An Investigation of the Effect of Long-Term Electrical Stimulation on Lower Esophageal Sphincter (LES) Pressure and Esophageal Acid Exposure in Patients with Gastroesophageal Reflux Disease (GERD)

Gastroesophageal Reflux Disease (GERD) is a common problem affecting
approximately 250 million patients worldwide and 30 million patients in the US
suffer from GERD. Among the 12 million Americans who suffer from daily
heartburn (the main symptom of GERD) almost 5 million do not respond to any
medications and many more do not want or cannot take medications due to risk or
side-effects. These patients have few satisfactory alternatives, and almost
50-100,000 of these patients choose to undergo a major surgical procedure,
Nissen fundoplication, each year. The goals of treatment in GERD are to
relieve symptoms, heal esophagitis if present, and prevent recurrence of
symptoms and complications. Medical acid-suppressive therapy with PPI heals
esophagitis, relieves symptoms and improves quality of life. However, acid
suppressive therapy does not correct the underlying pathophysiology and hence
symptoms of reflux persist in the majority of patients. Prior endoscopic
techniques for the treatment of GERD may be categorized into 3 groups: (1)
sewing/plication at the cardia and gastroesophageal (GE) junction, (2)
radiofrequency (RF) thermal therapy to the lower esophageal sphincter (LES),
and (3) injection/implantation of biopolymers at the GE junction. Minimally
invasive endoluminal procedures for GERD are designed to provide long-lasting
symptom relief and abolish or lessen medication dependency. Most endoluminal
modalities that were introduced into clinical practice have failed due to lack
of efficacy or due to complications. Surgical therapy decreases symptoms and
improves the quality of life in GERD; however, there remain concerns regarding
postoperative adverse events and the durability of the surgical procedure.
Abnormalities in the structure and function of the LES, such as hypotensive LES
or inappropriate transient LES relaxation (t-LESR) may predispose patients to
GERD, making the LES the ideal target for therapy. Recent reports in animals
have suggested that electrical stimulation of the LES results in an increase in
the LES pressure and restoration of normal LES function. EndoStim has developed
an investigational medical device specifically designed to deliver electrical
stimulation to the LES and has completed two clinical feasibility studies using
an external version of the EndoStim stimulation system in fifteen subjects. In
these two studies, acute, short-term electrical stimulation resulted in
significant increases in LES pressure with no adverse effects reported.
Results of these studies are promising and warrant additional clinical study to
evaluate the effectiveness of EndoStim stimulation system to treat GERD over
time.

Primary Safety Endpoint:
Safety will be assessed by incidence and severity of adverse events through
12-weeks (3 month) follow-up. Included in this assessment will be the
proportion of subjects with any of the following outcomes between device
implant and completion of the Week 12 evaluation: (1) death, or (2) medical
morbidity associated with the device and/or implantation procedure, including
cardiac arrhythmias, pneumonia, wound infection, IPG or lead perforation, or
significant lead dislocation requiring hospitalization. Safety variables will
be tabulated and presented for all patients in the treatment group. Number of
patients undergoing device implantation and any reasons for discontinuation of
study treatment will be tabulated
Primary Functionality Endpoint:
Functionality will be assessed by the ability of the device to initiate
stimulation as programmed and to accurately detect the patient*s posture.
Indication of device detection when the patient is lying horizontally and when
standing up will be recorded.

Secondary Efficacy Endpoints:
1. Change in patient*s GERD-HRQL from baseline (as measured while off PPI) to 3
months.
2. The baseline LES end expiratory pressure (LESPpre) and the on-stimulation
LES end expiratory pressure (LESPpost) at three months.
3. The baseline pH values of % 24-hour esophageal pH< 4.0, and number of reflux
events >1minute and >5 minute duration with the same on-stimulation pH
parameters at three months.
4. Baseline symptoms as measured by patient symptom diary and patients quality
of life measured by SF-12 with on-stimulation symptoms and QOL at three months.
5. Decrease in antisecretory medication use compared to baseline.

