Clinical trial NCT05832528: Low FODMAP Diet in FD (PDS)
Official title: The Effect of a Low FODMAP Diet in Functional Dyspepsia Patients With Meal Related Symptoms on Complaint Pattern and Urinary Histamine Excretion
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Functional Gastrointestinal Disorders
Lead sponsor: Universitaire Ziekenhuizen KU Leuven
Sponsor class: OTHER
First posted: 2023-04-27
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Dietary intervention trial
Primary purpose: TREATMENT

Brief summary: The goal of this dietary intervention study is to assess the efficacy and mechanisms of a low-FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) diet in functional dyspepsia patients. The main questions it aims to answer are:

* If a low-FODMAP diet can reduce dyspeptic complaints
* How a low-FODMAP diet can reduce dyspeptic complaints in functional dyspepsia (FD).

Participants will follow a 6-week during low-FODMAP diet followed by powder reintroduction of 6 FODMAPs and 1 control substance.

Detailed description: Functional dyspepsia Functional dyspepsia (FD) is defined as "symptoms affecting daily life which are thought to originate from the gastroduodenal region, such as postprandial fullness, early satiation, epigastric pain and burning, without underlying organic disease likely to explain the symptoms". FD is very common, with estimates of 10% to 30% prevalence in the general population, and is associated with substantial medical care costs and a considerable health economic impact. A proportion of 20%-25% of the patients with severe and refractory GI symptoms also have psychosocial co-morbidities such as anxiety, depression or somatization and severely impaired daily functioning (about 10% of these patients have work disability). This subgroup is often referred to advanced care, which may be associated with even higher health economic costs.

The pathophysiology of FD remains poorly understood and is most likely heterogeneous. The majority of FD patients have meal-related symptoms (early satiation, postprandial fullness, or epigastric pain or burning or nausea occurring or worsening after a meal). These are referred to as having Postprandial Distress Syndrome (PDS) according to the Rome IV consensus.

Leaky duodenal mucosa Duodenal and small intestinal perturbations seem to play an important role in the generation of dyspeptic symptoms. Through neuro-humoral feedback mechanisms, the duodenum plays a major role in controlling gastric functions. Mechanistic studies support the hypothesis that altered duodenal content or altered duodenal mucosal integrity are present in FD and may trigger impaired nutrient tolerance and impaired accommodation. Closely associated are signs of low grade inflammation with increased numbers of mast cells and eosinophils in the duodenal mucosa, which has been associated to symptoms of postprandial fullness and early satiation. While acute stress can increase intestinal permeability, changes in luminal factors are key candidate mechanisms to explain both mucosal permeability and immune inflammation. Duodenal acid exposure is increased in FD patients and may lead to loss of mucosal integrity and mast cell activation.

Dietary triggers The use of dietary therapeutic approaches such as the FODMAP (Fermentable Oligosaccharides, Disaccharides, Monosaccharides, And Polyols) diet to manage gastrointestinal symptoms has been frequently described and controlled studies have showed significant favorable on irritable bowel syndrome (IBS) symptoms such as abdominal pain, bloating and flatulence and it has been shown to be associated to changes in fecal microbiota. A recent study from our group showed that fructans and fructose (two of the FODMAPs) interfere with the normal meal-induced drop in intragastric pressure (IGP) and induce early postprandial occurrence of gastrointestinal symptoms, reminiscent of what happens in FD.

Measuring urinary histamine excretion McIntosh et al made an effort to identify pathophysiological mechanisms by which FODMAPs could cause gastrointestinal symptoms. They studied 20 IBS patients on a high FODMAP diet and 20 IBS patients on a low FODMAP diet. Urine samples were tested using Mass Spectrometry Analysis for metabolites that could potentially be linked to FODMAP induced post prandial distress. Patients on a low FODMAP diet had lower urinary histamine levels than IBS patients on a high FODMAP diet. The investigators hypothesize that urinary histamine excretion could be a surrogate marker for duodenal mastcell activation in patients with FD like described previously. The investigators will also measure the urinary N-methyl histamine excretion which is a more stable metabolite than histamine itself.

