Assessment of Gastro-esophageal Reflux Using Endo-Flip vs Bravo
Condition: Heartburn; Gastro-esophageal Reflux
MeSH terms: Gastroesophageal Reflux; Esophagitis, Peptic; Heartburn
Study type: Observational

Summary: 
      Monitoring oesophageal pH provides a definitive diagnosis of patients with gastro-oesophageal
      reflux disease (GORD), especially those in whom the association between reflux and symptoms
      is uncertain and those under consideration for anti-reflux surgery. Standard ambulatory
      investigation is normally performed by naso-oesophageal catheter however this is associated
      with considerable discomfort and in turn altered behaviour which reduces reflux provoking
      activities. Furthermore results of catheter based ambulatory pH studies are compromised by
      the high variability of acid exposure in patients with suspected GORD.

      Prolonging pH measurements by the catheter-free Bravo™ system from 24 to 48 and 96hrs
      significantly improves the consistency (reliability) and reproducibility of diagnoses based
      on oesophageal acid exposure, as well as the ability to associate acid reflux to symptom
      episodes. This improves diagnosis especially in those with intermittent symptoms.

      However pH monitoring does not provide a direct assessment of the underlying pathophysiology.
      Incompetence of the oesophago-gastric junction (OGJ) related to disruption of its structure
      and function is considered to be the most important cause of GORD. A more relevant assessment
      of the reflux barrier may be its distensibility (i.e. the ease with which the OGJ is opened
      to allow retrograde passage of gastric contents); however this is not assessed by current
      clinical investigations.

      Endo-FLIP (Crospon Medical Devices) is a new tool which assesses OGJ structure and function,
      and appears to provide relevant information regarding its distensibility and competence.

      This study applies to using Endo-Flip to record OGJ distensibility and Bravo to record acid
      exposure and symptom association in patients with reflux symptoms. The variability of pH
      measurements and symptoms and diagnostic accuracy will be assessed over 96hrs. Endo-FLIP
      results will then be compared against Bravo. The outcome of post investigation therapy will
      then be compared with Endo-Flip and Bravo results to assess if baseline testing can predict
      the outcome of acid suppression therapy.

      Study Hypothesis

        1. There is a positive, continuous association between OGJ distensibility measured by
           Endo-FLIP on % acid exposure assessed by prolonged Bravo pH monitoring

        2. The results of Endo-FLIP and prolonged Bravo predict treatment outcome of a trial of
           proton pump inhibitor therapy
    

Detailed description: 
      This is a single centre study of patients (n=60) referred for investigation of reflux
      symptoms. Each patient is investigated by Endo-FLIP™, endoscopy, and 96 hour Bravo™ pH
      monitoring off acid suppressant medication.

      After calibration the Endo-FLIP catheter will be inserted orally or nasally until the
      liquid-filled compliant bag at the distal segment of the catheter (which houses 16 impedance
      sensors) straddles the OGJ. Stepwise bag distensions of 10, 20 and 30 ml will then be
      conducted and the associated intra-bag pressure measured. The Endo-FLIP display will allow
      real-time imaging of OGJ intra-luminal geometry during distension. Intra-bag pressure and CSA
      at the impedance planimetry segment best localized within the OGJ will be reported as mean ±
      SEM.

      An endoscopy will then be performed to confirm the position of the squamo-columnar junction
      (SCJ). Images will be taken of the SCJ using standard white light and narrow band imaging.
      Then 2 x 2 biopsies from the SCJ and 2 cm proximally will be taken. In conclusion, the Bravo®
      delivery system will be passed orally with the patient lying in the left lateral decubitus
      position and the capsule will be deployed 6 cm proximal to the SCJ after 1 minute of suction
      to stabilize the position.

      After 2 measurements for 48 hours (separated by a battery change) the patient will return the
      receiver for the final download and analysis. In addition to pH measurement and symptom
      documentation during the 96hr period, pepsin lateral flow tests (Technostics, Hull, UK) will
      be performed by collecting expectorated saliva on returning to the lab on day 2 and day 4.
      Patients will also be provided with two further kits to be used if and when they experience
      symptoms during the 4 day study.

      The primary outcome assessment of oesophageal acid exposure will be percent time pH<4 over
      the measurement period (e.g. 24, 48 or 96h). Other parameters that will be analysed are the
      number of reflux events and the association of these events with symptoms recorded on the
      Bravo™ receiver. The presence or absence of pepsin in expectorated saliva will also be
      assessed.

      All subjects will complete a quality of life assessment (SF-36). Symptom severity will be
      assessed at baseline and at follow-up and will be documented by validated questionnaires
      (Eraflux) before and after resumption of routine acid reducing therapy. Those that undergo
      anti-reflux surgery will also be followed up at 3 and 6 months.

      LOS distensibility measurements using Endo-FLIP will also be collected in those diagnosed
      with achalasia on manometry in order to be used as reference values for the Bravo study.

      Patient symptoms will be reviewed at baseline off treatment and again after six weeks of
      returning back onto their standard acid reducing medication. Patients referred for
      anti-reflux surgery will be reviewed 3 and 6 months after the procedure.

      This is a prospective study of 60 consecutive patients referred for the investigations
      typical reflux symptoms (power calculations to allow comparison of 24hr vs. 48hr pH testing).

      Analysis

      Bravo:

        1. Retrospective analysis: Formal statistical analysis of the pH and symptom database that
           was collected prospectively over the last 4 years (contains >200 Bravo pH studies). This
           will establish the correlation between pH results from 24, 48 and 96hr monitoring with
           clinical variables (e.g. severity of reflux symptoms, symptom association) and outcome
           (e.g. response to PPI, response to fundoplication).

        2. Prospective analysis: The day-to-day variability of pH measurements will be calculated.
           Patients will be classified by acid exposure (abnormal: >4.2% time pH<4) and symptom
           index (positive SI: >50% association of reflux events and any symptom) during each 24hr
           and 48hr test period. The reproducibility and accuracy of 24hr vs. 48hr pH testing will
           be assessed with 96hr results as the reference standard.

      Endo-Flip: Stepwise bag distensions of 10, 20 and 30 ml will be conducted and the associated
      intra-bag pressure measured. The Endo-FLIP display will allow real-time imaging of OGJ
      intraluminal geometry during distension. The primary outcome assessment of OGJ distensibility
      will be the intra-bag pressure and cross-sectional area at the impedance planimetry segment
      best localized within the LOS as mean ± SEM for each consecutive volume distension. The
      correlation of OGJ distensibility with oesophageal acid exposure will then be assessed.

      The correlation and interaction between OGJ distensibility, acid exposure, reflux-symptom
      association and symptom characteristics (e.g. severity and predominant symptom) at baseline
      and on treatment will be assessed by co-variant regression analysis.
    

Observational model: Case-Control
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Patients with typical reflux symptoms (heartburn, acid regurgitation)
      
Biospecimen description: 
      Biopsies taken at the gastro-oesophageal junction will be sent to histology lab and analysed
      as per routine histology specimens. These will be stored as all samples at our hospital are
      stored and only results reported by the appointed histologist will be used for analysis.
    
Keywords: Gastro-oesophageal reflux disease; pH measurement; symptom association; wireless pH monitoring system; Functional Heartburn; Gastro-esophageal reflux disease