<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03788109</url>
  </required_header>
  <id_info>
    <org_study_id>S57615</org_study_id>
    <nct_id>NCT03788109</nct_id>
  </id_info>
  <brief_title>Relationship Between Gastric Accommodation, TLESRs and Reflux in HV and in GERD With or Without Overlapping Dyspepsia</brief_title>
  <official_title>The Relationship Between Gastric Accommodation, Transient Lower Esophageal Sphincter Relaxations and Reflux Events in Healthy Subjects and in Gastro-esophageal Reflux Disease Patients With or Without Overlapping Dyspepsia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Universitaire Ziekenhuizen KU Leuven</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Universitaire Ziekenhuizen KU Leuven</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Our group recently studied the relationship between intra-gastric pressure (IGP) and reflux&#xD;
      events after a meal, both in gastro-esophageal reflux disease (GERD) and in healthy&#xD;
      volunteers (HV). Ingestion of a meal was accompanied by a drop in IGP, probably representing&#xD;
      gastric accommodation (GA). However, the magnitude of this IGP drop varied, and was inversely&#xD;
      correlated with the number of transient lower esophageal sphincter relaxations (TLESRs) and&#xD;
      the number of reflux events, both in patients and in HV: a smaller meal-induced drop in IGP&#xD;
      was associated with a higher rate of reflux events, and vice versa. These findings suggest&#xD;
      that impaired GA is a trigger for reflux. Furthermore, impaired GA is a well-established&#xD;
      mechanism underlying symptom generation in functional dyspepsia (FD). Hence, the&#xD;
      investigators hypothesize that impaired GA is an important pathophysiological feature&#xD;
      explaining the overlap between GERD and FD. To evaluate this hypothesis, the investigators&#xD;
      will study the relationship between GA, TLESRs and reflux events in HV and in a group of GERD&#xD;
      patients which will be categorized as pure GERD or GERD/FD overlap.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      1. INTRODUCTION Gastro-esophageal reflux (GER), the retrograde flow of gastric contents in&#xD;
           the esophagus, is a physiologic phenomenon. However, when GER causes symptoms&#xD;
           (heartburn/regurgitation) or lesions (esophagitis/Barrett's esophagus), it is referred&#xD;
           to as gastro-esophageal reflux disease (GERD). GERD is a highly prevalent condition,&#xD;
           occurring in up to 20% of the Western population. Gastric acid has been considered the&#xD;
           main pathological factor in GERD and the development of proton pump inhibitors (PPIs),&#xD;
           reducing gastric acid secretion, was a major break-through in GERD treatment. However, a&#xD;
           large number of GERD patients remain symptomatic in spite of PPI therapy. Combined&#xD;
           pH-impedance recordings identified ongoing weakly acidic reflux as the major factor&#xD;
           underlying these refractory GERD symptoms. One therapeutic option to eliminate also&#xD;
           weakly-acidic reflux is anti-reflux surgery, but this is not devoid of side-effects and&#xD;
           has a higher risk of unfavorable outcome in refractory GERD. Hence, intense research was&#xD;
           devoted to drugs inhibiting all types of reflux by controlling transient lower&#xD;
           esophageal sphincter relaxations (TLESRs), the main mechanism underlying reflux. TLESRs&#xD;
           are relaxations of the lower esophageal sphincter (LES) that are not triggered by&#xD;
           swallowing and allow reflux of ingested air and gas during belching. They occur mainly&#xD;
           postprandially and are triggered by gastric distension, which activates mechanoreceptors&#xD;
           in the proximal stomach and a vago-vagal pathway resulting in release of nitric oxide at&#xD;
           the LES. Although TLESR frequency is similar in GERD and healthy volunteers (HV), the&#xD;
           selectivity of TLESRs to gas reflux is lost in patients and liquid reflux is more likely&#xD;
           to occur.&#xD;
&#xD;
           Pharmacological approaches to inhibit TLESRs, more specifically gamma-aminobutyric&#xD;
           acid-B (GABA-B) receptor agonism and metabotropic glutamate receptor type 5 (mGLUR5)&#xD;
           antagonism, were evaluated in larger-scale clinical trials. Short-term&#xD;
           proof-of-principle studies showed the ability of these agents to increase postprandial&#xD;
           LES pressure, inhibit TLESRs and decrease the number of reflux events. Clinical trials&#xD;
           mainly evaluated the use of these drugs as add-on therapy in refractory GERD, but all&#xD;
           trials failed to show substantial improvement in control of persisting reflux symptoms,&#xD;
           with both agents over placebo. Two main problems were identified: 1) these drugs&#xD;
           inhibited neurotransmission in the vago-vagal reflex pathways controlling TLESRs.&#xD;
           However, it seems that parallel pathways using multiple neurotransmitters exists, as&#xD;
           inhibition of TLESRs and reflux events with both agents was in the range of 30-50%; 2)&#xD;
           it was suggested that these trials failed to distinguish between ongoing GERD symptoms&#xD;
           and functional dyspepsia (FD) symptoms, and that only the former were likely to respond&#xD;
           to reflux inhibition.&#xD;
&#xD;
           FD is one of the most common gastrointestinal (GI) disorders and is defined by the Rome&#xD;
           III criteria as the presence of chronic dyspeptic symptoms in the absence of underlying&#xD;
           structural or metabolic disease that readily explains the symptoms. Based on these&#xD;
           symptoms, the Rome III consensus proposed the subdivision of functional dyspepsia into&#xD;
           postprandial distress syndrome (PDS), characterized by postprandial fullness and early&#xD;
           satiation, and epigastric pain syndrome (EPS), characterized by epigastric pain or&#xD;
           burning. Several studies have established a major overlap between GERD and FD, and&#xD;
           against this background overlap of both symptom complexes is not surprising.&#xD;
&#xD;
        2. RATIONALE AND OBJECTIVES Our group recently studied the relationship between&#xD;
           intra-gastric pressure (IGP) and reflux events after a meal, both in GERD and in HV.&#xD;
           Ingestion of a meal was accompanied by a drop in IGP, probably representing gastric&#xD;
           accommodation (GA). However, the magnitude of this IGP drop varied, and was inversely&#xD;
           correlated with the number of TLESRs and the number of reflux events, both in patients&#xD;
           and in HV: a smaller meal-induced drop in IGP was associated with a higher rate of&#xD;
           reflux events, and vice versa. These findings suggest that impaired GA is a trigger for&#xD;
           reflux. Furthermore, impaired GA is a well-established mechanism underlying symptom&#xD;
