To demonstrate the safety and effectiveness of the EndoStim® Lower Esophageal Sphincter (LES) Stimulation System in the treatment of subjects with gastroesophageal reflux disease (GERD)
ID
Source
Brief title
Condition
- Gastrointestinal disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety Endpoint: Rate of occurrence of device- and/or procedure-related serious
adverse events at the 12-month follow-up visit as adjudicated by the Data
Safety Monitoring Board with a sufficient level of precision
Efficacy Endpoint: Comparison between treatment and control group of percentage
(%) of subjects achieving pH success defined as a normalization (distal
esophageal pH < 4 for no more than 5.3% of monitoring time) or > 50%
improvement in their distal esophageal pH at 6 months compared to their
baseline distal esophageal pH performed after at least 5 days off PPIs and at
least 2 days off H2 blocker.
Secondary outcome
Secondary Endpoint
Patient-Focused
Number of subjects achieving GERD symptom success defined as an improvement in
their composite GERD-HRQL score of 50% or more after 12 months of stimulation
compared to their baseline off-PPI or H2 blocker composite GERD-HRQL score.
Secondary Endpoints, Blinded Phase (comparison between Treatment and Control
Groups at the 6-month follow-up visit).
Change from baseline to the 6-month follow-up visit of the mean percentage (%)
of time distal esophageal pH is <4.0 using Bravo Esophageal pH Monitoring
performed after at least 5 days off PPIs and at least 2 days off H2 blocker
Heartburn symptom frequency and severity (day and night) as measured by Subject
Diary
Mean acid-suppression (PPI and H2 blocker) medication use
Regurgitation symptom frequency and severity (day and night) as measured by
Subject Diary
Mean Quality of life scores as measured by SF-12
Secondary Endpoints, Open-Label Treatment Phase (comparison between baseline
data and after 12 months of stimulation where each subject serves as its own
control)
Mean percentage (%) of time distal esophageal pH is <4.0
Number of subjects reporting 50% or more reduction in severity of heartburn
symptoms as measured by daily Subject Diary
Number of subjects reporting 50% or more reduction in severity of regurgitation
symptoms as measured by daily Subject Diary
Number of subjects able to stop regular use of acid-suppression medication
(defined as 50% or more Subject Diary days without PPI use)
Number of subjects able to stop all use of acid-suppression medication (defined
as 100% Subject Diary days without PPI use)
Number of subjects reporting 50% or more reduction in nocturnal symptoms of
heartburn as measured by daily Subject Diary
Number of subjects reporting 50% or more reduction in nocturnal symptoms of
regurgitation as measured by daily Subject Diary
Number of subjects achieving symptom success compared to PPI defined as an
improvement in their composite GERD-HRQL score of 50% or more compared to their
baseline on-PPI or H2 blocker composite GERD-HRQL score
Mean quality of life scores as measured by SF-12
Background summary
BACKGROUND AND JUSTIFICATION
Gastroesophageal Reflux Disease (GERD) is a common problem affecting 14-17% of
the population in the United States (US). Approximately 250 million subjects
worldwide and 30 million subjects in the US suffer from GERD. Among the 12
million Americans who suffer from daily heart-burn (the main symptom of GERD)
almost 5 million do not respond completely to medications and many more do not
want or cannot take medications due to side-effects. The total annual cost of
care of GERD in the US is estimated at $9.8 billion, $5.8 billion of which are
spent on medication.1
The goals of treatment in GERD are to relieve symptoms, heal esophagitis if
present, prevent recurrence of symptoms and esophagitis, and prevent
complications. Medical acid-suppressive therapy with proton pump inhibitors
heals esophagitis, relieves symptoms and improves quality of life. However,
acid suppressive therapy does not correct the underlying pathophysiology of
dysfunction lower esophageal sphincter and hence symptoms of reflux due to
weakly acidic or non-acid reflux persist in the majority of subjects. Recent
reports about the safety of long-term proton pump inhibitors and drug
interactions have raised concerns about safety of these drugs.2
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.3 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. The
results reported from operations performed in community hospital lower-volume
centers have been different than those achieved in centers of excellence. It
has been reported that between 23% and 62% of patients who have undergone
laparoscopic Nissen fundoplication use acid suppression medications at
long-term follow-up. Due to these issues patient and physician acceptance of
surgical procedures remains low and is mainly limited to patients with severe
GERD or those non-responsive to medications.4-8
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.9-12
EndoStim has developed a medical device specifically designed to deliver
electrical stimulation to the LES. The results of EndoStim clinical feasibility
studies suggested that, in GERD subjects, LES electrical stimulation therapy is
a safe, and likely an effective method for treating GERD by enhancing LES tone
and restoring normal LES function, which results in significant and sustained
improvement in GERD symptoms, reduction in esophageal acid exposure , reduction
in GERD medication use and improvement in patients* quality of life.13-19
Results of these ongoing studies are promising and warrant additional clinical
studies, including a sham-controlled study, to evaluate the safety and
effectiveness of the EndoStim LES Stimulation System to treat GERD.
