SUMMARY OF SAFETY AND EFFECTIVENESS DATA

Endoscopic Implantation of Enteryx™ for the Treatment

of Gastroesophageal Reflux Disease (GERD)

Enteric Medical Technologies, Inc.

551 Foster City Blvd., Suite G

Foster City, California 94404

U.S.A.

\(650\) 574-2867

TABLE OF CONTENTS

####  [Page]{.underline} {#page .unnumbered}

#### GENERAL INFORMATION 4 

##### A. [Device generic name]{.smallcaps} 4  {#a.-device-generic-name-4 .unnumbered}

###### B. [Device trade name]{.smallcaps} 4  {#b.-device-trade-name-4 .unnumbered}

###### C. [Applicant's name and address]{.smallcaps} 4  {#c.-applicants-name-and-address-4 .unnumbered}

###### D. [Date of panel recommendation]{.smallcaps} 4  {#d.-date-of-panel-recommendation-4 .unnumbered}

> E. [PMA No.]{.smallcaps} 4

###### F. [Date of GMP inspection]{.smallcaps} 4  {#f.-date-of-gmp-inspection-4 .unnumbered}

G.  [Date of notice of approval to applicant]{.smallcaps} 4

#### INDICATION FOR USE 4

#### DEVICE DESCRIPTION 4

######## **CONTRAINDICATIONS, WARNINGS, & PRECAUTIONS 5**

A.  [Contraindications 5]{.smallcaps}

B.  [Precautions 5]{.smallcaps}

#### POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH 6

######## **ALTERNATIVE PRACTICES & PROCEDURES 6**

### MARKETING HISTORY 7

V.  **SUMMARY OF NON-CLINICAL STUDIES 7**

> A. [Biocompatibility testing]{.smallcaps} 7
>
> B. [Carcinogenicity testing]{.smallcaps} 8
>
> C. [Long-term esophageal implantation studies]{.smallcaps} 9

###  1. Canine LES Implant Study 10 {#canine-les-implant-study-10 .unnumbered}

> 2\. Yucatan Minipig LES Implant Study 10
>
> [D. Conclusions 11]{.smallcaps}

VI. SUMMARY OF CLINICAL STUDIES 11

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A.  [Study objective 11]{.smallcaps}

B.  [Study design 12]{.smallcaps}

> 1\. Effectiveness Parameters 12
>
> 2\. Safety Parameters 12

C.  [Study protocol 12]{.smallcaps}

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1.  Inclusion Criteria 12

2.  Exclusion Criteria 13

> 3\. Treatment Procedures 13

D.  [Description of study population and results 14]{.smallcaps}

> E. [Effectiveness results]{.smallcaps} 14
>
> F. [Safety results]{.smallcaps} 22

VII. [CONCLUSIONS 24]{.smallcaps}

VIII. [PANEL RECOMMENDATIONS 25]{.smallcaps}

IX. [CDRH DECISION 25]{.smallcaps}

X.  [APPROVAL SPECIFICATIONS 25]{.smallcaps}

#### I. [GENERAL INFORMATION]{.underline} {#i.-general-information .unnumbered}

**A. Device Generic Name:** EVOH-T (Ethylene Vinyl Alcohol Copolymer
with Tantalum)

B. Device Trade Name: Enteryx

**C. Applicant's Name and Address:** Enteric Medical

> 551 Foster City Blvd., Suite G
>
> Foster City, California 94404
>
> U.S.A.

\(650\) 574-2867

**D. Date of Panel Recommendation:** TBD

#### E. Premarket Approval Application PMA Shell M010024 {#e.-premarket-approval-application-pma-shell-m010024 .unnumbered}

> **(PMA) Number:**

#### F. Date of Good Manufacturing TBD {#f.-date-of-good-manufacturing-tbd .unnumbered}

> **Practice Inspection:**

#### G. Date of Notice of Approval TBD {#g.-date-of-notice-of-approval-tbd .unnumbered}

> to Applicant:

#### II. [INDICATIONS FOR USE]{.underline} {#ii.-indications-for-use .unnumbered}

Enteryx™ is indicated for endoscopic injection into the lower esophageal
sphincter (LES) for the treatment for gastroesophageal reflux disease
(GERD).

######## **[DEVICE DESCRIPTION]{.underline}**

Enteryx is a medical device comprised of an injectable solution of
ethylene vinyl alcohol copolymer (EVOH) dissolved in dimethyl sulfoxide
(DMSO). Upon contact with polar physiologic fluid, the DMSO solvent
diffuses away, resulting in solidification of the hydrophobic copolymer,
which forms a spongy solid mass. The liquid Enteryx polymer is delivered
endoscopically into and along the muscle layer of the lower esophageal
sphincter (LES) via a sclerotherapy type catheter.

The Enteric Medical Technologies, Inc. Enteryx System for the treatment
of gastroesophageal reflux disease (GERD) is comprised of:

-   One 10 cc glass vial of sterile Enteryx solution.

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-   One 10 cc glass vial of sterile dimethyl sulfoxide (DMSO) for
    priming the injection catheter.

# Accessories {#accessories .unnumbered}

-   One Enteryx Injection Catheter, for injecting the Enteryx solution.

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-   Two DMSO compatible sterile syringes for priming and loading the
    Injection Catheter with DMSO or Enteryx.

-   Two DMSO compatible sterile needles for use with the syringes.

The Enteryx solution consists of a biocompatible polymer, 8%
Ethylene-Vinyl Alcohol copolymer (EVOH), dissolved in dimethyl sulfoxide
(DMSO) as the solvent. Micronized tantalum powder (30%) is added to the
polymer/solvent mixture to serve as the contrast for visualization under
fluoroscopy. Upon injection through a syringe and contact with aqueous
body fluids, the solvent rapidly diffuses away causing *in-situ*
precipitation of the polymer and formation of a spongy mass.

The liquid Enteryx material is delivered via an injection catheter to
the lower esophageal sphincter. The liquid quickly transforms into a
solid spongy mass as the DMSO solvent diffuses into the blood and
interstitial spaces.

