. Efficacy of
psychotropic drugs in functional dyspepsia: systematic review and meta-analysis Gut
8
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2017; 66: 411-20) (doi:10.1136/gutjnl-2015-310721) Bollegala NP, Khanna R, Moayyedi P, Leontiadis GI. Prokinetics for functional
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dyspepsia (Protocol). Cochrane Database of Systematic Reviews 2011, Issue 11. Art. No.: CD009431. DOI: 10.1002/14651858.CD009431 9
Irvine E J, Tack J, Crowell M D, Gwee K A, Ke M, Schmulson M J, Whitehead W E,
Spiegel B. Design of treatment trials for functional gastrointestinal disorders. Gastroenterology 2016; 150: 1469 - 1480 10
Parkman H P, van Natta M L, Abell T L, McCallum R W, Sarosiek I, Ngyuen L, Snape
W J, Koch K L, Hasler W L, Farrugia G, Lee L, Unalp-Arida A, Tonascia J, Hamilton F,
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Pasricha P J. Effect of nortriptyline on symptoms of idiopathic gastroparesis: The NORIG randomized clinical trial. Journal of the American Medical Association 2013; 310: 2640 -
11
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2649 Holtmann G, Talley N J, Liebregts T, Adam B, Parow C. A placebo-controlled trial of
itopride in functional dyspepsia. New England Journal of Medicine 2006; 354: 832 – 840 12
VAKIL N, VAN ZANTEN SV, CHANG L, TOTH G, SHERMAN J, FRASER M, COHARD-RADICE
13
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Pharmacol Ther. 2005 Dec;22(11-12):1147-55.
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M. Comprehension and awareness of symptoms in women with dyspepsia. Aliment
VAKIL N, STELWAGON M, SHEA EP, MILLER S. Symptom burden and consulting
behavior in patients with overlapping functional disorders in the US population. United European Gastroenterol J. 2016 Jun;4(3):413-22. 14
VAKIL N, LAINE L, TALLEY NJ, ZAKKO SF, TACK J, CHEY WD, KRALSTEIN J, EARNEST DL,
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LIGOZIO G, COHARD-RADICE M. Tegaserod treatment for dysmotility-like functional dyspepsia: results of two randomized, controlled trials. Am J Gastroenterol. 2008 Aug;103(8):1906-19.
Guidance for Industry Patient-Reported Outcome Measures:
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15
Use in Medical Product Development to Support Labeling Claims
16
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http://www.fda.gov/downloads/Drugs/Guidances/UCM193282.pdf accessed 12/25/2016 Carbone F, Vandenberghe A, Holvoet L, Vanuytsel T, Van Oudenhove L, Jones M,
Tack J. Validation of the Leuven Postprandial Distress Scale, a questionnaire for symptom assessment in the functional dyspepsia/postprandial distress syndrome. Aliment Pharmacol Ther. 2016 Nov;44(9):989-1001.
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17
http://www.ema.europa.eu/ema/index.jsp?curl=pages/includes/document/document_de
tail.jsp?webContentId=WC500198874&mid=WC0b01ac058009a3dc accessed on
18
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12/12/16
Tack J, Carbone F, Holvoet L, Vanheel H, Vanuytsel T, Vandenberghe A. The use of
pictograms improves symptom evaluation by patients with functional dyspepsia.Aliment
19
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Pharmacol Ther. 2014 Sep;40(5):523-30.
Tack J, Janssen P, Masaoka T, Farré R, Van Oudenhove. Efficacy
of buspirone,
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a fundus-relaxing drug, in patients with functional dyspepsia. Clin Gastroenterol Hepatol. 2012 Nov;10(11):1239-45 20
Tutuian R, Vos R, Karamanolis G, Tack J. An audit of technical pitfalls of gastric
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barostat testing in dyspepsia. Neurogastroenterol Motil. 2008 Feb;20(2):113-8.
Piessevaux H, Tack J, Walrand S, Pauwels S, Geubel A.Intragastric distribution of a
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standardized meal in health and functional dyspepsia: correlation with specific
22
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symptoms. Neurogastroenterol Motil. 2003 Oct;15(5):447-55.
