Nitrous Oxide For Endoscopic Ablation of Refractory Barrett's Esophagus (NO FEAR-BE)

Eligibility will be determined based on historical local pathology and medical record
information. Informed consent will be obtained and eligible subjects will be treated with the
Cryoballoon Focal Ablation System (CbFAS) at baseline.

Subjects will return every 3 months +/- 6 weeks for repeat treatment for up to 12 months OR
until complete eradication of intestinal metaplasia (CEIM) and complete eradication of
dysplasia (CED) are achieved (at which point subjects enter the follow-up phase), whichever
occurs first.

Treatment procedures will be performed on an outpatient basis according to the site's
standards of care for anesthesia and sedation during esophagogastroduodenoscopy (EGD)
procedures. EGD examinations will be performed using high definition White Light Endoscopy
(WLE), plus Narrow Band Imaging (NBI) or i-SCAN to assess BE Prague Score and identify tissue
landmarks and ablation zones.

A high definition endoscope will be used for all ablations performed with the CryoBalloon
Focal Ablation System (CbFAS). The System will be used according to the instructions for use
provided with the product and in accordance with the current standard of care for treatment
of BE.

Repeat cryoablation may be performed if esophageal columnar mucosa is visible on EGD or if
intervening biopsies (if a site chooses to obtain intervening biopsies as standard of care)
are positive for any esophageal columnar epithelium until complete eradication of all
unwanted tissue is achieved.

Intervening endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD)
after enrollment may be performed for nodular areas detected after baseline. EMR/ESD may be
performed at the same session as the cryoablation if the EMR/ESD site is >=3cm away from the
ablation target site. Cryoablation should be performed before EMR/ESD. If the EMR/ESD site is
within 3cm of target treatment area, then CbFAS will be delayed for at least 6 weeks.

Residual islands of columnar mucosa of <5 mm in diameter each and <= 3 total can be treated
with Argon Plasma Coagulation (APC) and/or CbFAS at the discretion of the treating physician
to avoid over treatment of neo-squamous mucosa.

Stenosis requiring treatment based on the physician's discretion, which develops after
enrollment, will be treated with standard of care balloon- or wire-guided dilation.
Cryoablation may be performed at the same session if the dilated site is >= 3 cm from the
target cryoablation site. Otherwise, cryoablation will be postponed to another visit within 1
month +/- 2 weeks.

When CbFAS treatment is received, subjects will be asked to complete assessments immediately
after CbFAS treatment, and will be contacted 1 day, 7 days, and 30 days after the procedure.

If no visible BE is present during the endoscopy, then biopsies will be taken following the
standard Seattle biopsy protocol (4 quadrant biopsies at 1cm intervals starting at the
gastric cardia 1cm distal to the gastroesophageal junction (GEJ) (top of the gastric folds)
and continuing proximally throughout the length of the original extent of BE, including any
neosquamous or re-epithelialized tissue).

Biopsies will be read by local expert pathologist. If biopsies indicate CEIM and CED, then
subjects will enter the 12 month follow-up phase. If biopsies do not indicate CEIM and CED,
then subjects will return for additional CbFAS treatment in 3 months +/-6 weeks.

Non-responders are defined as subjects who have not achieved CEIM and CED at 12 months post
baseline CbFAS treatment. Non-responders at 12 months will exit the study and continue
treatment at the physician's discretion and according to standard of care at each site.

Subjects who achieve CEIM and CED within 12 months of the baseline CbFAS procedure will enter
a 12 month follow-up phase. Subjects will be followed per routine care guidelines for their
condition, described below:

Subjects with baseline LGD will return at 6 and 12 months from the initial CEIM and CED date
for follow-up (+/-2 weeks). Subjects with baseline HGD or IMC will return at 3, 6, 9, and 12
months from initial CEIM and CED date for follow-up (+/- 2 weeks).