Enteryx is packaged as 10 ml of sterile product in a glass vial. DMSO,
the solvent for priming the injector, is also packaged as 10 ml of
sterile product in a glass vial. The vials are sealed with Teflon-lined
silicone stoppers and aluminum closures. Enteryx is used with
DMSO-compatible disposable sterile syringes, injectors, and needles
provided by Enteric Medical.

IV\. [CONTRAINDICATIONS & PRECAUTIONS]{.underline}

A.  CONTRAINDICATIONS

Enteryx must not be used in patients with portal hypertension.

B. PRECAUTIONS

The safety and effectiveness have not been established in patients with
Barrett's epithelium, scleroderma, esophageal motility disorders,
esophageal or gastric cancer, large hiatal hernias, prior gastric or
GERD surgery, persistent high grade esophagitis, esophageal or gastric
varices, gross obesity, or immune suppressant therapy. The safety and
effectiveness have not been established in women who are pregnant or
lactating.

V. [POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH]{.underline}

The following device-related adverse events were observed during the
clinical study:

-   Retrosternal chest pain

-   Dysphagia

-   Fever

-   Belching/burping

-   Bloating/flatulence

-   Body odor/bad taste

-   Rib pain

-   Flu syndrome

The following procedure-related adverse events were observed during the
clinical study:

-   Pharyngitis

-   Nausea and vomiting

-   Nausea

-   Shoulder pain

-   Dry mouth

-   Anxiety

-   Breast pain

There were no unanticipated adverse device effects reported during this
investigation.

VI\. [ALTERNATIVE PRACTICES AND PROCEDURES]{.underline}

Alternative practices and procedures available for the treatment of GERD
include:

-   Drug therapy with proton pump inhibitors (PPIs), such as Prilosec®
    and Prevacid®

-   Drug therapy with H~2~ receptor antagonists, such as Pepcid®,
    Tagamet®, and Zantac®

-   Antireflux surgery

-   Diet modification

VII. [MARKETING HISTORY]{.underline}

Enteryx received the CE mark in May 2000, at which time limited
marketing of the device in select European countries began. Enteryx has
not been withdrawn from marketing for any reason related to the safety
and effectiveness of the device.

VIII\. [SUMMARY OF NON-CLINICAL STUDIES]{.underline}

A.  Biocompatibility Testing

Biocompatibility testing of Enteryx (EVOH-T) was performed according to
the requirements of ISO 10993-1 for permanent implants. This testing
included cytotoxicity (MEM elution) of EVOH-T and DMSO alone,
sensitization by guinea pig maximization (Magnusson/Kligman), USP
intracutaneous reactivity, USP acute systemic toxicity, subacute
toxicity, and acute rabbit intramuscular implant (seven days). Chronic
toxicity of EVOH with and without tantalum was evaluated in rabbits.
Genotoxicity testing, including Ames reverse mutation, mouse lymphoma
cell, and mouse micronucleus test, was also performed. The results of
these tests demonstrate that Enteryx is non-toxic and biocompatible. A
summary of the biocompatibility testing is presented in *Table 1*.

Biocompatibility Testing for EVOH-T and EVOH

+---------------+----------------------------------+------------------+
| **Test        | **Title**                        | **Results**      |
| Description** |                                  |                  |
+===============+==================================+==================+
| Cytotoxicity  | MEM Elution Test Evaluation of   | No evidence of   |
|               | EVOH-T                           | cytotoxicity     |
+---------------+----------------------------------+------------------+
| Cytotoxicity  | MEM Elution Test Evaluation of   | No evidence of   |
|               | DMSO (Dilution Series)           | cytotoxicity     |
| (DMSO Only)   |                                  |                  |
+---------------+----------------------------------+------------------+
| Sensitization | Evaluation of EVOH-T by Guinea   | Grade I weak     |
|               | Pig Maximization                 | response,        |
|               | (Magnussen/Kligman Method)       | equivalent to    |
|               |                                  | negative control |
+---------------+----------------------------------+------------------+
| I             | USP Intracutaneous Reactivity    | Met USP          |
| ntracutaneous | Evaluation of EVOH-T             | requirements     |
| Reactivity    |                                  |                  |
+---------------+----------------------------------+------------------+
| Acute         | USP Acute Systemic Toxicity      | Met USP          |
| Systemic      | Evaluation of EVOH-T             | requirements     |
| Toxicity      |                                  |                  |
+---------------+----------------------------------+------------------+
| Subacute      | Fourteen-Day Subacute            | Non-toxic        |
| Toxicity      | Intravenous Dosing Study of      |                  |
|               | EVOH-T in Mice                   |                  |
+---------------+----------------------------------+------------------+
| Muscle        | USP Seven Day Muscle Implant     | USP requirements |
| Implantation  | Evaluation of EVOH-T             | not met due to   |
|               |                                  | acute tissue     |
|               |                                  | response         |
+---------------+----------------------------------+------------------+
| Chronic       | One Year Intramuscular Implant   | Stabilized as    |
| Toxicity      | Evaluation of EVOH and EVOH-T in | mild             |
|               | Rabbits                          | inflammatory     |
|               |                                  | response;        |
|               |                                  | non-toxic        |
+---------------+----------------------------------+------------------+
| Genotoxicity  | Bacterial Reverse Mutation Assay | Extracts were    |
|               | Conducted with Test Article      | negative, passed |
|               | Extracts -- EVOH-T               |                  |
+---------------+----------------------------------+------------------+
| Genotoxicity  | In Vitro Mammalian Cell Gene     | Extracts were    |
|               | Mutation Test Conducted with     | negative, passed |
|               | Test Article Extracts -- EVOH-T  |                  |
+---------------+----------------------------------+------------------+
| Genotoxicity  | Micronucleus Cytogenetic Assay   | Extracts were    |
|               | in Mice Conducted with Test      | negative, passed |
|               | Article Extracts -- EVOH-T       |                  |
+---------------+----------------------------------+------------------+
| Ca            | Carcinogenicity Evaluation of    | Not carcinogenic |
| rcinogenicity | EVOH and EVOH-T using the        |                  |
|               | *ras*H2 Transgenic Mouse Model   |                  |
+---------------+----------------------------------+------------------+

B. Carcinogenicity testing

Carcinogenicity testing was performed utilizing the *ras*H2 transgenic
mouse model. The purpose of this study was to evaluate the potential
carcinogenicity of Enteryx.

