Clinical trial to evaluate safety and dose response using the C2 CryoBalloonTM 180 Ablation system for the treatment of dysplastic Barrett*s esophagus

Barrett's Esophagus (BE) is a premalignant condition, which can lead to
esophageal adenocarcinoma. This particular cancer is one of the most rapidly
increasing and deadliest cancers in the western world. Patients with BE are up
to 40 times more at risk of adenocarcinoma than individuals without BE. Once
diagnosed with BE, a patient enters a life-long surveillance program in which
upper endoscopies with biopsies are performed to survey the progression of the
Barrett's tissue to cancer. For more than 20 years, many technologies have been
evaluated for ablation of BE. Elimination of BE and restoration of squamous
esophageal lining has been demonstrated through ablation; however, no ablation
technology currently provides the necessary attributes for wide-spread
adoption. The CryoBalloon 180 Ablation System (System) is designed to address
many of the limitations of current ablation technologies. The simplicity of the
System allows for many potential benefits to the patient, the physician, and
hospital. Potential benefits are a shorter and safer procedure, easier
deployment minimizing the need for anesthesiology, smaller inventory
requirements and no capital equipment improving capital resource utilization.
Additionally, patients may experience less pain after cryoablation compared
with other ablation techniques. First, the System has undergone acute and
chronic animal testing. The testing was conducted to study safety,
deliverability and performance characteristics of the System. The studies were
conducted for the evaluation of the device in a normal pig esophagus at
dimensions very similar to a human esophagus. General follow-up time frames
were either 4 days or 28 days. Hereafter, three human trials have been
performed with the Focal cryoablation system, which evaluated the safety of the
Focal system with several doses, the device perfomance status, and the
efficacy. The studies showed safe treatment and high efficacy for cryoablation,
with 100% eradication of Barrett*s epithelium in the patients treated with the
maximal dose (10 sec). Currently, several trials are enrolling patients to
further evaluate efficacy of the System. Anyhow, this Focal system is only able
to treat relatively little areas of Barrett*s tissue. When ablating larger
areas with this focal device an important risk is that certain areas won*t be
treated or will be overtreated and, additionally, it can be a very
time-consuming procedure. Therefore the Cryoballoon 180 Ablation Sytem was
recently introduced by C2 Therapeutics. This device ablates a larger area (50%
of the circumference over a length of 3cm) in one ablation, thereby enabling
the ablation of larger BE tissue. This system was investigated in animal and
human trials, and judged to be safe. Now, we want to evaluate the efficacy of
the device in different doses, in order to find the optimal dose with maximal
efficacy and minimal burden for the patient.

The objective of this study is to determine the safe and efficacious dose
required to eradicate LGD or HGD in BE, or residual BE after endoscopic removal
of early cancer (*therapeutic dose*), using the C2 CryoBalloon 180 Ablation
System. *Dose* is defined as the rate at which the diffuser traverses the
length of the Balloon (in millimeters per second) while emitting cryogen.

Multi-center, prospective, single arm, phase 1 safety study.

Endoscopic balloon based cryoablation. The C2 Cryoballoon 180 Ablation system
has three main components: a delivery catheter with a spray-hole covered by a
balloon probe, a controller and a cartridge containing the cryogenic fluid. The
catheter can be inserted into the working channel of a therapeutic endoscope.
Once deployed, the balloon is simultaneously inflated and cooled with cryogenic
fluid from the cartridge. The BE cells of the esophagus will be ablated if they
come into contact with the cooled balloon. In the Cryoballoon 180 ablation
system, the spray hole of the catheter will automatically be pulled back during
ablation. In this way, an area of 3 cm length covering about 50% of the
circumference will be treated. The dosing will be expressed in the speed (in
mm/sec) whereby the catheter will be pulled back during the ablation (lower
speeds means a higher dose). Patients will undergo two Swipes, to treat the
esophageal circumferentially.

Patients will undergo 2 endoscopies in this study, which would have been
performed for regular medical care as well. The difference compared to regular
treatment is that during the first endoscopy patients will be treated with the
Cryoballoon 180 Ablation system instead of regular radiofrequency ablation
treatment. During follow-up endoscopy a thorough inspection of the esophagus,
and biopsies as well, will be performed. If necessary, additional treatment
will be performed with RFA. Patients need to adhere to a liquid diet after the
cryoablation (not different from standard care with RFA). Furthermore patients
will be contacted by telephone 1, 7 and 30 days after the cryoablation to ask
for dysphagia and pain. Finally, patients may experience temporary limited
pain, which can be treated with analgesics (paracetamol for example).