           generation in FD. Hence, the investigators hypothesize that impaired GA is an important&#xD;
           pathophysiological feature explaining the overlap between GERD and FD. To evaluate this&#xD;
           hypothesis, the investigators will study the relationship between GA, TLESRs and reflux&#xD;
           events in HV and in a group of GERD patients which will be categorized as pure GERD or&#xD;
           GERD/FD overlap.&#xD;
&#xD;
        3. GENERAL DESCRIPTION OF THE STUDY In 20 HV, a combined solid state high resolution&#xD;
           esophageal impedance and manometry (HRiM) catheter will be placed into the stomach. The&#xD;
           investigators will record 30 min before and 60 min after administration of a high&#xD;
           carbohydrate and high fat meal (1000 kcal). Esophageal body contractility, LES pressure,&#xD;
           TLESRs and reflux events will be identified and classified using established criteria.&#xD;
           The number of TLESRs and the number of reflux events will be counted. In sensors 5 cm&#xD;
           below the lower border of LES, the magnitude of the meal-induced drop in IGP (deltaIGP)&#xD;
           will be measured. Upper gastrointestinal symptoms will be recorded throughout the&#xD;
           studies. These measures will provide normal range reference data for further&#xD;
           pathophysiological and mechanistic studies in GERD and FD.&#xD;
&#xD;
           The same protocol will also be used to study 50 GERD patients who will be categorized as&#xD;
           pure GERD or GERD/FD overlap (26). GA, quantified as deltaIGP, and the prevalence of&#xD;
           impaired GA will be determined in both groups. The correlation between diagnostic&#xD;
           category and size of GA will be evaluated, and the investigators will analyze the&#xD;
           presence of a hiatal hernia (HH), esophageal peristalsis, fasting and postprandial LES&#xD;
           pressure, occurrence of TLESRs, occurrence and characterization of reflux events and&#xD;
           their possible correlation with GA. Based on previous studies in GERD, FD and health,&#xD;
           the numbers should be sufficient to detect differences in IGP with a power of 80% at a&#xD;
           significance level of 0.05.&#xD;
&#xD;
        4. MATERIALS AND METHODS&#xD;
&#xD;
      STUDY SUBJECTS This study will be performed in 20 HV, and in 25 GERD and 25 GERD/FD overlap&#xD;
      patients. All subjects are aged between 18 and 65 years, and will receive and sign a copy of&#xD;
      the informed consent, before initiation of the study. Discontinuation of all acid suppressive&#xD;
      therapy for at least 7 days is mandatory in all patients.&#xD;
&#xD;
      --&gt; HEALTHY VOLUNTEERS&#xD;
&#xD;
      Exclusion criteria:&#xD;
&#xD;
        -  history of any upper gastrointestinal (GI) symptoms or GI surgery;&#xD;
&#xD;
        -  psychological disorders;&#xD;
&#xD;
        -  any drug history;&#xD;
&#xD;
        -  use of medication altering GI motility;&#xD;
&#xD;
        -  pregnant or nursing women.&#xD;
&#xD;
             -  GERD PATIENTS&#xD;
&#xD;
      Inclusion criteria:&#xD;
&#xD;
        -  typical symptoms of reflux, such as heartburn and/or regurgitation;&#xD;
&#xD;
        -  gastro-esophageal reflux assessed by 24-h pH-impedance monitoring or a positive symptom&#xD;
           association or;&#xD;
&#xD;
        -  esophagitis assessed by upper GI endoscopy with careful evaluation of the presence and&#xD;
           extent of a hiatal hernia (HH).&#xD;
&#xD;
      Exclusion criteria:&#xD;
&#xD;
        -  psychological disorders;&#xD;
&#xD;
        -  any drug history;&#xD;
&#xD;
        -  use of medication affecting GI motility;&#xD;
&#xD;
        -  pregnant or nursing women;&#xD;
&#xD;
        -  history of GI surgery.&#xD;
&#xD;
           --&gt;DETECTION OF FD OVERLAP IN THE GERD POPULATION&#xD;
&#xD;
        -  FD symptoms according to the Rome III criteria. The symptoms of FD include one or more&#xD;
           of: bothersome postprandial fullness occurring after normal sized meals, early satiation&#xD;
           that prevents finishing a regular meal, epigastric pain, and epigastric burning at least&#xD;
           several times per week during the last 6 months.&#xD;
&#xD;
        -  The investigators will stratify to have equal numbers of overlap and non-overlap&#xD;
           patients.&#xD;
&#xD;
      STUDY PROTOCOL Patients and volunteers will be fasted for at least 12 h before the manometry&#xD;
      study. Furthermore, they will be asked to refrain from alcohol, tea and coffee at least 12 h&#xD;
      before participation, and to refrain from smoking cigarettes at least 1 h before the start of&#xD;
      the experiment.&#xD;
&#xD;
      The HRiM catheter (Medical Measurement Systems, Enschede, The Netherlands) incorporating 36&#xD;
      pressure sensors, spaced at 2 cm in the stomach and esophagus and at 1 cm in the LES and&#xD;
      upper esophageal sphincter (UES), and 16 impedance channels throughout the esophagus, will be&#xD;
      placed transnasally, after topical anesthesia. Manometry will be used to record pressures in&#xD;
      the stomach, the esophagus, the LES and the UES. In this way, it is possible to detect and&#xD;
      characterize TLESRs, and to measure GA. The impedance channels will be used to measure bolus&#xD;
      movement, and thus to detect and characterize gastro-esophageal reflux.&#xD;
&#xD;
      Patients and volunteers will be studied in a semi-recumbent fashion for a 5-10 min&#xD;
      stabilization period after the placement of the catheter. Thereafter, subjects will be given&#xD;
      10 wet swallows of 5 ml saline to study esophageal peristalsis. Recordings will be made for&#xD;
      30 minutes after which all subjects will receive a high carbohydrate and high fat meal of&#xD;
      1000 kcal (mashed potatoes, meatloaf, and apple sauce). After meal ingestion, subjects will&#xD;
      be monitored for 5 h, after which the catheter will be removed.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 12, 2018</start_date>
  <completion_date type="Actual">June 15, 2018</completion_date>
  <primary_completion_date type="Actual">June 15, 2018</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in number transient lower esophageal sphincter relaxations</measure>
    <time_frame>6-hour study period</time_frame>
    <description>Change in number TLESRs between preprandial and postprandial period</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in number of reflux episodes</measure>
    <time_frame>6 hour study period</time_frame>
    <description>Change in number of reflux episodes between preprandial and postprandial period</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in intragastric pressure</measure>
    <time_frame>6 hour study period</time_frame>
    <description>Change in intragastric pressure between preprandial and postprandial period</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Gastro-esophageal Reflux Disease</condition>
  <condition>Functional Dyspepsia</condition>
  <condition>Health</condition>
  <arm_group>