The *ras*H2 transgenic mouse model was selected for this study because
it offers a test system for the evaluation of carcinogenic potential of
implanted biomaterials without the confounding factors related to the
existence of foreign body sarcomagenesis (FBS) mechanism in rodents.

The development of transgenic mice carrying a human prototype C-Ha-ras
gene (*ras*H2 mice) has been recognized as an opportunity to evaluate
carcinogenic potential of biomaterials, since rapid carcinogenicity
testing of mutagenic and non-mutagenic chemical compounds has been
validated in this animal model. In these mice, the foreign body
sarcomagenesis response can be differentiated from chemically mediated
carcinogenicity within the six-month exposure period to the test
article.

In this study, Millipore filters (MF) with a pore size of 0.65 µm and
0.05 µm were implanted as FBS control groups. Urethane, alone and loaded
onto Millipore filters, was utilized as the chemical carcinogen control
based on a review of the current literature.

Enteryx was administered subcutaneously in 400 mice, with 10 animals
from each sex and genotype (transgenic and non-transgenic) assigned to
each of the treatment groups.

No differences in body weight gain, terminal mean body weights, or
relative tissue weights were observed between animals exposed to the
test articles or animals that had implanted Millipore discs. Similarly,
no significant histologic findings were observed in any animals exposed
to the test articles either at the site of implantation or in any of the
50 tissues that were examined microscopically. No tumors were observed
at the site of implantation of the 0.05 µm MF discs, however, an
increased level of fibroplasia and decreased level of histiocytic
infiltration was observed in these animals. These changes are consistent
with early histopathologic alterations, which were found in the
literature to be precursors of induction of foreign body sarcomas using
small pore (less than 0.10 µm) filters.

In contrast, the cellular character of the test site response observed
in animals injected with Enteryx was similar to the response elicited by
the 0.65 µm MF discs used as a negative control, establishing the
absence of any precursors of induction of foreign body sarcomas. Mice
exposed to urethane administered either subcutaneously or on a coated MF
disc had a significantly increased incidence of lung and splenic tumors
in comparison to their non-transgenic littermates.

In conclusion, the findings of this study establish that Enteryx is
non-carcinogenic in the *ras*H2 transgenic mouse.

C. Long-term ESOPHAGEAL Implantation Studies

The long-term safety of Enteryx was evaluated in two animal models,
canines and Yucatan minipigs. The long-term safety of intramural and
extramural LES implants was evaluated in canines and the long-term
safety and effect on resting LES pressure was evaluated in minipigs.

### 1. Canine LES Implant Study {#canine-les-implant-study .unnumbered}

Intramuscular implantation was performed in 16 canines to evaluate the
safety of EVOH-T when injected intramurally at the lower esophageal
sphincter (LES) and transmurally above and below the LES. An additional
study objective was to develop an endoscopic technique of placement of
EVOH-T at the gastroesophageal junction, to augment the LES.

Cranial, chest and abdominal x-rays were performed immediately after
injection of EVOH-T, and again four weeks post-implantation to assess
the location of the EVOH-T, and of any migration. Endoscopy was
performed at three days and one month following EVOH-T injection, to
assess mucosal and local response to the device material. Hematology was
performed for evidence of any signs of systemic toxicity. Of the 16
animals, 13 were intended for short-term evaluation, and were sacrificed
at one month, while the three additional dogs were followed for 12
months to evaluate implant stability.

Twelve-month follow up data on three animals showed very minimal or no
tissue reaction around major vessels, the trachea, and the right atria.
Full body x-ray exams established the absence of migration of the
EVOH-T. These study results demonstrate that EVOH-T can be injected
safely into the dog with minimal long-term response.

### 2. Yucatan Minipig LES Implant Study {#yucatan-minipig-les-implant-study .unnumbered}

The long-term safety of EVOH-T was evaluated in 15 Yucatan minipigs to
evaluate the dosing and location of EVOH-T, to assess the safety of
submucosal or intramuscular LES implants, and in selected animals, to
assess LES (lower esophageal sphincter) compliance changes, or yield
pressures.

All animals tolerated the implants well and no complications were
observed. Histology was performed on animals sacrificed at two weeks,
four weeks, five weeks, six weeks, three months, six months, and one
year. Over the first month following injection, an inflammatory response
consisting predominantly of macrophages was observed, and this response
is associated with the production of fibrotic capsule that surrounds the
mass of the implanted material. By three months, (and most certainly by
six months) post-implantation, the tissue surrounding the implant sites
was quiescent. Mature, well-delineated capsules of varying thickness
surrounded the sites, separating them from the esophageal muscle or the
interstitial connective tissue.

Pre-injection and post-injection manometric evaluation of the LES area
was performed in a subset of animals, to determine overall total LES
length, intra-abdominal LES length, and LES pressure. Yield pressure was
assessed using both gas insufflation and water infusion to determine the
pressures and volumes required to cause the LES to open. When comparing
pre-injection and post-injection yield volumes, considerably higher
yield volumes were observed post-injection, indicating that the LES was
able to withstand much higher pressures before yielding.

##### D. Conclusions {#d.-conclusions .unnumbered}

In the USP seven-day rabbit muscle implant study, EVOH-T was compared to
a negative control (polyethylene implants), and was found to cause a
more significant local effect in the muscle tissue. However, this
observation was consistent with the course of foreign body reaction
observed in the other EVOH-T implantation studies, in which there is an
initial tissue reaction, which resolves over time, and is consistent
with the extensive body of published data on the host response to the
three most commonly implanted biomaterials, i.e., polyethylene
terephthalate, expanded polytetrafluoroethylene, and polypropylene.

