Randomized trial in postprandial functional dyspepsia: Reassurance and diagnostic explanation with or without traditional dietary advice

Almost 80% of individuals with functional dyspepsia experience meal‐related symptoms and are diagnosed with postprandial distress syndrome (PDS). However, studies evaluating dietary modifications in PDS are sparse. We performed a single‐center randomized trial comparing reassurance and diagnostic explanation (RADE) with or without traditional dietary advice (TDA) in PDS.


| INTRODUC TI ON
Dyspepsia is common, affecting 7.2% of the global population, and is characterized by gastroduodenal symptoms of postprandial fullness, early satiety, epigastric pain, or burning. 1,2Over 85% of individuals with dyspepsia do not have an underlying organic disease to explain the symptoms and are diagnosed as having functional dyspepsia, 3 a disorder of gut-brain interaction in which the pathophysiology is incompletely understood but includes visceral hypersensitivity, motor disturbances, impaired gastric accommodation, and central sensitization. 4Functional dyspepsia can be further divided into the predominant meal-related subtype-termed postprandial distress syndrome (PDS)-which represents 80% of functional dyspepsia cases, or the non-meal-related epigastric pain syndrome variant. 4ile functional dyspepsia does not impact mortality, it represents a significant societal burden, being associated with increased healthcare use, mood disturbances, reduced quality of life, and impaired work productivity through presenteeism and absenteeism. 1,5erapies for functional dyspepsia are limited and generally ineffective. 6Only 15%-20% of patients appear to experience symptom improvement after a reassuringly normal upper GI endoscopy, [7][8][9] and with little change to psychological well-being and health-related quality of life. 9Acid-suppressive medication such as proton pump inhibitors are frequently prescribed yet benefit 1 in 11. 10 Despite food typically triggering symptoms in PDS there is sparse data regarding dietary modifications in this patient group.Commonly reported food triggers include fatty foods, milk and dairy, alcohol, coffee, red meat, carbonated drinks, vegetables, spicy foods, carbohydrates, wheat, and citrus. 11While reducing the intake of such foods-in the form of either traditional dietary advice (TDA) or a diet low in fermentable carbohydrates-is recommended in irritable bowel syndrome (IBS), 12 this cannot be extrapolated to PDS in which there is currently insufficient evidence due to a lack of clinical trials.An Australian study reported only 3 of 19 (16%) patients with functional dyspepsia improved with TDA 13 but was limited to being a small non-randomized trial and without differentiating functional dyspepsia subtypes.A single-center randomized trial from India found that after 4 weeks of TDA, clinical improvements were seen in 57% of participants with functional dyspepsia and 53% of those with PDS symptoms. 14These two studies differ with regard to their design, participant numbers, and cultural settings.Hence, further studies of TDA in PDS are needed, a message corroborated by the recently published British and European Guidelines on its management. 15 performed a randomized trial evaluating the clinical efficacy of TDA in PDS, comparing it with a model of reassurance and diagnostic explanation (RADE) alone.We hypothesized that the addition of TDA will lead to greater symptom improvement than RADE alone.

| Participants and setting
The study was carried out in accordance with the Declaration of Helsinki and approved by West Midlands Black Country Research Ethics Committee.The clinical trials.gov number is NCT05718960.
The study was conducted at Sheffield Teaching Hospitals (UK) between September and December 2022.Recruitment was through poster advertisements within the endoscopy units.The inclusion criteria were adults aged 18-60 years who fulfilled criteria for PDS, in accordance with the Rome IV diagnostic criteria, and had undergone a normal upper GI endoscopy within the last year.Additional inclusion criteria included being English literate and having internet access to complete questionnaire data.compared with RADE alone.Alternate dietary strategies should be explored in this cohort.

K E Y W O R D S
diet, functional dyspepsia, postprandial distress syndrome, reassurance

Key points
What is established knowledge?
• Functional dyspepsia affects 7.2% of the global population.
• Approximately 80% of patients with functional dyspepsia report meal-related symptoms and are diagnosed with postprandial distress syndrome (PDS).
• There are limited data on the efficacy of dietary therapies in PDS.

What are the new findings from this study?
• The addition of traditional dietary advice (TDA) did not lead to significantly greater symptom reduction compared with reassurance and diagnostic explanation alone.
• The study was performed in a predominantly white British cohort and may not apply to other ethnicities/ cultures with different cuisines.
Exclusion criteria were body mass index <20, history of eating disorders, current dietary interventions, inflammatory bowel disease, celiac disease, gastrointestinal cancer, previous abdominal surgery, scleroderma, poorly controlled diabetes, severe liver/ respiratory/cardiac/psychiatric disease (with "severe" defined as repeated flares, recurrent hospital or general practitioner attendances, numerous medications, clinically appearing unwell due to that disease process), memory impairment, pregnant, current use of antibiotics/anti-inflammatory drugs/narcotics, or currently titrated antidepressants or acid-suppressive medication (i.e., not on a stable dose).