Screening
The Investigator will determine if the patient is eligible to participate in
this study. Within two to four weeks prior to the scheduled laparoscopic study
procedure to implant the investigational device, the patient will see the study
doctor to complete baseline tests. The patient will be taken off of any acid
suppressive therapy 5-14 days prior to this baseline testing visit and remain
off the medications until after completion of baseline testing. While the
patients are off of these medications, they will be permitted to use antacids
on an as-needed basis to reduce any GERD symptoms they experience. The baseline
tests include a physical examination, a blood test, EKG test to assess
patients* heart*s function, and endoscopy to examine the interior of the
patients* esophagus. The patient will be asked to complete a questionnaire
regarding the severity of their GERD symptoms. The severity of the patients*
GERD symptoms and the function of patients* esophagus will also be assessed
using esophageal manometry. Esophageal manometry measures the strength and
muscle coordination of patients* esophagus when the patient swallows. During
the manometry test, a tube is passed through the patients* nose, along the back
of the throat, down the esophagus and into the stomach. The tube does not
interfere with their breathing. The tube is connected to a machine that records
the contractions of the esophageal muscles on a graph. The patient will be
asked to not eat or drink anything eight hours prior to the manometry test. A
topical anesthetic (pain-relieving medication) may be applied to the patients*
nose to make the passage of the tube more comfortable. At this time, the doctor
will also place pH capsule or tube in the patients* esophagus to measure the
acidity level. The pH tube is passed through the patients* nose or mouth, along
the back of the throat, down the esophagus and into the stomach and left in
place, until it passes. A data recorder is worn on the patients* belt and
records the pH data from their esophagus. If the pH capsule is used, it will be
placed using a catheter that is swallowed. The capsule is attached to the
esophageal lining and the catheter is then removed. The capsule records the pH
data from the patients* esophagus for 24-48 hrs. The next day the patient will
return to see the doctor at which time the data recorder will be removed. If a
capsule is used, it will fall off in 7-10 days and naturally passes in the
stool. If a tube is used, it will be removed the same time the data recorder is
returned. The patient will also be asked to complete antacid use and symptoms
diary.
The next day the patient will return to see the doctor at which time the data
recorder and the pH tube will be removed.
If the patient underwent endoscopy, manometry or pH-metry any time within the
last 6 months prior to enrollment to the study, the results of these tests can
be used as their baseline and there will be no need to repeat them for the
baseline evaluation. If, at any time during the study (in the opinion of the
patients* physician), the results of manometry or pH tests are compromised due
to noncopliance or equipment malfunction, the relevant test(s) may be repeated.



Implantation procedure
At the time that the patients are admitted into the hospital for the
laparoscopic study procedure, a study doctor will perform a physical
examination, a blood test, an EKG and endoscopy test prior to surgery. During
the laparoscopic study procedure, the study doctor will attach the
investigational device, called a stimulation lead, to the lower part of the
patients* esophagus. The study doctor will also place a small battery-operated
electrical stimulator, much like a pacemaker, in the patients* abdomen. The
stimulation lead will then be connected to the electrical stimulator so that
electrical energy can be delivered to the esophagus. After surgery, the
patients will stay in a hospital for a day or two until they recover. During
the first day after surgery, the study doctor will monitor the patients*
condition. Once the patients have recovered from the surgery, the study doctor
will turn on the investigational device and initiate the investigational
therapy. The doctor will monitor the patients* heart condition upon starting
the therapy and observe how the patients are responding. Once the doctor
determines it is safe for the patient to go home, the patient will be
discharged from the hospital.

Therapy adjustment and Follow-up
From this point until the patient complete the study, the patient will receive
investigational therapy (electrical stimulation to their lower esophagus) in
place of any acid suppressive therapy the patient may have been receiving. The
patients are permitted to take antacids to relieve any GERD symptoms the
patient experience while receiving the investigational therapy. The patients
will be asked to keep a diary to track their antacid use and symptoms while
they are participating in the study.