The results of these extensive in vitro and animal studies support the
use of Enteryx for implantation in the lower esophageal sphincter for
the treatment of gastroesophageal reflux disease (GERD).

IX\. [SUMMARY OF CLINICAL STUDIES]{.underline}

A.  STUDY OBJECTVE

A prospective, multicenter clinical study was conducted under IDE
G000065. The purpose of the clinical trial was to evaluate the safety
and effectiveness of Enteryx as an implantable agent for the treatment
of GERD.

B.  STUDY DESIGN

This study was designed to evaluate the safety and efficacy of
endoscopic implantation of Enteryx for the treatment of GERD.
Eighty-five (85) subjects were enrolled at eight sites. The assessment
of safety and efficacy of Enteryx was based on results of the
twelve-month examination.

1.  **Effectiveness Parameters**

Patients were assessed for a reduction in dose of medication, an
improvement in GERD-Health Related Quality of Life (HRQL) and SF-36
scores, a reduction in acid reflux measured by intraesophageal pH
monitoring, and LES function assessed by esophageal manometry.

2\. Safety Parameters

Subjects were clinically assessed, adverse events were evaluated, and
endoscopy results were recorded. The location and quantity of the
implant were assessed by x-ray.

C.  STUDY PROTOCOL

Patients who were considered capable of comprehending the nature of the
study, who were likely to comply with the visit schedule, who provided
informed consent, and who conformed to the following inclusion/exclusion
criteria were considered for enrollment in the study.

Patients with a previous diagnosis of GERD who were under medical
therapy with PPIs (proton pump inhibitors) for at least three months
with successful alleviation of GERD symptoms were enrolled into the
study.

**1. Inclusion Criteria**

Patients who met all of the following initial inclusion criteria were
eligible for inclusion in the study:

-   History of heartburn, regurgitation, or both prior to the initiation
    of proton pump inhibitor therapy

-   Taking daily proton pump inhibitor for at least the last three
    months

-   Responsive to a standard dose of PPI as manifested by a baseline
    GERD-HRQL symptom score of ≤11

-   Surgical candidates in the unlikely event of a complication related
    to this procedure (ASA I or II)

-   At least 18 years of age

-   Not pregnant by history or had a negative pregnancy test or surgical
    sterilization

-   Patients who agreed to participate, understood the content of the
    consent form, and signed the consent form

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-   Had GERD symptoms that returned upon discontinuing PPI therapy for
    10-14 days, as manifested by a GERD-HRQL symptom score of ≥ 20

-   A confirmed diagnosis of gastroesophageal reflux disease by
    prolonged (\>12 hour) pH--metry with ≥ 5% of total time pH \< 4 OR ≥
    3% of the supine hours pH \< 4

**2. Exclusion Criteria**

Patients with the following conditions were excluded from the study:

-   Esophageal motility disorder other than GERD manifested by ≥ 50%
    nonpropagated primary waves after wet swallows

-   Any significant multisystem disease that would compromise their
    ability to tolerate an endoscopic procedure

-   Prior gastric or GERD surgery

-   Scleroderma

-   Persistent esophagitis ≥ Grade III (Savary-Miller)

-   Barrett's epithelium

-   Hiatus hernia ≥ 3cm by endoscopic evaluation

-   Gross obesity (BMI ≥ 35)

-   Any autoimmune disorder that required therapy within the last two
    years

-   Suspected or confirmed esophageal or gastric cancer

-   Esophageal or gastric varices

-   Anticoagulant use, other than 300mg aspirin or equivalent per day

-   Patients who were unwilling to participate in all of the follow-up
    studies

3\. Treatment Procedures

All patients were screened for study eligibility. The following
information was obtained and testing was performed for all subjects
enrolled in the study: a medical history, esophageal manometry, UGI
endoscopy, and barium esophagram. Prior to treatment, subjects completed
the GERD‑specific Health Related Quality of Life (GERD-HRQL) and the
SF-36 Health Survey questionnaires. They were asked to first complete
the questionnaires based on their current PPI medications. Proton pump
inhibitors (PPIs) were then discontinued for at least 10 days, after
which subjects completed the questionnaires a second time. In addition,
a prolonged (\>12 hour) pH study was performed while the subjects were
off PPI therapy. Subjective and objective tests were completed again at
the one, three, six and twelve-month treatment follow‑up visits, as
defined in the event schedule.

D.  DESCRIPTION OF STUDY POPULATION AND RESULTS

Of the 85 subjects enrolled in the study and treated with Enteryx, 49
(57.6%) subjects were male and 36 (42.4%) were female. The mean age for
the study population was 49.6 years (SD 11.7, range 26.8 - 73.7 years),
and the majority of subjects (78%) were over 40 years of age at the time
of treatment. The majority of the enrolled subjects were Caucasian
(92.9%); 3.5% of subjects were Black; 2.4% were Hispanic, and 1.2% were
Asian. The mean body mass index (BMI) was 28.3 (SD 3.97, range 18.5 -
37.4), with the majority of subjects (67.1%) with BMI over 26 but less
than 35.

E. EFFECTIVENESS RESULTS

A successful outcome was defined as elimination of all PPI use or a
reduction in use of PPIs by at least 50% as compared to baseline usage.
Patients who experienced a smaller reduction in use of PPIs, i.e.,
\<50%, who continued to use PPIs at the baseline levels, or who required
an increase in PPI usage were considered not improved.

At 12 months, 80.3% of all study subjects (C.I. 69.9% to 88.3%) were
able to completely eliminate (70.4%) or reduce ≥ 50% their use of PPIs
(9.9%). Since the 95% confidence interval (69.9% to 88.3%) is entirely
above the 50% criterion, it can be stated that the primary hypothesis of
a statistically significant reduction of PPI utilization was
demonstrated (p\<0.0001 by the sign test).

