Gastric Functions & Proton Pump Inhibitor( PPI) Study
Condition: Functional Dyspepsia
MeSH terms: Dyspepsia
Study type: Interventional
Phase: Phase 4

Summary: 
      Functional dyspepsia is one of the most common digestive disorders. The pathophysiology of
      functional dyspepsia is uncertain. Proton pump inhibitor (PPI) has been recommended as the
      first line treatment for functional dyspepsia. However, the mechanism of symptom relief is
      unclear. Most of the previous studies were performed on healthy volunteers who received only
      a very short course of PPI. The correlation between symptom and gastric emptying is lacking
      in these studies.

      Demographic data and anthropometric measurements will be obtained for baseline assessment.
      Patients are required to complete FGI Screening Questionnaire, Functional dyspepsia symptom
      questionnaire, gastroesophageal reflux disease (GERD) symptom questionnaire and irritable
      bowel syndrome (IBS) symptom questionnaire to have a thorough assessment of their GI
      symptoms. (1) Satiety test and ghrelin profile, and (2)gastric emptying test will be arranged
      as two individual visits.

      After baseline investigations, patients will be randomly assigned to either Nexium 20 mg
      daily or identical looking placebo for 8 weeks. The patients will report their individual
      dyspeptic symptoms on weekly basis using a self-administered symptom questionnaire.

      Satiety test and ghrelin profile, gastric emptying study will be repeated at the end of
      8-week treatment.

      Hypothesis: Long-term PPI relieves dyspeptic symptom through acceleration of gastric emptying
      rate.
    

Detailed description: 
      Background

      Functional dyspepsia is one of the commonest digestive disorders. It is a functional
      gastrointestinal disorder which is characterized by chronic recurrent epigastric symptoms
      such as pain, burning and a variety of postprandial symptoms with absence of demonstrable
      organic pathology identified on investigations. It has been reported that functional
      dyspepsia affects 10-30% of adult population.

      The pathophysiology of functional dyspepsia is uncertain. It is thought to be a heterogeneous
      disorder. Various factors have been implicated in the pathophysiology of functional
      dyspepsia. It has been reported that delayed gastric emptying, impaired proximal gastric
      accommodation, visceral hypersensitivity and Helicobacter pylori gastritis play a role in
      development of functional dyspepsia. However, the correlation between these physiological
      abnormalities and symptomatology of functional dyspepsia is poor. It is still controversial
      whether these pathophysiological factors are responsible for specific symptoms in functional
      dyspepsia.

      While mechanism of functional dyspepsia is unclear, treatment has also been far from
      satisfactory. Proton pump inhibitor has been recommended as the first line treatment for
      functional dyspepsia and it has been shown that the use of PPI is associated with a 14%
      reduction in risk of persistent dyspepsia compared to placebo. However, the mechanism of
      symptom relief is unclear. While PPI exerts its effect primarily through suppression of
      acid-induced symptoms, recent studies have shown that PPI may affect gastric motility
      function such as gastric volume, gastric emptying and trigger of migratory motor complex.
      Most of these studies were performed on healthy volunteers who received only a very short
      course of PPI. The correlation between symptom and gastric emptying is lacking in these
      studies.

      Aims

        -  To evaluate the effect of esomeprazole on gastric emptying

        -  To evaluate the relationship between dyspeptic symptom and gastric emptying

      Hypothesis

      Long-term PPI relieves dyspeptic symptom through acceleration of gastric emptying rate

      Study design

      Double-blind randomized placebo-controlled trial

      Baseline assessment

        -  Demographic: age, gender

        -  Anthropometric measurements: body mass index, height, weight and waist circumference

        -  FGI Screening Questionnaire (v.2, 20090106) for screening of functional gastrointestinal
           disorder according to Rome III criteria.

        -  Functional dyspepsia symptom questionnaire (FDSQ) (20080416): an 8-item dyspeptic
           symptom score questionnaire: 4-point Likert scale for assessment of epigastric pain,
           epigastric burning, belching, bloating, postprandial fullness, early satiation, nausea
           and vomiting and a global dyspeptic symptom assessment.

        -  GERD Symptom questionnaire (GERDSQ) (20080416): GERD symptom score questionnaire.

        -  Irritable Bowel Syndrome Symptom questionnaire (IBSSQ) (20080428): IBS symptom score
           questionnaire.

      Satiety test and ghrelin profile

      After an overnight fast, the patients are instructed to ingest Ensure® (1.06 kcal/ml; 22%
      fat, 64% carbohydrate, and 14% protein) at constant rate of 30ml/min, and complete a Fullness
      Rating Scale (FRS) at 3-min intervals (ie. 0min, 3min, 6min…). The test will stop when a
      score of 4, which is equivalent to unbearable fullness, is reached in FRS. The volume
      (calorie) of Ensure that is ingested will be recorded and it serves as surrogate marker of
      satiety function. Serial blood sample (2ml each) will also be taken at 0, 30, 60, 90, 120min
      during test for assay of ghrelin and gastrin profile. If the test is stopped before 120
      minutes, the remaining blood will still be taken according to schedule.

      Gastric emptying test with FANci2

      Measurement of gastric emptying rate of solid meal will be accomplished using 13C-octanoic
      acid breath test within 7 days after satiety test. After 12-hour fasting, the patient is
      required to ingest a pan-fried egg with 2 pieces of bread that contains 100 ul of
      13C-octanoic acid dissolved in egg yolk. The exhaled gas will be collected at 15-minute
      intervals until 4 hours have passed. The 13CO2 content of the exhaled gas will be measured by
      a breath test device (FANci2, FAN GmbH.,Germany). 13CO2 is released after the 13C-octanoic
      acid enriched meal is emptied into the stomach and digested in duodenum.

      Randomization of treatment

      After baseline investigations, patients will be randomly assigned to either Esomeprazole 20
      mg daily or identical looking placebo for 8 weeks. The random allocation sequence will be
      obtained from a computer-generated list of random numbers in blocks of 10. Concealed
      allocation is achieved by an independent staff who assigns treatments according to
      consecutive numbers in sealed envelopes. Study medications are dispensed as sealed packages
      in consecutive numbers. Medication adherence is measured by pill counts during interval
      visits.

      Follow-up assessment

      The patients will report their individual dyspeptic symptoms on weekly basis using a
      self-administered symptom questionnaire. At week 4 and week 8, they will need to give an
      additional rating on their overall symptom response using global symptom assessment. The
      patients are required to give a dichotomous response of either "yes" or "no" to the question
      stating "Do you have adequate relief of symptoms over the past 7 days?". Satiety test and
      blood sampling, gastric emptying study will be repeated at the end of 8-week treatment.
    

Intervention name(s): Esomeprazole; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Esomeprazole 20mg daily for 8 weeks; Placebo in the form of study drug
Other intervention name(s): Nexium
Intervention MeSH terms: Esomeprazole
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Functional dyspepsia; PPI; postprandial fullness; delayed gastric emptying