    <arm_group_label>device: combined solid state HRiM</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>combined solid state high resolution esophageal impedance and manometry (HRiM)</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>device: combined solid state HRiM</intervention_name>
    <description>The HRiM catheter (Medical Measurement Systems, Enschede, The Netherlands) incorporating 36 pressure sensors, spaced at 2 cm in the stomach and esophagus and at 1 cm in the LES and upper esophageal sphincter (UES), and 16 impedance channels throughout the esophagus, will be placed transnasally, after topical anesthesia. Manometry will be used to record pressures in the stomach, the esophagus, the LES and the UES. In this way, it is possible to detect and characterize TLESRs, and to measure GA. The impedance channels will be used to measure bolus movement, and thus to detect and characterize gastro-esophageal reflux.</description>
    <arm_group_label>device: combined solid state HRiM</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  GERD patients:&#xD;
&#xD;
               -  typical symptoms of reflux, such as heartburn and/or regurgitation;&#xD;
&#xD;
               -  gastro-esophageal reflux assessed by 24-h pH-impedance monitoring or a positive&#xD;
                  symptom association or;&#xD;
&#xD;
               -  esophagitis assessed by upper GI endoscopy with careful evaluation of the&#xD;
                  presence and extent of a hiatal hernia (HH).&#xD;
&#xD;
          -  GERD/FD overlap:&#xD;
&#xD;
               -  FD symptoms according to the Rome III criteria. The symptoms of FD include one or&#xD;
                  more of: bothersome postprandial fullness occurring after normal sized meals,&#xD;
                  early satiation that prevents finishing a regular meal, epigastric pain, and&#xD;
                  epigastric burning at least several times per week during the last 6 months.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Healthy volunteers:&#xD;
&#xD;
               -  history of any upper gastrointestinal (GI) symptoms or GI surgery;&#xD;
&#xD;
               -  psychological disorders;&#xD;
&#xD;
               -  any drug history;&#xD;
&#xD;
               -  use of medication altering GI motility;&#xD;
&#xD;
               -  pregnant or nursing women.&#xD;
&#xD;
          -  GERD patients:&#xD;
&#xD;
               -  psychological disorders;&#xD;
&#xD;
               -  any drug history;&#xD;
&#xD;
               -  use of medication affecting GI motility;&#xD;
&#xD;
               -  pregnant or nursing women;&#xD;
&#xD;
               -  history of GI surgery.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jan Tack, Prof. Dr.</last_name>
    <role>Principal Investigator</role>
    <affiliation>KULEUVEN, UZLEUVEN</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven Campus Gasthuisberg O&amp;N1</name>
      <address>
        <city>Leuven</city>
        <state>Vlaams-Brabant</state>
        <zip>3000</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Belgium</country>
  </location_countries>
  <verification_date>December 2019</verification_date>
  <study_first_submitted>July 25, 2016</study_first_submitted>
  <study_first_submitted_qc>December 21, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 27, 2018</study_first_posted>
  <last_update_submitted>December 4, 2019</last_update_submitted>
  <last_update_submitted_qc>December 4, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">December 6, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Universitaire Ziekenhuizen KU Leuven</investigator_affiliation>
    <investigator_full_name>Prof Dr Jan Tack</investigator_full_name>
    <investigator_title>Prof. Dr.</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Gastroesophageal Reflux</mesh_term>
    <mesh_term>Esophagitis, Peptic</mesh_term>
    <mesh_term>Dyspepsia</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03788109
org study id: S57615
nct id: NCT03788109
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Our group recently studied the relationship between intra-gastric pressure (IGP) and reflux
      events after a meal, both in gastro-esophageal reflux disease (GERD) and in healthy
      volunteers (HV). Ingestion of a meal was accompanied by a drop in IGP, probably representing
      gastric accommodation (GA). However, the magnitude of this IGP drop varied, and was inversely
      correlated with the number of transient lower esophageal sphincter relaxations (TLESRs) and
      the number of reflux events, both in patients and in HV: a smaller meal-induced drop in IGP
      was associated with a higher rate of reflux events, and vice versa. These findings suggest
      that impaired GA is a trigger for reflux. Furthermore, impaired GA is a well-established
      mechanism underlying symptom generation in functional dyspepsia (FD). Hence, the
      investigators hypothesize that impaired GA is an important pathophysiological feature
      explaining the overlap between GERD and FD. To evaluate this hypothesis, the investigators
      will study the relationship between GA, TLESRs and reflux events in HV and in a group of GERD
      patients which will be categorized as pure GERD or GERD/FD overlap.
1. INTRODUCTION Gastro-esophageal reflux (GER), the retrograde flow of gastric contents in
           the esophagus, is a physiologic phenomenon. However, when GER causes symptoms
           (heartburn/regurgitation) or lesions (esophagitis/Barrett's esophagus), it is referred
           to as gastro-esophageal reflux disease (GERD). GERD is a highly prevalent condition,
           occurring in up to 20% of the Western population. Gastric acid has been considered the
           main pathological factor in GERD and the development of proton pump inhibitors (PPIs),
           reducing gastric acid secretion, was a major break-through in GERD treatment. However, a
           large number of GERD patients remain symptomatic in spite of PPI therapy. Combined
           pH-impedance recordings identified ongoing weakly acidic reflux as the major factor
           underlying these refractory GERD symptoms. One therapeutic option to eliminate also
           weakly-acidic reflux is anti-reflux surgery, but this is not devoid of side-effects and
           has a higher risk of unfavorable outcome in refractory GERD. Hence, intense research was
           devoted to drugs inhibiting all types of reflux by controlling transient lower
           esophageal sphincter relaxations (TLESRs), the main mechanism underlying reflux. TLESRs
           are relaxations of the lower esophageal sphincter (LES) that are not triggered by
           swallowing and allow reflux of ingested air and gas during belching. They occur mainly
           postprandially and are triggered by gastric distension, which activates mechanoreceptors
           in the proximal stomach and a vago-vagal pathway resulting in release of nitric oxide at
           the LES. Although TLESR frequency is similar in GERD and healthy volunteers (HV), the
           selectivity of TLESRs to gas reflux is lost in patients and liquid reflux is more likely
           to occur.