PPI Use 12 Months post-procedure

  --------------------------------- ----------- -------------------------
                                    **n**       **% (CI)** [^1]

  **Medication Improved**           65/81       80.3% (69.9 to 88.3% )

  Off all PPIs                      57          70.4%

  Dose reduced ≥ 50%                8           9.9%

                                                

  **Medication Not Improved**       16/81       19.7%

  Dose reduced \< 50%               1           1.2%

  Dose maintained                   12          14.8%

  Dose increased                    3           3.7%
  --------------------------------- ----------- -------------------------

The proportion of patients using supplementary non-PPI medications for
treatment of GERD was very low for the overall study population. At the
12-month examination 14.8% of subjects (12 subjects) reported use of
antacids on an as-needed basis and 3.7% of subjects (3 subjects) used
antacids on a daily basis. Only three subjects reported using H~2~
antagonists at a frequency of less than daily use. These data suggest
that treatment with Enteryx allowed the majority of patients to
discontinue use not only of PPIs, but also of other GERD medications,
including antacids and H~2~ antagonists.

#### SF-36 HEALTH SURVEY {#sf-36-health-survey .unnumbered}

The SF-36 Health Survey questionnaire, a secondary efficacy measurement,
was completed by each study subject at baseline while on PPI treatment,
at baseline following withdrawal of PPI treatment for 10-14 days, and at
one month, three months, six-months and 12 months following treatment
with Enteryx.

#### Physical Component  {#physical-component .unnumbered}

SF-36 PCS mean scores at baseline were better for subjects while on PPI
therapy than off PPIs. At 12 months following treatment with Enteryx,
mean physical component scores were also significantly improved over the
mean score at baseline for subjects off PPI therapy (49.4 vs 43.4,
p\<0.001) and were comparable to scores reported at baseline for
subjects while on PPIs.

**Mental Component**

SF-36 MCS mean scores were *not* significantly different for subjects
while on PPI therapy than off PPIs at baseline. At 12 months following
treatment with Enteryx, mean scores were not significantly different
than subjects either on PPI therapy at baseline (50.0 vs. 51.4, p=0.444)
or off PPIs at baseline (50.5 vs. 50.2, p=0.160). Since the change from
baseline for SF-36 MCS was not statistically significant by the Wilcoxon
signed ranks test, the results were examined for the patients who were
improved at 12 months (i.e., PPI use eliminated or reduced ≥ 50%) using
the sign test. While a less powerful statistical tool, patients whose
medication use improved following Enteryx treatment continued to have
statistical significance (p=0.026), suggesting a favorable trend in
treatment responders.

Together, these findings suggest that Enteryx is capable of replacing
PPIs with no change in SF-36 scores.

**Baseline (on PPIs) Baseline (off PPIs)**

**N Mean (SD) N Mean (SD) p value**

**Quality of life score**

SF-36 MCS 81 51.2 (9.44) 81 48.5 (11.49) 0.077

SF-36 PCS 81 47.8 (9.43) 81 43.1 (10.13) \<0.001

**Baseline (off PPIs) 12 Months post-Treatment**

**N Mean (SD) N Mean (SD) p value**

**Quality of life score**

SF-36 MCS 74 50.2 (9.71) 74 50.5 (10.76) 0.160

SF-36 PCS 74 43.4(10.16) 74 49.4 (9.32) \<0.001

##  {#section .unnumbered}

## **VELANOVICH GERD-HRQL SYMPTOM SCORE** {#velanovich-gerd-hrql-symptom-score .unnumbered}

The Velanovich GERD-HRQL questionnaire consists of a series of questions
related to symptoms experienced by the subject in the last five days.
The following scale was used to record the intensity of the symptoms:

> 0 = no symptoms (very satisfied)
>
> 1 = symptoms noticeable but not bothersome (satisfied)
>
> 2 = symptoms noticeable and bothersome but not every day (neutral)
>
> 3 = symptoms bothersome every day (dissatisfied)
>
> 4 = symptoms affect daily activities (very dissatisfied)
>
> 5 = symptoms are incapacitating -- unable to do daily activities

###  {#section-1 .unnumbered}

### The questionnaire was completed by each subject at baseline while on PPI treatment, at baseline with PPI therapy withdrawn, and at one month, three months, six months, and twelve months following treatment with Enteryx. Results were reported as the sum of questions related to heartburn scores (sum of questions 1-9) and to sum of questions related to regurgitation scores (sum of questions 10-13). {#the-questionnaire-was-completed-by-each-subject-at-baseline-while-on-ppi-treatment-at-baseline-with-ppi-therapy-withdrawn-and-at-one-month-three-months-six-months-and-twelve-months-following-treatment-with-enteryx.-results-were-reported-as-the-sum-of-questions-related-to-heartburn-scores-sum-of-questions-1-9-and-to-sum-of-questions-related-to-regurgitation-scores-sum-of-questions-10-13. .unnumbered}

###  {#section-2 .unnumbered}

### Sum of Questions 1-9 (Heartburn Score) {#sum-of-questions-1-9-heartburn-score .unnumbered}

The mean severity score for the sum of questions 1-9 was significantly
worse at baseline with patients off PPI therapy as compared to baseline
on PPI medications (26.4 vs 5.4, p\<0.001). Mean severity score improved
significantly following treatment with Enteryx as compared to baseline
scores while off PPIs at each follow-up interval (p\<0.001). Consistent
with the findings for each of the individual questions that are
comprised in the summary score, scores following Enteryx treatment were
comparable to those observed for patients on PPI therapy at baseline,
further confirming that treatment with Enteryx is an effective
alternative to chronic use of PPI therapy.