Tack J, Caenepeel P, Piessevaux H, Cuomo R, Janssens J.Assessment of meal
induced gastric accommodation by a satiety drinking test in health and in severe functional dyspepsia.Gut. 2003 Sep;52(9):1271-7. 23
Tack J, Ly HG, Carbone F, Vanheel H, Vanuytsel T, Holvoet L, Boeckxstaens G,
Caenepeel P, Arts J, Van Oudenhove L. Efficacy of Mirtazapine in Patients With
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Functional Dyspepsia and Weight Loss. Clin Gastroenterol Hepatol. 2016 Mar;14(3):385-392.e4
Janssen P, Verschueren S, Ly HG, Vos R, Van Oudenhove L, Tack J. Intragastric
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pressure during food intake: a physiological and minimally invasive method to assess
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gastric accommodation.Neurogastroenterol Motil. 2011 Apr;23(4):316-22, e153-4.
PII: DOI: Reference:
S1542-3565(17)30588-8 10.1016/j.cgh.2017.05.013 YJCGH 55241
To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 5 May 2017 Please cite this article as: Vakil NB, Howden CW, Moayyedi P, Tack J, White Paper AGA: Functional Dyspepsia, Clinical Gastroenterology and Hepatology (2017), doi: 10.1016/j.cgh.2017.05.013. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1 White Paper AGA: Functional Dyspepsia
Colin W. Howden MD, AGAF2
Jan Tack MD4
Affiliations: 1
SC
Paul Moayyedi MD AGAF3
RI PT
Nimish B. Vakil MD, AGAF1
M AN U
University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
2
University of Tennessee Health Science Center, Memphis, Tennessee 3
McMaster University, Hamilton ON Canada University of Leuven, Leuven Belgium
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4
Corresponding author Nimish Vakil MD Aurora Summit Hospital 36500 Aurora Drive Summit WI 53066 Tel: 262-434-5761 e-mail: [email protected]
ACCEPTED MANUSCRIPT 2 Funding Sources: None
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Key words: Dyspepsia, Functional Dyspepsia, patient reported outcome
Disclosures: 1
Otsuka, US World Meds and Actavis.
2
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Dr. Vakil is a consultant for AstraZeneca, Ironwood, Restech, Yuhan, Allergan,
M AN U
Dr. Howden is a consultant for Otsuka, Takeda, Ironwood, Allergan, Aralez,
Pfizer Consumer Health, SynteractHCR and US World Meds.
3
Dr. Moayyedi is a consultant for Allergan, Shire, and Salix Pharmaceuticals. He
4
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has received research funds from Allergan and Takeda.
Dr. Tack is a consultant to Abide Therapeutics, AlfaWassermann, Allergan,
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Christian Hansen, Danone, EA pharma, Genfit, Ironwood, Janssen, Kiowa Kirin, Menarini, Mylan, Novartis, Nutricia, Ono Pharma, Rhythm, Shionogi, Shire, SK
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Life Sciences, Takeda, Theravance, Tsumura, Yuhan; Zealand, Zeria. He has received research grants or support from Abide Therapeutics, Shire, Zeria. Speaker bureau: Abbott, Allergan, AstraZeneca, Janssen, Kiowa Kirin, Menarini, Mylan, Novartis, Shire, Takeda, Zeria.
ACCEPTED MANUSCRIPT 3
Dyspepsia is a widely prevalent disorder throughout the world with populationbased estimates varying according to the definition used. The prevalence
RI PT
declines as the definition becomes more restrictive with 7% (95% confidence interval 5 to 11%) of the general population having Rome III criteria dyspepsia.1 The majority of patients with dyspepsia have no organic pathology identified at
SC
esophagogastroduodenoscopy that could explain symptoms and thus fulfill the definition of functional dyspepsia (FD; previously called non-ulcer dyspepsia).2
M AN U
The Rome IV classification of FD largely coincides with that of Rome III and retains the two categories of epigastric pain syndrome (EPS) and post-prandial distress syndrome (PDS).3 EPS consists of bothersome epigastric pain or epigastric burning on 1 or more days per week in the preceding 3 months with at least a 6-month history. PDS consists of bothersome early satiety or postprandial
TE D
fullness on 3 or more days per week in the preceding 3 months with at least a 6month history. FD is a global problem that significantly reduces quality of life.4
EP
The economic cost of dyspepsia is also substantial with time lost from work, reduced productivity at work and medical costs for care accounting for most of
AC C
the costs.5
On Oct. 27-28, 2016, a meeting was held in Washington, DC, sponsored by the American Gastroenterological Association’s Center for Diagnostics and Therapeutics that included members of the Food and Drug Administration (FDA) and the pharmaceutical industry, experts in FD and representatives of patient organizations.