Study objective
To demonstrate the safety and effectiveness of the EndoStim® Lower Esophageal
Sphincter (LES) Stimulation System in the treatment of subjects with
gastroesophageal reflux disease (GERD)
Study design
A multicenter, randomized, double-blind, sham-controlled study.
All subjects undergo screening and baseline visits, followed by system
implantation, and randomization to either a Treatment Group (immediate
stimulation) or Control Group (delayed stimulation).
Randomized subjects complete a 6-month, double-blind phase.
At the 6-month visit, subjects are unblinded, Control Group subjects begin
receiving stimulation, and are followed for an additional 12-month open-label
treatment phase and Treatment Group subjects continue treatment for an
additional 6 months.
Subjects continue receiving stimulation for an extended follow-up phase
involving a phone interview 18 months post stimulation and annual visits
through 5 years.
Intervention
Bravo Esophageal pH Monitoring
Esophageal Manometry (HRM)
Endoscopy
12-Lead ECG Monitoring
Laparoscopy and System Implantation, ECG Monitoring
Urine Pregnancy Test
HbA1c
Chem7 or Basic Metabolic Panel
Complete Blood Count
Study burden and risks
Results from this study could validate 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.
Potential Increased Risk Analysis
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.).
Specific risks associated with the implantation procedure include: Infection or
fever, allergic reaction, pain or discomfort, perforation, tissue abrasion /
erosion, cardiac arrhythmia, cardiopulmonary depression, complications (pain,
phlebitis/ infection) associated with the intravenous canula insertion,
aspiration pneumonia, hematoma, seroma, wound separation, risks associated with
laparoscopy and the use of anesthesia/sedatives.
Laparoscopy risks include but not limited to unstable blood pressure, vertigo,
swelling, injury to organs, blood vessels or other structures and internal
bleeding.
Anesthesia risks include but are not limited to nausea, vomiting, fever,
hypoxia, pneumonia, adverse drug reactions, urine retention, clumsiness,
drowsiness, blurred vision and death.
Potential risks associated with the LES electrical stimulation therapy include:
chest pain or discomfort, abdominal pain or discomfort, worsening of GERD
symptoms, and dysphagia or odynophagia.
There is a potential that any system component could malfunction, become
damaged, infected, or, in the case of the leads, become dislodged or fractured.
System component malfunction or other clinical circumstances (eg, sepsis) may
require noninvasive corrective actions or possibly even a surgical revision
(repositioning, replacement, or removal) of the malfunctioning component(s).
Risks associated with the implant procedure are mitigated by selection of
experienced laparoscopic surgeons and providing detailed training on the
EndoStim implantation procedure. Risks associated by adverse effects of the
electrical stimulation are mitigated by EKG monitoring during the first
stimulation session of each patients. No stimulation related adverse events
have been encountered thus far in prior clinical trials.
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.).
In relation to the physiological assessment techniques:
Manometry and pH testing procedure
Although manometry and pH testing is commonly used to assess GERD, there are
possible risks associated with this procedure. The patients may experience pain
or discomfort when the manometry or pH tube is placed in the oesophagus. The
patients will be given a local anaesthetic to prevent any pain or discomfort.
The patient may also experience retching or vomiting which could increase the
risk of aspirating a food particle into the lungs. There is a small chance that
this could lead to sinusitis or pneumonia. To ensure that no food particles are
present in your stomach that could be aspirated into the lung, the patients
will fast prior to manometry tube placement.
Endoscopy
Endoscopy is generally a safe procedure, however complications can occur. There
is a risk of bleeding if a piece of tissue was removed for testing. If a piece
of tissue was removed, there is a risk of tearing (perforation) through the
upper digestive tract. This may require hospitalisation and sometimes surgery
to repair it. There is also a risk of an infection in the part when endoscopes
are used for the examination. In order to treat the infection, the patient will
usually be prescribed antibiotics which are a common treatment.
Risks to Pregnancy
The risks of implanting the EndoStim device in a pregnant woman are unknown.
Pregnant women may not take part in this research trial. Women with child
bearing potential will only be considered as potential candidates if they have
been on two forms of effective 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.