###  {#section-3 .unnumbered}

### Sum of Questions 10-13 (Regurgitation Score) {#sum-of-questions-10-13-regurgitation-score .unnumbered}

The mean regurgitation severity score for the sum of questions 10-13 was
significantly worse at baseline with patients off PPI therapy as
compared to baseline PPI medications (11.1 vs 2.8, p\<0.001). Mean
severity scores following Enteryx treatment were significantly improved
compared to baseline scores for patients off PPI treatment (p\<0.001).
Also consistent with the scores for the individual questions, scores for
the sum of questions 10-13 were comparable for patients at baseline
while on PPIs and following treatment with Enteryx.

**Baseline (on PPIs) Baseline (off PPIs)**

**N Mean (SD) N Mean (SD) p value**

**Symptom score**

GERD-HRQL (Q1-9) 85 5.4 (3.74) 85 26.4 (6.62) \<0.001

GERD-HRQL (Q10-13) 85 2.8 (3.33) 85 11.1 (5.31) \<0.001

**Baseline (off PPIs) 12 Months post-Treatment**

**N Mean (SD) N Mean (SD) p value**

**Symptom score**

GERD-HRQL (Q1-9) 77 26.2 (6.67) 77 8.9 (9.70) \<0.001

GERD-HRQL (Q10-13) 77 10.9 (5.40) 77 3.1 (4.22) \<0.001

In conclusion, the GERD-HRQL data indicate that at 12 months following
Enteryx treatment, study subjects felt significantly better compared to
baseline symptoms off PPIs and had comparable symptom control to
baseline scores on PPIs. These data illustrate that the Enteryx
procedure can relieve heartburn and regurgitation symptoms and provide
an effective alternative to chronic PPI use.

**pH-Metry**

Subjects underwent prolonged (\> 12 hour) pH probe monitoring at
baseline off PPI therapy for at least 10 days, and at twelve months
following Enteryx treatment. The following data were recorded:

-   \% total time pH [\<]{.underline} 4

-   \% upright time pH [\<]{.underline} 4

-   \% supine time pH [\<]{.underline} 4

-   total number of episodes

-   longest episode duration (minutes)

**Percentage of Time pH \< 4**

For all subjects with paired data at Month 12, 26/67 (39%) of subjects
normalized their pH measurement, as compared to baseline. Further, 43.1%
(25/58) of patients who experienced an improvement in PPI use at 12
months also had normalized pH. In contrast, among patients who did not
experience an improvement in PPI use at 12 months, only 11.1% (1/9) had
normalized pH.

At baseline for the cohort of patients who had baseline and 12 month pH
metry performed, the mean percentage of time during testing that pH was
\< 4 was 14.34% (SD 14.68%). At twelve months following Enteryx
treatment, the mean percentage of time at pH \< 4 was 9.21% (SD 9%). The
mean overall percentage of time at pH \< 4 was significantly reduced
(improved) at twelve months following Enteryx treatment (p = 0.002)
compared to baseline off PPIs. These statistically significant
reductions in overall time at pH \< 4 are indicative of a significant
improvement in pH-metry at six and twelve months post-treatment with
Enteryx.

**Percentage of Upright Time pH \< 4**

At baseline for the cohort of patients who had baseline and 12 month pH
metry performed, the mean percentage of upright time during testing that
pH was \< 4 was 14.27% (SD 15.35%). At twelve months following Enteryx
treatment, the mean percentage of upright time at pH \< 4 was 9.92% (SD
10.72%). The mean percentage upright time at pH \< 4 was significantly
reduced (improved) at twelve months following Enteryx treatment (p =
0.026) compared to baseline off PPIs. These statistically significant
reductions in upright time at pH\<4 are indicative of a significant
improvement in pH-metry at six and twelve months post-treatment with
Enteryx.

**Percentage of Supine Time pH \< 4**

At baseline for the cohort of patients who had baseline and 12 month pH
metry performed, the mean percentage of supine time during testing that
pH was \< 4 was 12.01% (SD 18.57%). At twelve months following Enteryx
treatment, the mean percentage supine time at pH \< 4 was 6.97% (SD
12.08%). The mean percentage supine time at pH \< 4 was significantly
reduced (improved) at twelve months following Enteryx treatment (p =
0.032) compared to baseline off PPIs. These statistically significant
reductions in supine time at pH\<4 are indicative of a significant
improvement in pH-metry at six and twelve months post-treatment with
Enteryx.

**Total Number of Episodes**

At baseline for the cohort of patients who had baseline and 12 month
pH-metry performed, the mean total number of episodes with pH was \< 4
was 162.04 (SD 112.12). At twelve months following Enteryx treatment,
the mean total number of episodes with pH \< 4 was 114.82 (SD 77.21).
The mean total number of episodes with pH \< 4 was significantly reduced
(improved) at twelve months following Enteryx treatment (p = 0.002)
compared to baseline off PPIs. These statistically significant
reductions in the mean total number of episodes with pH\<4 are
indicative of a significant improvement in pH-metry at six and twelve
months post-treatment with Enteryx.

##### Longest Episode Duration {#longest-episode-duration .unnumbered}

The longest recorded episode duration of pH \< 4 in study subjects at
baseline for the patients with baseline and 12 month data was 33.5
minutes (SD 45.89), while the longest recorded episode duration at 12
months follow-up after treatment with Enteryx, was 21.4 min. (SD 25.54).
These results indicate that there was a reduction in the maximum episode
duration at the twelve month visit following Enteryx treatment as
compared to baseline off PPI treatment, although this difference did not
reach statistical significance (p=0.209).

  ------------------- ------------ ---------------- ---------- ---------------- -------------
  **Symptom**         **Baseline                    **12                        **p
                      (off PPI)**                   Months**                    value**[^2]

                      **n**        **Mean(SD)**     **n**      **Mean (SD)**    

  pH ≤ 4 (%) total    67           14.34 (14.68)    67         9.21 (9.00)      0.002

  pH ≤ 4 (%) upright  58           14.27 (15.35)    58         9.92 (10.72)     0.026

  pH ≤ 4 (%) supine   59           12.01 (18.57)    59         6.97 (12.08)     0.032

  Episodes            67           162.04 (112.12)  67         114.82 (77.21)   0.002
  (Normalized)                                                                  

  Longest episode     65           33.5 (45.89)     65         21.4 (25.54)     0.209
  (min)                                                                         
  ------------------- ------------ ---------------- ---------- ---------------- -------------

**MANOMETRY**

Subjects underwent manometry before treatment with Enteryx (i.e., within
the three months prior to enrollment), six months, and twelve months
following Enteryx treatment. Lower esophageal sphincter (LES) pressure
and length were recorded, as was peristaltic amplitude and residual LES
pressure during relaxation.