           Pharmacological approaches to inhibit TLESRs, more specifically gamma-aminobutyric
           acid-B (GABA-B) receptor agonism and metabotropic glutamate receptor type 5 (mGLUR5)
           antagonism, were evaluated in larger-scale clinical trials. Short-term
           proof-of-principle studies showed the ability of these agents to increase postprandial
           LES pressure, inhibit TLESRs and decrease the number of reflux events. Clinical trials
           mainly evaluated the use of these drugs as add-on therapy in refractory GERD, but all
           trials failed to show substantial improvement in control of persisting reflux symptoms,
           with both agents over placebo. Two main problems were identified: 1) these drugs
           inhibited neurotransmission in the vago-vagal reflex pathways controlling TLESRs.
           However, it seems that parallel pathways using multiple neurotransmitters exists, as
           inhibition of TLESRs and reflux events with both agents was in the range of 30-50%; 2)
           it was suggested that these trials failed to distinguish between ongoing GERD symptoms
           and functional dyspepsia (FD) symptoms, and that only the former were likely to respond
           to reflux inhibition.

           FD is one of the most common gastrointestinal (GI) disorders and is defined by the Rome
           III criteria as the presence of chronic dyspeptic symptoms in the absence of underlying
           structural or metabolic disease that readily explains the symptoms. Based on these
           symptoms, the Rome III consensus proposed the subdivision of functional dyspepsia into
           postprandial distress syndrome (PDS), characterized by postprandial fullness and early
           satiation, and epigastric pain syndrome (EPS), characterized by epigastric pain or
           burning. Several studies have established a major overlap between GERD and FD, and
           against this background overlap of both symptom complexes is not surprising.