Approximately two weeks after being discharged from the hospital, the patient
will return to the investigator*s office for follow-up. The patients will be
asked to complete questionnaires regarding their GERD symptoms and their device
will be checked to make sure it is functioning properly.
The patient will be asked to return to the study doctor*s office periodically
for evaluation. The patients will return to the study doctor*s office
approximately one month, three months and six months after the implant. The
patients will be asked to fast for at least 8 hours prior to their visits.
These follow-up visits are much like the baseline visit they received prior to
the surgical procedure. At these visits, the patient will receive a physical
examination, a blood test, an EKG test to assess the patients* heart function
(only at the 3 months visit) and endoscopy (only at the 3 months visit). The
patients will be asked to complete questionnaires regarding the severity of
their GERD symptoms. The severity of their GERD symptoms and the function of
the patients* esophagus will also be assessed using 24-hour esophageal
manometry and pH tests. The manometry tube and pH tube or capsule is placed
into the patients* esophagus and a data recorder attached to their belt. The
next day the patient will return to see the doctor at which time the data
recorder, manometry tube, and pH tube or capsule, will be removed. Video
recordings may be taken. Any (fluoroscopic, xray or video) images will be
confidential and used only by the study doctor or the study sponsor (EndoStim)
to document the research session. In each of these visits the device will be
checked to assure that it is working properly.

The study doctor*s office will also contact the patient on the telephone each
month that the patients are not scheduled for a visit (two, four and five
months after the implant) to ensure the patients are not experiencing any
complications. During the phone call, the doctor*s office will evaluate how the
patient is doing and ask questions to evaluate their GERD symptoms. If the
patient is experiencing any issues or has any questions or concerns, the
patient is asked to notify the study doctor during their next phone call or
follow up visit.

Post study
At the end of the study (approximately six months after the implantation
procedure), the patients will meet with their study doctor to discuss whether
the device should be removed. The decision will be based on the doctor*s
opinion and the patients* evaluation of the extent to which the patient has
benefitted from the device. If, at the discretion of the study doctor, a
decision has been made to remove the device, a date will be set when the
patient will be admitted into the hospital for removal of the investigational
device. Once the patient has recovered, the study doctor will discharge the
patient home. The patient will be asked to return to the doctor*s office
approximately one week later for a follow-up evaluation to ensure the patient
is not experiencing any complications. This will complete the patient
participation in the study. If the device is not removed, the patients will be
asked to return to the hospital for follow up approximately every three months.

Any test samples obtained during this study will be only for the purpose of
this present study. The samples will not be stored for any use other than this
research study and will be identified by the patients* study ID and not by the
patient*s name.

Laparoscopy:
During the laparoscopic study procedure, the study doctor will attach the
investigational device, called a stimulation lead, to the lower part of the
patients* esophagus. The study doctor will also place a small battery-operated
electrical stimulator, much like a pacemaker, in the patients* abdomen. The
stimulation lead will then be connected to the electrical stimulator so that
electrical energy can be delivered to the esophagus.

Results from this study could lead to the development of a new, minimally
invasive therapy for the effective treatment of GERD. If proven effective, the
therapy could provide the subject with improved LES function and reduced
symptoms of GERD and therefore reduce or eliminate the need for acid
suppressive therapy or other more invasive treatment.
The potential adverse events and risks associated with this study and the use
of the LES Stimulation System are identical to those normally associated with
standard gastrointestinal stimulation therapy or an invasive, clinical
procedure (e.g., IPG and electrode placement, etc.).

Any new medical device or procedure may have unknown, as well as known, side
effects, discomforts and risks. The following side effects are possible if you
take part in this study.

There is a small chance that you may develop an infection or fever from the
procedures used in this research study including the laparoscopic procedure to
implant and remove the investigational device. All of the instruments that
contact you will be sterilized and used in a sterile setting using adequate
techniques for laparoscopic procedures. Additionally, you may be given
antibiotics prior to the procedure as a preventative measure. Following the
procedure, a physician or nurse will do a visual examination of the incision in
your abdomen to look for any signs of bleeding, redness, inflammation or
discharge, and you may be treated with antibiotics if needed. Likewise, your
temperature will be monitored for a fever and you may be treated with
acetaminophen or ibuprofen if needed.