| Randomization
Patients with PDS were randomized 1:1 to a leaflet providing RADE-alone or RADE plus TDA.The randomization was computergenerated and stratified according to the presence or absence of IBS, the latter elicited during the initial screening period.This was deemed relevant as between 30%-50% of patients with functional dyspepsia have coexisting IBS, 1 which might influence response rates to assigned interventions.
The RADE-alone group was provided a leaflet explaining dyspeptic symptoms, their prevalence and burden, and reassurance that no organic disease (i.e., cancer, ulcers, and infection) was found at recent upper gastrointestinal endoscopy.Participants were informed of the diagnosis "functional dyspepsia," with the basic explanation of disturbed communication between the stomach and the brain, leading to sensitive nerves and inadequate stomach muscle function.Individuals were informed that following upper gastrointestinal endoscopy and RADE their symptoms might improve, which we plan to assess over a 4-week period.
The TDA group were given the aforementioned RADE information but also advised to adopt dietary modifications, with recommendations to eat small, regular meals and reduce the intake of caffeine/alcohol/fizzy drinks and high fat/processed/spicy foods.
Both the RADE and TDA leaflets are available within supplementary materials.

| Questionnaires
Participant baseline characteristics (age, gender, race, smoking status, alcohol use, and medication) were documented and they completed the following questionnaires during the 4-week trial: a. Leuven postprandial distress scale (LPDS)-the LPDS is a sensitive and reliable patient-reported outcome instrument to assess symptoms in functional dyspepsia/PDS. 16 abdominal) symptoms with the current treatment compared with the baseline period?" with a yes or no answer.This question has been used in randomized trials in functional dyspepsia to assess symptom response. 17,18Short form Nepean Dyspepsia Index (NDI)-this 10-item questionnaire assesses dyspepsia-related quality of life across five subscales, that is, tension/anxiety, interference with daily activities, disruption to regular eating/drinking, knowledge toward/ control over disease symptoms, and interference with work/ study.Each item is measured by a 5-point Likert scale ranging from 1 (not at all or not applicable) to 5 (extremely).19 d.Gastrointestinal symptom rating scale for IBS (GSRS-IBS)-this 13-item measures IBS-related gastrointestinal symptom severity over the last 7 days.The items belong to five symptom clusters: pain, bloating, constipation, diarrhea, and early satiety.The items are scored between 1 and 7, where 1 corresponds to "no discomfort at all" and 7 to "very severe discomfort."20 e. Hospital Anxiety and Depression Scale (HADS)-is a psychological screening tool to which there are in total 14 items, seven each for depression and anxiety.Each item is rated from 0 (not present) to 3 (maximum), giving a cumulative score for each subscale to range from 0 to 21.A subscale score of ≥11 is used to indicate a clinically significant level of anxiety or depression. 21The patient health questionnaire (PHQ)-12 non-GI somatic symptoms scale-this records 12 bothersome non-GI symptoms over the past month, with each item scored as 0 ("not bothered at all"), 1 ("bothered a little"), or 2 ("bothered a lot").A total score of >12 implies high somatic symptom reporting.22 The group-allocated TDA also self-reported dietary adherence as "never/rarely" (followed the dietary advice <25% of the time), "sometimes" (25%-50% of the time), "frequently" (51%-75% of the time), or "always" (76%-100% of the time).13 Individuals following TDA >50% of the time were deemed adherent.

| Endpoints
The co-primary endpoints to define clinical response were evaluated over Weeks 3-4 as (i) ≥50% adequate relief of dyspeptic symptoms and (ii) >0.5-point reduction in the PDS subscale compared to baseline.Secondary endpoints included changes in individual LPDS items, NDI-QOL, GSRS-IBS, and the presence of anxiety, depression, and high somatic symptom reporting.

| Sample size and statistical analysis
Based on the assumption of up to 20% improvement following a normal upper GI endoscopy and RADE 7,8 and a 57% response rate with TDA as per a previous randomized clinical trial, 14 we aimed to randomize 25 patients per arm, with 80% power at α = 0.05.
Categorical variables were summarized by descriptive statistics, including total numbers and percentages, with comparisons between groups performed using chi-square test.Continuous data were summarized by mean and standard deviation, with comparisons between and within groups performed using (un)paired student test as appropriate.Statistical significance was set at p < 0.05.

| RE SULTS
A total of 83 individuals registered interest in the study, of which 53 with PDS were randomized to RADE-alone (n = 27) or additional TDA (n = 26); see study flow chart, Figure 1.The mean age of participants was 39 years (range 21-59), 70% female, 83% white British, and coexistent IBS in 66% (n = 35).Baseline demographics and clinical characteristics were comparable between the groups; see Table 1.EPS subtype is the average of pain and burning scores in LPDS.