Trained staff will undertake the management of any adverse effects. The
facilities where subjects will be assessed are fully equipped for emergency
situations.
Toernooiveld 300
Nijmegen 6525
NL
Toernooiveld 300
Nijmegen 6525
NL
Listed location countries
Age
Inclusion criteria
Subject is 22 * 75 years of age at the time of informed consent
Subject with documented symptoms of GERD for longer than 6 months (regurgitation and/or heartburn which is defined as burning epigastric or substernal pain which responds to acid neutralization or suppression) which requires daily use of proton pump inhibitors (PPIs) or other antireflux drug therapy, who continue to have symptoms despite maximum medical therapy or are *intolerant* severe
sideeffects (e.g. anaphylaxis or severe allergic reaction, recurrent C. difficile, severe hypomagnesaemia) to one PPI or mild/moderate side effect (e.g.
nausea, vomiting, diarrhea or abdominal pain) to at least 2 PPIs of different chemical classes. Subjects with symptomatic improvement on PPI therapy demonstrated by a composite GERDHRQL score of *20 off PPI, and with *10 point improvement on PPI when comparing to their off PPI composite GERDHRQL score.
Subject has exhibited excessive lower esophageal acid exposure during pH monitoring (defined as distal esophageal pH < 4 for > 6.0% of the monitoring time) performed after at least 5 days off of PPIs and at least 2 days off of H2 blockers.
Subject has esophagitis * Grade B (LA classification) as measured by upper endoscopy off PPI and H2 blockers for at least 10 days.
Exclusion criteria
Exclusion Criteria
Subjects must not meet any of the following study exclusion criteria:
a. Subject had a previous EndoStim LES System implant and/or implant attempt
b. Subject underwent previous surgery involving the gastroesophageal junction or the lead implant site, such as a Nissen fundoplication
c. Subject underwent previous endoscopic intervention for the treatment of GERD and/or Barrett*s esophagus
d. Subject has a hiatal hernia larger than 3 cm as determined by endoscopy
e. Subject has history of gastroparesis
f. Subject has any nonGERD esophageal motility disorders that in the opinion of investigator precludes an antireflux procedure
g. Subject has history of or known esophageal stricture or significant esophageal anatomic abnormalities (obstructive lesions, etc.)
h. Subject has Barrett*s esophagus or any grade of dysplasia
i. Subject has documented history of esophagitis Grade C or D (LA Classification)
j. Subject has a history of suspected or confirmed esophageal or gastric cancer
k. Subject has esophageal or gastric varices
l. Subject has symptoms of dysphagia more than once per week every week within the last 3 months
m. Subject is unable to tolerate withdrawal from H2 Blockers or PPI medications
n. Subject has suspected or known allergies to titanium, platinum, iridium, stainless steel, silicone, epoxy, or nylon
o. Subject has a body mass index (BMI) > 35 kg/m2
p. Subject has any significant multisystem diseases
q. Subject has an autoimmune or a connective tissue disorder (scleroderma, dematomyositis, CalcinosisRaynaud*sEsophagus Sclerodactyly Syndrome (CREST), Sjogren*s Syndrome, Sharp*s Syndrome, etc.) requiring therapy in the preceding 2 years
r. Subject has Type 1 diabetes mellitus or uncontrolled Type 2 diabetes mellitus (T2DM) defined as HbA1c > 9.5 in the previous 6 months or at screening/baseline
s. Subject has significant cardiac arrhythmia or ectopy or significant cardiovascular disease (i.e. unstable angina pectoris, hemodynamically significant valvular disease, severe congestive heart failure), or any cardiac therapeutic intervention within the last 6 months.
t. Subject has had a significant cerebrovascular event within the last 6 months
u. Subject has an existing implanted electrical stimulator (pacemaker, implantable cardioverter defibrillator, DBS, bone growth or pelvic floor stimulators, drug pumps, etc.)
v. Female subject of childbearing potential and is pregnant or nursing, or intends to become pregnant during the trial period, who is not using a reliable form of birth control
w. Subject is currently enrolled in other potentially confounding research
x. Subject has an active infection as determined by the investigator
y. Subject has a history of any malignancy in the last 2 years
z. Subject has a life expectancy less than 3 years
aa. Subject has a diagnosed major psychiatric disorder (bipolar, schizophrenia, etc.)
bb. Subject has any condition that, at the discretion of the investigator or sponsor, would interfere with accurate interpretation of the study endpoints or preclude participation in the trial
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| ClinicalTrials.gov | NCT02749071 |
| CCMO | NL58772.091.16 |