There is a potential that any system component could malfunction, become
damaged, infected, or, in the case of the leads, become dislodged. Malfunction
of any of these components or other clinical circumstances (e.g., sepsis) may
require noninvasive corrective actions or possibly even a surgical correction
(repositioning, replacement, or removal) of the malfunctioning component(s).

As with any procedure, there is a small chance that you may have an allergic
reaction or other unanticipated reaction to the materials or medications used
in this research study.
You may develop unanticipated adverse reactions to the medications used for
sedation or anesthesia and control of discomfort or pain. These medications
have been used for many years and rarely cause serious problems, but there is a
potential for a harmful side effect including decreased blood pressure, nausea,
vomiting, seizures, hallucinations, allergic reaction, skin rash, fever, or
cardiac arrhythmia (irregular heartbeats) and respiratory depression (slowed
breathing). Cardiac arrhythmia may rarely lead to cardiac arrest, coma or
death. If respiratory depression occurs, your breathing could rarely slow to a
dangerous level or even stop. This could require that a breathing tube be
temporarily inserted while the medication wears off, or longer, if necessary.
The discomforts of the sedatives / anesthesia include possible headaches or a
sore throat and aspiration pneumonia (inflammation of the lungs and airways to
the lungs from breathing in foreign material).


You may develop unanticipated adverse reactions to the laparoscopic procedure
including hematoma, seroma and wound separation. You will be monitored after
the procedure to ensure that any complications are promptly and appropriately
treated prior to your discharge home.

Although manomtetry is commonly used to assess GERD, there are possible risks
associated with this procedure. You may experience pain or discomfort when the
manometry tube is placed in your esophagus. Your doctor will give you a local
anesthetic to prevent any pain or discomfort. You may also experience increased
salivation which could increase your risk of breathing a food particle into
your lungs. There is a small chance that this could lead to pneumonia. To
ensure that no food particles are present that could be breathed in, you will
fast before the manometry tube is placed each time.

You may experience pain or discomfort resulting from the electrical stimulation
delivered by the investigational device. If at any time you experience pain or
discomfort, the doctor will modify the electrical stimulation parameters or
discontinue delivery of the electrical stimulation and prescribe medications to
alleviate the pain if needed.

There is a small chance that the investigational device could cause a small
hole in your esophagus, called a perforation. The doctor will secure the
investigational device at the time of surgery to ensure that it will not become
loose and lead to a perforation. Also, the doctor will be checking the
investigational device periodically throughout the entire study to ensure that
it will not become loose. If the investigational device causes a perforation,
it maybe treated with antibiotics alone or a surgery may be required to close
the hole and prevent any further complications.

There is a small chance that the investigational device could lead to irregular
or abnormal electrical activity in your heart. Such an irregularity is called a
cardiac arrhythmia. To ensure that your heart is not experiencing cardiac
arrhythmia, the doctor will use EKG, a device to monitor your heart*s
electrical activity, at the study visits.
All these potential risks are treatable, and if treated timely, your life
should not be at risk. Your doctor will discuss with you all the signs and
symptoms so that you pay attention to them. If you experience any of the signs
and symptoms discussed with your doctor, call him immediately and he will tell
you if you should go to a hospital for any treatment.

There may be other device-related problems that are not known yet. If you
receive the EndoStim device you will be notified of any new risks that become
known during the study that may affect your decision of whether to continue in
the study.

Risks to Pregancy
The risks of implanting the investigational device in a pregnant woman are
unknown. Pregnant women may not take part in this research trial.

Child bearing age women could only be considered as potential candidates if
they underwent surgical sterilization or have been on oral contraception for
the last three months and are committed to keep using oral contraception
throughout the study, and/or for as long as they have the EndoStim device
implanted. Women who plan to become pregnant during the study may not
participate.