        2. RATIONALE AND OBJECTIVES Our group recently studied the relationship between
           intra-gastric pressure (IGP) and reflux events after a meal, both in GERD and in HV.
           Ingestion of a meal was accompanied by a drop in IGP, probably representing gastric
           accommodation (GA). However, the magnitude of this IGP drop varied, and was inversely
           correlated with the number of TLESRs and the number of reflux events, both in patients
           and in HV: a smaller meal-induced drop in IGP was associated with a higher rate of
           reflux events, and vice versa. These findings suggest that impaired GA is a trigger for
           reflux. Furthermore, impaired GA is a well-established mechanism underlying symptom
           generation in FD. Hence, the investigators hypothesize that impaired GA is an important
           pathophysiological feature explaining the overlap between GERD and FD. To evaluate this
           hypothesis, the investigators will study the relationship between GA, TLESRs and reflux
           events in HV and in a group of GERD patients which will be categorized as pure GERD or
           GERD/FD overlap.

        3. GENERAL DESCRIPTION OF THE STUDY In 20 HV, a combined solid state high resolution
           esophageal impedance and manometry (HRiM) catheter will be placed into the stomach. The
           investigators will record 30 min before and 60 min after administration of a high
           carbohydrate and high fat meal (1000 kcal). Esophageal body contractility, LES pressure,
           TLESRs and reflux events will be identified and classified using established criteria.
           The number of TLESRs and the number of reflux events will be counted. In sensors 5 cm
           below the lower border of LES, the magnitude of the meal-induced drop in IGP (deltaIGP)
           will be measured. Upper gastrointestinal symptoms will be recorded throughout the
           studies. These measures will provide normal range reference data for further
           pathophysiological and mechanistic studies in GERD and FD.