ACCEPTED MANUSCRIPT 4
Session 1: Present Status and Lessons from Current therapies The first session was devoted to a review of the present status of FD and its
RI PT
treatment. Dr. Paul Moayyedi presented data on currently available treatments
for FD using data from systematic reviews that were being updated. Despite the high prevalence of the disorder, there are no approved treatments for FD in the
SC
United States, Canada or the European Union. A number of approaches that are available in Western countries are not specifically approved for use in FD but
M AN U
may have efficacy in reducing symptoms. These include eradication of Helicobacter pylori (H. pylori), acid inhibition with proton pump inhibitors (PPIs), prokinetic drugs and tricyclic antidepressants (TCAs). H. pylori eradication has been evaluated in 22 randomized, controlled trials (RCTs) including 4896
TE D
patients with functional dyspepsia of any symptom subtype. H. pylori eradication has modest efficacy with a relative risk reduction (RRR) of 0.91 (95% CI = 0.88 to 0.94) and a number needed to treat (NNT) of 12.5 (95% CI = 10 to 20) in
EP
reducing overall dyspepsia symptoms. It is important to point out that these trials demonstrate that antibiotic therapy has a modest impact on FD. This may be
AC C
related to the eradication of H. pylori but also may be related to more general changes in the microbiome of the upper gastrointestinal tract.6 There were 15 RCTs with 5389 FD patients of any subtype (excluding those with predominant heartburn) that compared PPI therapy with placebo. The RRR was 0.83 (95% CI = 0.77 to 0.89) and the NNT was 8 (95% CI = 6 to 14). There were 3 RCTs that compared TCAs (amitriptyline or imipramine) with placebo in 339
ACCEPTED MANUSCRIPT 5 patients with FD. The RRR was 0.74 (95% CI = 0.61 to 0.91) with a NNT of 6 ( 95% CI = 4 to 13).7 There were 23 RCTs of prokinetic drugs compared to placebo in 8788 FD patients.8 The RRR was 0.92 (95% CI = 0.88 to 0.97) with a
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NNT of 12.5 (95% CI = 8 to 25) at improving overall FD symptoms. When
symptom improvement was used as the end-point in clinical trials, the results
were more robust than when complete absence of symptoms was used. These
SC
studies emphasize the unmet need for medications to treat patients with FD and
M AN U
the limited efficacy of currently available treatment.
Session 2: Trial design in functional dyspepsia
The second session was devoted to current trial design in FD. Dr. Colin Howden began by summarizing the trial design issues that are inherent to all trials in
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functional gastrointestinal disorders (FGIDs) and then defined trial design concerns that are specific to FD. All trials in FGIDs rely on a symptom-based definition and end-points. The symptom complex can have many underlying
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etiologies and the placebo response rate in these studies is generally high.9 FD trials have additional problems because PDS may overlap with gastroparesis and
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EPS may overlap with acid-peptic disorders such as GERD.10
The importance of defining a patient population or sub-population that meets the Rome criteria for FD was emphasized. Small changes in the criteria for recruitment into trials or a shift in the population (primary care versus specialist care) can alter the outcome of the study as illustrated by the favorable results
ACCEPTED MANUSCRIPT 6 seen with itopride in phase 2 studies but the subsequent lack of efficacy in phase 3 trials.11 This session emphasized that the Rome definition required “bothersome” symptoms as a requirement for the definition of the disorder with
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“bothersome” defined as severe enough to interfere with regular activities.3 Therefore an end-point based on the definition would require not only an
improvement in symptoms but a measure of how the bothersomeness of the
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symptoms was alleviated. The FDA defines clinical benefit as a favorable effect
on a meaningful aspect of how the patient feels, functions or survives as a result
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of treatment. Survival is not a meaningful endpoint in FD and therefore a robust measure of symptom improvement and the impact of symptom improvement on functioning is required.