| Primary endpoint results
Following intervention, there was no significant difference between the groups with regard to meeting the primary endpoints (Figure 2).
Adequate relief of dyspeptic symptoms was met by 33% (n = 9) in the RADE-alone group versus 39% (n = 10) in the TDA group; pvalue = 0.70, while (ii) a reduction of >0.5 points in the PDS subscale was met by 37% (n = 10) in the RADE group versus 27% (n = 7) in the TDA group; p-value = 0.43.Adequate adherence to TDA was reported by 84%, with 65% following the diet frequently and 19% always.The RADE group reported not following any additional diet while in the trial.

| Secondary endpoint results
While significant within-group reductions in LPDS were noted for both RADE-alone and TDA, there was no between-group difference in changes for early satiety, postprandial fullness, upper abdominal bloating, epigastric pain, epigastric burning, nausea, belching, and heartburn (Table 2).
Following the 4-week intervention, there were no significant within-or between-group changes in NDI quality of life indices (tension, interference, eating and drinking, knowledge, and work) and GSRS-IBS domains (pain, bloating, constipation, diarrhea, and satiety); Table 3.At the end of the study period, there was also no difference between TDA and RADE in clinical anxiety (44% vs. 54%, p = 0.50), depression (26% vs. 27%, p = 0.93) or high levels of somatic symptom reporting (19% vs. 11.5%,p = 0.48).

| DISCUSS ION
This UK-based study is the first randomized trial comparing the efficacy of RADE-alone versus additional TDA for the management of PDS.Almost one in three participants demonstrated an improvement in dyspeptic symptoms, which was similar between the groups, and not affected by the presence or absence of associated IBS.The assigned interventions did not lead to significant within-or betweengroup changes in GSRS, mood, or quality of life.
It has been demonstrated that comprehensive web-based educational tools-which include concepts aligned to RADE-are effective measures toward improving symptom severity, quality of life, and health anxiety in patients with functional dyspepsia. 23The lack of additional benefit seen with TDA might, in part, be due to subtle dietary modifications having been made before study entry which we could not capture.For example, individuals with functional dyspepsia may eat smaller, more frequent meals with reduced fat content compared with healthy controls. 24,25It could also be speculated that certain concepts of TDA, such as reducing the intake of spicy food, may not apply to a predominantly white British population.Notably, TDA had a minimal effect on functional dyspepsia symptoms in an Australian study. 13In contrast, it might be of greater importance among those ethnicities and cultures where spice is commonly used within cuisines.For example, high consumption of spicy food among Iranian adults is associated with an increased severity of dyspeptic symptoms. 26Similarly, a study from India reported almost 70% of individuals with functional dyspepsia eat hot/spicy food more than once per day, and the symptom improvement following TDA was 57%. 14Hence, the role of TDA and its individual elements should F I G U R E 2 Clinical response in dyspepsia symptoms following RADE ± TDA.
be considered on an individualized basis in people with functional dyspepsia.
Moving forward, it would be useful to explore other dietary therapies in PDS, such as a diet low in fermentable oligo/di/monosaccharides and polyols (low FODMAP diet) for which there is an emerging but limited evidence base.An Australian group reported a low FODMAP diet to be superior to TDA in functional dyspepsia, with response rates of 50% versus 16%, but this was a small nonrandomized observational study and did not evaluate PDS per se. 13single-center randomized trial from India found no difference between a low FODMAP diet and TDA in functional dyspepsia, with response rates at Week 4 being 67% versus 57%, respectively.14 However, while not powered to look at individual subtypes, it did suggest that those with PDS have a better response to a low FODMAP diet.14 There might also be future interest in evaluating a gluten-/wheat-free diet in PDS, given that approximately a third of people with functional dyspepsia report sensitivity to wheatbased products.27 A small open-label study comprising 22 patients with functional dyspepsia reported that 80% improved following a gluten-free diet, albeit only a quarter subsequently reacted to It asks for eight dyspeptic symptoms (early satiety, postprandial fullness, upper abdominal bloating, epigastric pain, epigastric burning, nausea, belching, and heartburn), each scored on a 5-point scale (0 = absent to 4 = very severe).The first three dyspeptic symptoms can be combined to give an average postprandial distress syndrome (PDS) domain score.Following intervention, a reduction in the average PDS domain score of >0.5 points from baseline is a validated, meaningfully important difference that denotes clinical response. 16b.Adequate symptom relief of ≥50%-phrased as "Did you experience overall satisfactory relief of dyspepsia (stomach/upper F I G U R E 1 Study flow chart.RADE, reassurance and diagnostic explanation; TDA, traditional dietary advice.
Baseline data.
Note: Values presented as mean (SD) or n (%).PDS subtype is the average of early satiety, fullness, and upper stomach bloating in LPDS.
Within-and between-group changes in Nepean Dyspepsia Index (NDI) and GSRS-IBS subscales following RADE ± TDA.
TA B L E 2 Within-and between-group changes in LPDS subscales following RADE ± TDA.TA B L E 3