           The same protocol will also be used to study 50 GERD patients who will be categorized as
           pure GERD or GERD/FD overlap (26). GA, quantified as deltaIGP, and the prevalence of
           impaired GA will be determined in both groups. The correlation between diagnostic
           category and size of GA will be evaluated, and the investigators will analyze the
           presence of a hiatal hernia (HH), esophageal peristalsis, fasting and postprandial LES
           pressure, occurrence of TLESRs, occurrence and characterization of reflux events and
           their possible correlation with GA. Based on previous studies in GERD, FD and health,
           the numbers should be sufficient to detect differences in IGP with a power of 80% at a
           significance level of 0.05.

        4. MATERIALS AND METHODS

      STUDY SUBJECTS This study will be performed in 20 HV, and in 25 GERD and 25 GERD/FD overlap
      patients. All subjects are aged between 18 and 65 years, and will receive and sign a copy of
      the informed consent, before initiation of the study. Discontinuation of all acid suppressive
      therapy for at least 7 days is mandatory in all patients.

      --> HEALTHY VOLUNTEERS

      Exclusion criteria:

        -  history of any upper gastrointestinal (GI) symptoms or GI surgery;

        -  psychological disorders;

        -  any drug history;

        -  use of medication altering GI motility;

        -  pregnant or nursing women.