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Entry criteria for FD trials can be too restrictive or too inclusive. Early trials on FD required a symptom diagnosis coupled with an endoscopy that showed no abnormalities, to allow patients to enter a trial. Concerns about overlapping
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conditions led to other trials that went to extraordinary measures to exclude GERD (by performing 48-hour wireless pH-metry and single-blind run-in PPI
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treatment) and to exclude gastroparesis (with gastric emptying studies). There was concern about overlap between FD and other FGIDs such as irritable bowel syndrome (IBS). Excluding patients with all overlapping conditions has led to difficulty enrolling patients in FD trials and the generalizability of the results may be called into question because the resulting, narrowly defined patient populations do not resemble those patients typically seen in routine clinical
ACCEPTED MANUSCRIPT 7 practice.9
The recommendations of this session were to exclude patients with known
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causes of dyspeptic symptoms such as those with endoscopic abnormalities, those with H. pylori infection and those consuming non-steroidal anti-
inflammatory drugs (NSAIDs) on a regular basis. Patients with predominant
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heartburn should likewise be excluded. The role of gastric emptying studies was discussed as a means of excluding underlying gastroparesis as a cause of
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dyspeptic symptoms. Standardized criteria for the performance of a gastric emptying scintigraphy study have been developed. The FDA has recently approved a new gastric emptying breath test making measurement of gastric emptying accessible in small clinic settings. The consensus was that, while
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gastric emptying studies were important to understand the pathogenesis of symptoms in FD, they should not be an entry criterion for FD trials.
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In the ensuing discussion, it became clear that while the Rome criteria for diagnosis were necessary to define the disorder, the pharmacological properties
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of the investigational drug and the population likely to benefit should determine the inclusion criteria. Therefore the Rome criteria will determine the general criteria for trial inclusion but the specific properties of the drug will determine the subgroups of FD to be studied.
Session 3: End-points in functional dyspepsia trials
ACCEPTED MANUSCRIPT 8 In this session, Dr. Nimish Vakil presented information on the evolution of endpoints in clinical trials of FD. Inclusion criteria for clinical trials in FD inevitably influence trial results and outcome measures. Concepts on inclusion criteria for
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trials in FD were evaluated further. Phase 3 studies for tegaserod in FD
demonstrated that attempts to identify a cohort of patients with “pure” dyspepsia by excluding patients meeting the criteria for IBS or GERD led to a very small
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cohort of eligible patients (11%).12 Overlapping conditions have a significant
effect on the troublesomeness of symptoms as defined by the Rome criteria.
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Patients with two or more disorders have substantially more disruption to their lives than patients who meet the criteria for just one disorder.13 Therefore, patients with overlapping disorders may be more in need of treatment than those with just one disorder.
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The relevance of objective testing as an end-point in FD was discussed. The two potential objective tests that were considered were gastric emptying studies and the nutrient /saline load test. While both tests were felt to be useful in
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understanding the pathogenesis of dyspeptic symptoms, neither test is validated sufficiently as an end-point for dyspepsia trials. There was general agreement
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that no biomarker or diagnostic test is suitable as an end-point for clinical trials in FD at this time. As a syndrome defined by a collection of symptoms, the most appropriate end-point is based on improvement of symptoms. Composite endpoints have been used in the past.14 They evaluate various quantitative measures of symptoms and the number of days without symptoms. However,
ACCEPTED MANUSCRIPT 9 guidance from the FDA has changed our approach to the measurement of symptoms. Criteria for the development of a validated symptom assessment tool that obtains
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information regarding symptoms and bothersomeness directly from the patient were discussed. Based on the FDA’s guidance, the patient-reported outcome (PRO) measure requires the development of a conceptual framework of the
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relevant symptoms of the syndrome based on literature search and expert
review.15 The conceptual framework is adjusted based on patient interview and
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focus groups. A draft instrument is then developed and is tested in patients with the disorder to measure validity of the construct, the ability to respond to change and its reliability from test to re-test. Based on this information, the instrument is modified for use in clinical trials. A validated PRO measure is not yet available for
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FD but is an urgent need for future studies.
