Confocal Endomicroscopy for Non-Erosive Reflux Disease (CE NERD)

Study entry criteria:

The investigators plan to collaborate with three centers to ensure the data derived from
this study is generalizable to academic centers as a whole and also to expedite patient
recruitment. The centers that will participate are Virginia Commonwealth University, Ochsner
Health System and the Medical University of South Carolina.

Patients over the age of 18 presenting to clinic with symptoms typical for reflux disease
will be screened to determine if they wish to participate in the study. The site principal
investigator will directly contact potential patients to see if they wish to participate. If
they elect to participate they will be provided a copy of the informed consent 24 hours
before their first contact with study personnel to allow time to review and determine if the
wish to participate. All participants will sign a written informed consent.

Patients who wish to enter into the study and have signed an informed consent will complete
a reflux disease questionnaire (RDQ). This questionnaire consists of 12 items assessing
various aspects of reflux disease. A score of more than 12 will be required for study entry.
Individual with a score less than 12 will not participate further in the study.

Standard of care for patients with gastroesophageal reflux disease (GERD) not responsive to
proton pump inhibitors (PPI) is confirmatory testing with esophagogastroduodenoscopy (EGD)
to evaluate for erosive esophagitis (EE) and testing for acid exposure to the lower
esophagus with pH testing. For the purpose of this study the investigators will perform pH
testing off acid suppressing medication. This is a standard test for determining if the
patient has acid exposure to the esophagus. Typically patients are placed on twice daily
(BID) PPI or sucralfate if testing reveals significant acid exposure.

Erosive esophagitis will be differentiated from NERD by endoscopic findings aided by FICE
(or NBI/iScan) and magnification techniques that the investigators standardly employ in
clinical practice. Patients that are found to have EE will not participate further in the
study and will be treated appropriately for their illness with increased acid suppression.
Patients without EE at the time of endoscopy will be enrolled for study as presumed cases of
NERD refractory to PPI treatment.

After endoscopic confirmation of NERD, the probe based confocal endomicroscopy catheter will
be inserted (CellVisio). The probe will be placed 5cm above the gastroesophageal junction
(GEJ) defined as the top of gastric folds. Subsequently, 2.5cc of 10% fluorescein will be
injected. The investigators will initiate a video recording of the microscopic images that
is to start with the injection of the fluorescein and continue this video for 3 minutes.
This video will be reviewed at a later time by 2 blinded endoscopists trained in confocal
endomicroscopy interpretation. The goal is to see if the time to seeing fluorescein in the
intracellular spaces correlates to response to therapy. The investigators will record time
to first visualization of intrapapillary loops intracellular gaps, the time between
visualization of intrapapillary loops and visualization of intracellular gaps in the
entirety of the space between the loops. The investigators will also measurement of the
general overall appearance. Having the recording of the microscopic images will allow a
centralized reading time to each event and more accurate timing as the video can be stopped
and reviewed in slow motion.

The investigators then will perform endomicroscopic assessment in four quadrants at 2cm, 5cm
and 10cm above the gastroesophageal junction (GEJ). This will represent a single image
acquisition video at each measurement with 4 separate views included. Computer analysis of
the microscopic images will determine the average cell to cell junction distance, number of
intrapapillary capillary loops, size of those intrapapillary capillary loops and overall
saturation with fluorescein. Biopsies of the esophagus corresponding to the endomicroscopy
sites will be collected for microscopic analysis.

Following endoscopy all patients will receive a 48h Bravo capsule or 24h impedance pH probe
to quantitate acid and non-acid reflux events (if 24h probe used) . Standard calibration and
insertion techniques provided by the manufacturer will be used. Standard symptom event
recording for heartburn, regurgitation and non-cardiac chest pain will be used for the
duration of the pH and impedance monitoring. A blinded investigator will interpret impedance
and pH recording. The primary outcome will be the average Demeester Score.

For histopathology the specimen will be fixed in 10% formalin, embedded in paraffin and
sectioned per standard clinical protocols. An expert pathologist will review pathology
specimen for histological changes, specifically elongation of papillae, proliferation of
basal cells, eosinophilic infiltration and dilated intercellular spaces.

Following their endoscopic evaluation, all patients will be randomized in a 1:1 ratio to
receive either twice daily proton pump inhibitor (PPI) therapy for 8 weeks or sucralfate
slurry 1g four times a day for 8 weeks. The patients will not be blinded to the treatment
they receive. The patients will be contacted by phone to assess the symptoms, medication
compliance and tolerance and to complete a RDQ and SF-36 at week 4. They will be seen in
clinic 8 weeks as a follow-up visit and study wrap up. The 8 week visit is standard of care
as that is how long the investigators typically follow patients with reflux symptoms. The
investigators will also assess disease activity with a RDQ and SF-36 at this visit as well.
Patients without adequate response to the medication will be offered cross over to the
alternative medication with a 4 week phone assessment and 8 week clinic visit as described
above. The investigators plan to enroll 40 patients at each site (total of 120 patients) and
plan an interim analysis after the first 30 patients complete the protocol.

Inclusion Criteria:

1. Individuals with reflux disease between the ages of 18 and 79 who have failed a trial
of daily PPI.

Exclusion Criteria:

1. Barrett's esophagus

2. Use of high dose proton pump inhibitor within 4 weeks of study entry

3. Esophageal varices

4. Coagulopathy

5. GI cancer or mass

6. Previous surgery involving the esophagus, stomach or duodenum

7. Pregnancy

8. Allergy to either sucralfate or proton pump inhibitors