             -  GERD PATIENTS

      Inclusion criteria:

        -  typical symptoms of reflux, such as heartburn and/or regurgitation;

        -  gastro-esophageal reflux assessed by 24-h pH-impedance monitoring or a positive symptom
           association or;

        -  esophagitis assessed by upper GI endoscopy with careful evaluation of the presence and
           extent of a hiatal hernia (HH).

      Exclusion criteria:

        -  psychological disorders;

        -  any drug history;

        -  use of medication affecting GI motility;

        -  pregnant or nursing women;

        -  history of GI surgery.

           -->DETECTION OF FD OVERLAP IN THE GERD POPULATION

        -  FD symptoms according to the Rome III criteria. The symptoms of FD include one or more
           of: bothersome postprandial fullness occurring after normal sized meals, early satiation
           that prevents finishing a regular meal, epigastric pain, and epigastric burning at least
           several times per week during the last 6 months.

        -  The investigators will stratify to have equal numbers of overlap and non-overlap
           patients.

      STUDY PROTOCOL Patients and volunteers will be fasted for at least 12 h before the manometry
      study. Furthermore, they will be asked to refrain from alcohol, tea and coffee at least 12 h
      before participation, and to refrain from smoking cigarettes at least 1 h before the start of
      the experiment.

      The HRiM catheter (Medical Measurement Systems, Enschede, The Netherlands) incorporating 36
      pressure sensors, spaced at 2 cm in the stomach and esophagus and at 1 cm in the LES and
      upper esophageal sphincter (UES), and 16 impedance channels throughout the esophagus, will be
      placed transnasally, after topical anesthesia. Manometry will be used to record pressures in
      the stomach, the esophagus, the LES and the UES. In this way, it is possible to detect and
      characterize TLESRs, and to measure GA. The impedance channels will be used to measure bolus
      movement, and thus to detect and characterize gastro-esophageal reflux.

      Patients and volunteers will be studied in a semi-recumbent fashion for a 5-10 min
      stabilization period after the placement of the catheter. Thereafter, subjects will be given
      10 wet swallows of 5 ml saline to study esophageal peristalsis. Recordings will be made for
      30 minutes after which all subjects will receive a high carbohydrate and high fat meal of
      1000 kcal (mashed potatoes, meatloaf, and apple sauce). After meal ingestion, subjects will
      be monitored for 5 h, after which the catheter will be removed.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Change in number transient lower esophageal sphincter relaxations
time frame: 6-hour study period
description: Change in number TLESRs between preprandial and postprandial period
measure: Change in number of reflux episodes
time frame: 6 hour study period
description: Change in number of reflux episodes between preprandial and postprandial period
measure: Change in intragastric pressure
time frame: 6 hour study period
description: Change in intragastric pressure between preprandial and postprandial period
arm group label: device: combined solid state HRiM
arm group type: Other
description: combined solid state high resolution esophageal impedance and manometry (HRiM)
intervention type: Procedure
intervention name: device: combined solid state HRiM
description: The HRiM catheter (Medical Measurement Systems, Enschede, The Netherlands) incorporating 36 pressure sensors, spaced at 2 cm in the stomach and esophagus and at 1 cm in the LES and upper esophageal sphincter (UES), and 16 impedance channels throughout the esophagus, will be placed transnasally, after topical anesthesia. Manometry will be used to record pressures in the stomach, the esophagus, the LES and the UES. In this way, it is possible to detect and characterize TLESRs, and to measure GA. The impedance channels will be used to measure bolus movement, and thus to detect and characterize gastro-esophageal reflux.
arm group label: device: combined solid state HRiM
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Jan Tack, Prof. Dr.
role: Principal Investigator
affiliation: KULEUVEN, UZLEUVEN
facility: 
country: Belgium
responsible party type: Principal Investigator
investigator affiliation: Universitaire Ziekenhuizen KU Leuven
investigator full name: Prof Dr Jan Tack
investigator title: Prof. Dr.
mesh term: Gastroesophageal Reflux
mesh term: Esophagitis, Peptic
mesh term: Dyspepsia
sharing ipd: No