Session 4: The development of the Functional Dyspepsia Diary
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In March 2009, the Critical Path Institute (C-Path) in cooperation with the FDA and 27 pharmaceutical firms with representatives of government agencies (FDA,
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NIH), clinical consultants, academic researchers, patients, and clinical research organizations developed a consortium for the development and testing of PRO instruments. Ms. Robyn Carlson of Allergan Pharmaceuticals presented preliminary data on their efforts in developing a validated PRO instrument for use in FD trials. The group has developed the conceptual framework and is developing endpoints for EPS, PDS and the overlap of EPS with PDS. The most
ACCEPTED MANUSCRIPT 10 commonly reported symptoms by patients were bloating, stomach pain, early satiety, nausea, and burping. Seven items were included in the draft questionnaire: stomach pain, upper abdominal burning, nausea, bloating,
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postprandial fullness, early satiety, and burping/belching. Assessment of
measurement properties is in progress; appropriate further steps will be to modify the instrument and then to finalize it for initial use. This is a significant
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development in FD as a validated publicly available instrument will soon be
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available for dyspepsia trials.
Session 5: Evolution in pathophysiology, diagnosis and treatment of functional dyspepsia
In this session, Professor Jan Tack provided a view from Europe and discussed
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new potential markers for trials in FD. Using the principles elucidated by the PRO guidance from the FDA, the Leuven Post prandial distress Score has been developed for use in trials of PDS and received support from the European
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Medicines Agency.16,17 This PRO was developed independently from the Functional Dyspepsia Diary, and focuses on the PDS subgroup only. Recent
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studies have shown that providing pictograms may help patients understand symptom concepts in a way that words do not.18 New short-term markers were discussed such as a cumulative symptom score after a meal and nutrient volume tolerance. 22 19These offer insights into the pathophysiology of FD and one or more of them may be a potential marker of efficacy in FD trials.
ACCEPTED MANUSCRIPT 11 Putative mechanisms for meal-related dyspeptic symptoms include delayed gastric emptying, impaired accommodation and hypersensitivity to distention. Data were presented that suggest that patients with PDS either alone or
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overlapping with EPS have symptoms soon after ingesting a meal in contrast to patients with EPS. These observations are in support of the subdivision of FD in EPS and PDS as proposed in the Rome IV consensus.3 Clinical trials are
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underway looking at sub-groups of patients with FD. Amisulpride is being tested in a sub-group of PDS patients with delayed gastric emptying and prucalopride is
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being studied in patients with PDS and normal emptying. These novel studies show an exploration of subgroups of dyspeptic symptoms for whom targeted therapy may be easier to develop, than for the diverse group of dyspeptic patients.
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Impaired accommodation has been shown to be a potential cause of symptoms in FD. Relaxation of the proximal stomach (including the fundus) is important to accommodate a meal. There are limited measures that can be used to measure
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accommodation in large clinical trials. Barostat or scintigraphic studies of accommodation are not practical in large trials.20,21 The nutrient drink test has
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been proposed as an alternative. In this test a defined nutrient meal is ingested over a period of time until dyspeptic symptoms develop or the patient reports feeling full. Response to treatment can be measured by repeating the test after treatment.22,23 More recently, intragastric pressure measurement during a nutrient meal change has been proposed as a minimally invasive test of nutrient
ACCEPTED MANUSCRIPT 12 tolerance and accommodation in FD.24 The test needs further validation but could be an objective measure of outcome in the future.
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Discussion
Most of the discussion after the presentations focused on two main issues,
namely the inclusion or exclusion of H. pylori-infected patients in FD trials, and
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the utility of gastric emptying studies as inclusion criteria and end-points in FD trials.
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There was broad agreement that H. pylori infection is not a major cause for FD in western countries but may be a common cause for dyspepsia in other countries. Excluding H. pylori-infected patients seems reasonable in FD trials but should not be mandatory, particularly in Western countries where the infection is a relatively
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rare..
There was agreement that gastric emptying and nutrient load tests may have a role in understanding the pathophysiology of FD but they are not recommended
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as a therapeutic end-point at this time.
There was agreement that patients with overlapping syndromes should be
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included but criteria for inclusion of overlapping IBS and GERD need to be developed. Indeed, in general it is advisable not to restrict patients entering into FD trials on the basis of symptom subtype or result of gastric emptying test but it is important to carefully phenotype the patients entering the trial so that hypothesis generating subgroup analyses can be performed. The presentation of a validated PRO instrument in FD is anticipated.
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