3. Trial objectives and Design

3.1 Trial objectives In this study, the investigators will evaluate the FODMAP diet as an alternative treatment for functional dyspepsia and explore its effect on different aspects of the pathophysiology of FD.

3.2 Primary endpoints The primary endpoint is to evaluate the efficacy of low FODMAP diet on gastrointestinal symptoms in FD.

3.3 Secondary endpoints The secondary endpoint is to explore the mechanism of action of the low FODMAP diet by evaluating duodenal mucosal permeability and urinary histamine (microgram/g creatinin in 24 hour sample) and N-methyl histamine excretion (microgram/g creatinin in 24 hour sample).

3.4 Trial Design The study design includes a 2w running up phase ('baseline'), 6 weeks of a 'strict' FODMAP diet (not blinded), followed by a 5 week 'reintroduction' phase (single blind) and, finally 2 weeks of a diet 'moderate' in FODMAP levels (not blinded). The duration of 6 weeks is based on published clinical recommendations. To support the patients' strict adherence to the diet, patients will receive a booklet with information regarding FODMAP food lists and 50 examples of FODMAP meal recipes.

The 'reintroduction' period will involve patients being challenged with 1 FODMAP group per 4 days with a wash out of 1 day after each FODMAP (4 weeks and 2 days in total). There will also be a 5 days control with glucose as a control substance. At the end of the 6 weeks of 'strict' diet, patients will receive in a blinded manner (labelled A to G) 6 containers containing the different FODMAP sugars (fructose, lactose, sorbitol, mannitol, fructans, galacto-oligosaccharides) and 1 container of glucose. The concentrations will be based on previous studies and what is commonly used in the clinical breath testing setting. These sugars can be easily dissolved in water by the patients before consumption at their homes.

Based on the patients' symptom results following each of these challenges, they will then follow the 'moderate' FODMAP diet during 2 weeks, where the FODMAPs that did not trigger any symptoms during the challenge tests can now be consumed without restriction.

24h urine, and duodenal biopsies (collected by endoscopy) will also be collected at baseline and at the end of the 6 weeks strict diet to assess alterations in duodenal integrity/inflammation.

Eligibility criteria: Inclusion Criteria:

1. Patients with Functional dyspepsia/ postprandial distress syndrome as per Rome IV diagnostic criteria

   * Symptom characteristics of dyspepsia (upper gastrointestinal symptoms occurring in the last 6 months and meal related (PDS))
   * Negative endoscopy (maximum 12 months old)
2. Patients must provide witnessed written informed consent prior to any study procedures being performed
3. Patients aged between 18 and 70 years inclusive
4. Male or female patients

Exclusion Criteria:

1. Patients with any condition which, in the opinion of the investigator, makes the patient unsuitable for entry into the study
2. Patients with any major psychiatric disorders (including those with a major psychosomatic element to their gastrointestinal disease), depression, alcohol or substance abuse in the last 2 years
3. Patients presenting with predominant symptoms of irritable bowel syndrome (IBS) and of gastro-oesophageal reflux disease (GERD)
4. Patients who changed their diet over the last 3 months or have previously tried the low FODMAP diet are excluded from the study.
5. Females who are pregnant or lactating are excluded from the study.

Primary outcomes:
measure: Effect of a low-FODMAP diet on the LPDS (Leuven-postprandial distress scale)
timeFrame: Measurement before and after the diet (6 weeks)
Secondary outcomes:
measure: Effect of a low-FODMAP diet on urinary histamine and N-methylhistamine excretion
timeFrame: Measurement before and after the diet (6 weeks)
measure: Effect of a low-FODMAP diet on duodenal mucosal integrity
timeFrame: Measurement before and after the diet (6 weeks)
measure: Effect of a low-FODMAP diet on duodenal low-grade inflammation
timeFrame: Measurement before and after the diet (6 weeks)
Other outcomes:
Locations:
city: Leuven
country: Belgium
facility: KU Leuven
state: Vlaams-Brabant
Study officials:
References:
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