+-----------------------+------------------+----------+---------------+
| **Physiologic         |                  | **Ba     | **Month 12**  |
| Method**              |                  | seline** |               |
+-----------------------+------------------+----------+---------------+
| **LES pressure**      | N                | 69       | 69            |
|                       |                  |          |               |
| **(mm Hg)**           |                  |          |               |
+-----------------------+------------------+----------+---------------+
|                       | Mean             | 14.27    | 13.10         |
+-----------------------+------------------+----------+---------------+
|                       | Standard         | 7.03     | 7.75          |
|                       | deviation        |          |               |
+-----------------------+------------------+----------+---------------+
|                       | p-value[^3]      |          | 0.651         |
+-----------------------+------------------+----------+---------------+
| **LES length (cm)**   | N                | 59       | 59            |
+-----------------------+------------------+----------+---------------+
|                       | Mean             | 2.6      | 2.8           |
+-----------------------+------------------+----------+---------------+
|                       | Standard         | 1.04     | 1.28          |
|                       | deviation        |          |               |
+-----------------------+------------------+----------+---------------+
|                       | p-value          |          | 0.258         |
+-----------------------+------------------+----------+---------------+
| **Peristaltic         | N                | 68       | 68            |
| amplitude (mm Hg)**   |                  |          |               |
+-----------------------+------------------+----------+---------------+
|                       | Mean             | 74.7     | 79.2          |
+-----------------------+------------------+----------+---------------+
|                       | Standard         | 30.75    | 36.82         |
|                       | deviation        |          |               |
+-----------------------+------------------+----------+---------------+
|                       | p-value          |          | 0.502         |
+-----------------------+------------------+----------+---------------+
| **Residual LESP       | N                | 65       | 65            |
| during relaxation (mm |                  |          |               |
| Hg)**                 |                  |          |               |
+-----------------------+------------------+----------+---------------+
|                       | Mean             | 2.90     | 2.53          |
+-----------------------+------------------+----------+---------------+
|                       | Standard         | 5.39     | 3.84          |
|                       | deviation        |          |               |
+-----------------------+------------------+----------+---------------+
|                       | p-value          |          | 0.577         |
+-----------------------+------------------+----------+---------------+

DeMeester^5^ described the interaction of overall sphincter length and
pressure in maintenance of normal sphincter function. The shorter the
overall length of the LES, the higher the pressure must be to maintain
sufficient resistance to remain competency. While manometrically
measured LES length was significantly longer in the Enteryx group at 6
months, this difference was no longer significant at 12 months by the
Wilcoxon signed rank test (p=0.258). However, when examining results for
the patients who were improved at 12 months (i.e., PPI use eliminated or
reduced by at least 50%), the sign test, while a less powerful
statistical tool, showed that improved patients continued to have a
longer LES measurement (p = 0.012), suggesting a favorable trend in
treatment responders.

F. SAFETY RESULTS

Adverse events were classified as device related, procedure related, and
unrelated to the device or procedure. The severity of adverse events was
defined as follows:

-   Mild: causing no limitation of usual activities

-   Moderate: causing some limitation of usual activities

-   Severe: causing inability to carry out usual activities.

This definition of "severe" adverse events was in contrast with the
description used in the majority of clinical trials. Customarily,
"severe" is used to describe adverse events that may be reportable under
21 CFR 812.150 if they are serious and device related, i.e., lead to
death, are potentially life threatening, cause disability or require or
prolong hospitalization. In this trial, due to the general good health
of the study participants, more conservative definitions were applied.
On this basis, "severe" events were defined in terms of disruption of
the patient's daily life. The classification of mild, moderate, or
severe was not related to whether medical intervention was necessary.

There were no serious adverse device related events reported during the
course of this trial, i.e., there were no events that were potentially
life threatening or required surgical intervention.

A total of 122 device-related adverse events were reported for the study
population. These adverse events included retrosternal chest pain (78/85
or 91.8%), dysphagia (17/85, or 20.0%), fever (10/85, or 11.8%),
belching/burping (6/85, or 7.1%), bloating/flatulence (5/85, or 5.9%),
body odor/bad taste (4/85, or 4.7%), and one case each of rib pain and
flu syndrome. Of these adverse events, only five (4%) events were rated
as severe at onset, which as noted above, indicated interference with
the subject's daily life. The "severe" device-related adverse events
consisted of retrosternal chest pain (n=4) and bloating (n=1).

> Device-Related Adverse Events
>
> (85 Patients)

+----------------------------------+-----+---------+-----+----+------+
| > **Event**                      | **  | **Mod   | *   | ** | *    |
|                                  | Mil | erate** | *Se | \# | *%** |
|                                  | d** |         | ver | ** |      |
|                                  |     |         | e** |    |      |
+----------------------------------+-----+---------+-----+----+------+
| > Retrosternal Chest Pain        | 39  | 35      | 4   | 78 | 9    |
|                                  |     |         |     |    | 1.8% |
+----------------------------------+-----+---------+-----+----+------+
| > Dysphagia                      | 10  | 7       | 0   | 17 | 2    |
|                                  |     |         |     |    | 0.0% |
+----------------------------------+-----+---------+-----+----+------+
| > Fever                          | 7   | 3       | 0   | 10 | 1    |
|                                  |     |         |     |    | 1.8% |
+----------------------------------+-----+---------+-----+----+------+
| > Belching/Burping               | 3   | 3       | 0   | 6  | 7.1% |
+----------------------------------+-----+---------+-----+----+------+
| > Bloating/Flatulence            | 1   | 3       | 1   | 5  | 5.9% |
+----------------------------------+-----+---------+-----+----+------+
| > Other                          |     |         |     |    |      |
+----------------------------------+-----+---------+-----+----+------+
| > Body Odor/Bad Taste            | 2   | 2       | 0   | 4  | 4.7% |
+----------------------------------+-----+---------+-----+----+------+
| > Rib Pain                       | 0   | 1       | 0   | 1  | 1.2% |
+----------------------------------+-----+---------+-----+----+------+
| > Flu Syndrome                   | 1   | 0       | 0   | 1  | 1.2% |
+----------------------------------+-----+---------+-----+----+------+