During follow-up procedures, high definition WLE, plus NBI or i-SCAN will be used to assess
Prague score, and biopsies will be taken following the standard Seattle biopsy protocol (4
quadrant biopsies at 1cm intervals starting at the gastric cardia 1cm distal to the
gastroesophageal junction (GEJ) (top of the gastric folds) and continuing proximally
throughout the length of the original extent of BE, including any neosquamous or
re-epithelialized tissue). Biopsies will be read by local expert pathologist.

If recurrent BE is detected during follow-up endoscopy with biopsy demonstrating compatible
histology, then subjects will be exited from the study and treated at the physician's
discretion.

Study participation is complete if: 1) Subject has not reached CEIM and CED at 12 month post
baseline treatment; or 2) If BE or dysplasia recur after initial CEIM and CED post
enrollment; or 3) After completion of the 12 month follow-up EGD with biopsies.

Inclusion Criteria:

1. History of BE with LGD or HGD confirmed with biopsy, or resected intramucosal cancer
(IMC) with low risk of recurrence defined as EMR/ESD pathology results negative for:
positive margin, >T1a stage, poorly differentiated carcinoma, and lymphovascular
invasion.

2. Prior treatment with RFA who meet either of the following criteria at the enrolling
EGD:

2.1. History of at least 3 RFA treatments, with one of the following:

- 2.1.1. Residual BE Prague C1 - C3 and/or

- 2.1.2. Residual BE >=M1 - M8 and/or

- 2.1.3. One or more islands of residual BE >1 cm in diameter

- 2.1.4. Any residual dysplasia in tubular esophagus 2.2. History of at least 2 RFA
treatments and < 50% eradication of BE, as judged by estimation of the treating
physician.

3. 18 or older years of age at time of consent.

4. Provides written informed consent.

5. Willing to undergo an alternative approved standard of care treatment for their
condition.

6. Willing and able to comply with study requirements for follow-up.

7. No prior history of balloon or spray cryotherapy esophageal treatment. Prior APC is
allowable.

Exclusion Criteria:

1. Dysplasia or IM confined only to the gastric cardia (BE Prague C0M0).

2. Pre-existing esophageal stenosis/stricture preventing advancement of a therapeutic
endoscope during screening/baseline EGD. Subjects are eligible if the
stenosis/stricture is dilated to at least 15mm, but baseline treatment may need to be
delayed per protocol.

3. Symptomatic, untreated esophageal strictures.

4. Any endoscopically-visualized abnormalities such as ulcers, masses or nodules during
screening/baseline EGD. Subjects with nodular dysplasia or ImCA identified during
screening/baseline EGD may be treated with EMR or ESD and return for baseline
treatment in this study at least 6 weeks later given that:

4.1. Follow-up endoscopy must be negative for nodular dysplasia (visually clear of
nodular dysplasia).

4.2. Patients with intramucosal cancer (ImCA) must be at low risk for recurrence,
confirmed by EMR pathology results negative for: positive margin, >T1a stage, poorly
differentiated carcinoma, and lymphovascular invasion.

5. EMR or ESD < 6 weeks prior to baseline treatment.

6. Untreated invasive esophageal malignancy, including margin-positive EMR/ESD.

7. Active reflux esophagitis grade B or higher assessed during screening/baseline EGD.

8. Severe medical comorbidities precluding endoscopy, or limiting life expectancy to less
than 2 years in the judgment of the endoscopist.

9. Uncontrolled coagulopathy.

10. Inability to hold use of anti-coagulation medications or non-aspirin anti-platelet
agents (APAs) for the duration recommended per American Society for Gastrointestinal
Endoscopy (ASGE) guidelines for a high risk endoscopy procedure.

11. Active fungal esophagitis.

12. Known portal hypertension, visible esophageal varices, or history of esophageal
varices.

13. General poor health, multiple co-morbidities placing the patient at risk, or otherwise
unsuitable for trial participation.

14. Pregnant or planning to become pregnant during period of study participation.

15. Patient refuses or is unable to provide written informed consent.

16. Prior esophageal surgery with the exception of uncomplicated nissen fundoplication.