A total of 29 (34.1%) adverse events related to the procedure were
reported during the course of this study. None of these events were
considered to be severe. The events consisted of pharyngitis (n=9),
nausea and vomiting (n=7), nausea (n=5), shoulder pain (n=3), dry mouth
(n=2), anxiety (n=2), and breast pain (n=1).

Severity of Procedure-Related Adverse Events

**(85 patients)**

+----------------------------------+-----+---------+-----+----+------+
| > **Event**                      | **  | **Mod   | *   | ** | *    |
|                                  | Mil | erate** | *Se | \# | *%** |
|                                  | d** |         | ver | ** |      |
|                                  |     |         | e** |    |      |
+----------------------------------+-----+---------+-----+----+------+
| > Sore Throat (Pharyngitis)      | 8   | 1       | 0   | 9  | 1    |
|                                  |     |         |     |    | 0.6% |
+----------------------------------+-----+---------+-----+----+------+
| > Nausea / Vomiting              | 3   | 4       | 0   | 7  | 8.2% |
+----------------------------------+-----+---------+-----+----+------+
| > Nausea                         | 3   | 2       | 0   | 5  | 5.9% |
+----------------------------------+-----+---------+-----+----+------+
| > Other                          |     |         |     |    |      |
+----------------------------------+-----+---------+-----+----+------+
| > Shoulder Pain                  | 1   | 2       | 0   | 3  | 3.5% |
+----------------------------------+-----+---------+-----+----+------+
| > Dry mouth                      | 1   | 1       | 0   | 2  | 2.4% |
+----------------------------------+-----+---------+-----+----+------+
| > Anxiety                        | 1   | 1       | 0   | 2  | 2.4% |
+----------------------------------+-----+---------+-----+----+------+
| > Breast Pain                    | 0   | 1       | 0   | 1  | 1.2% |
+----------------------------------+-----+---------+-----+----+------+

The procedure related adverse events were anticipated and consistent
with what is generally expected during the course of therapeutic
endoscopy procedure.

X. [CONCLUSIONS]{.underline}

> In conclusion, the efficacy of treatment of GERD with endoscopic
> implantation of Enteryx is demonstrated by the following observations:

-   The primary hypothesis stating that drug use post-Enteryx
    implantation is less than pre-procedure drug use is fulfilled given
    the fact that at 12 months, 80.3% of all study subjects were able to
    completely eliminate (70.4%) use of PPIs or reduce ≥50% (9.9%) their
    use of PPIs (p\<0.0001, sign test).

> Several secondary efficacy endpoints and hypothesis tests underscore
> the findings regarding the primary efficacy endpoint:

-   The mean Velanovich GERD-HRQL symptom scores for each question and
    the two summary scores (heartburn and regurgitation) showed
    significant improvement following treatment with Enteryx as compared
    to baseline off PPI medications.

-   At all time points following Enteryx treatment, SF-36 Health Survey
    PCS (physical component) scores were significantly improved over the
    mean score at baseline for subjects off PPI therapy and were
    comparable to scores reported at baseline for subjects while on
    PPIs. SF-36 MCS (mental component) scores demonstrated a significant
    improvement (sign test) compared to baseline off PPI medications in
    patients who experienced an improvement in PPI use at 12 months,
    although SF-36 MCS scores in the overall study population was not
    significantly different between groups at 12 months. However, at all
    timepoints following Enteryx treatment, mean mental component scores
    were comparable to scores reported at baseline for subjects while on
    PPIs.

-   pH-metry findings were significantly improved following treatment
    with Enteryx as compared to baseline off PPI medications providing
    an objective measure of restoration of competency of the lower
    esophageal sphincter. Further, for those patients who experienced an
    improvement in PPI use at 12 months, 43.1% had normalized their pH.

-   Manometry findings demonstrated a significant increase in mean LES
    length (sign test) compared to baseline off PPI medications in
    patients who experienced an improvement in PPI use at 12 months,
    although LES length in the overall study population was not
    significantly different between groups at 12 months. LES length may
    play an important role in overall competency of the lower esophageal
    sphincter, as suggested by the relationship between continued
    improvement in LES length and successful outcome of Enteryx
    treatment.

> Treatment of GERD by endoscopic implantation of Enteryx was shown to
> be safe in this study, as evidenced by the low incidence, severity,
> and transient nature of device related adverse events and the complete
> absence of serious adverse device effects. No mortality was observed
> in this population.
>
> The data generated in this clinical study establish that endoscopic
> treatment of GERD by Enteryx implantation offers an alternative to
> life-long medical therapy and its related costs, non-compliance and
> intolerance. In addition, the risks associated with endoscopic Enteryx
> treatment are substantially lower than surgical intervention, with
> comparable health benefits, a reduced financial burden, and reduction
> in the loss of productivity associated with standard surgery for
> management of GERD.
>
> The findings of this study confirm the safety and effectiveness of
> Enteryx implantation for the treatment of GERD in human subjects.

XI\. [PANEL RECOMMENDATIONS]{.underline}

XII\. [CDRH DECISION]{.underline}

XI. [APPROVAL SPECIFICATIONS]{.underline}

[^1]: Clopper-Pearson 95% Confidence Interval

[^2]: Wilcoxon Signed-Rank

[^3]: Wilcoxon Signed-Rank