Endoscopic Pyloromyotomy for Refractory Gastroparesis

Gastroparesis is a disorder triggered by numerous causes and it is defined by symptoms and
with an objective evidence of delayed gastric emptying in the absence of obstruction (albeit
pyloric spasms may play a role in a subset of patients). Gastroparesis may be a consequence
of medication, surgery or diabetes but in approximately one third of patients, the cause
remains unknown and the patients are diagnosed with idiopathic gastroparesis. Effective
treatment for gastroparesis is challenging especially in patients with severe symptoms. The
efficacy of prokinetics is dubious since they have not proven real clinical efficacy in
placebo controlled trials. In refractory gastroparesis, endoscopic or surgical treatments may
therefore be considered. Endoscopic treatments include intrapyloric injection of botulinum
toxin and transpyloric insertion of a metallic stent. Surgical options involve implantation
of a gastric "pacemaker" (gastric stimulation), pyloroplasty and subtotal gastrectomy. The
partial effectiveness of botulinum toxin injection, stents and pyloroplasty suggests that
disruption of the pyloric muscle may lead to a decreased intrapyloric tone and consequently
to a symptomatic improvement in some patients with refractory gastroparesis.

Recently, a new endoscopic technique, gastric endoscopic per oral pyloromyotomy (G-POEM) has
been introduced with promising preliminary results. Uncontrolled studies with so far limited
number of patients have demonstrated a significant symptomatic improvement in approximately
70% of patients and improved or normalized of gastric emptying in more than a half of
patients after G-POEM. A prospective uncontrolled study suggested that patients with
idiopathic or post-surgical gastroparesis experiences higher success rate after G-POEM
(70-80%) compared to patients with diabetic gastroparesis (50%).

G-POEM is, in principle, adaptation of POEM (per-oral endoscopic myotomy) in the stomach.
POEM is now considered a standard treatment for esophageal achalasia and it has been shown to
be safe and effective. In contrast to achalasia, pathophysiology of pyloric function in
patients with gastroparesis is less understood and the explanation of how and why G-POEM
should work is some-how hypothetical. For example, presumed pylorospasm has not been
demonstrated as the predictive factor for treatment success of G-POEM yet. Refractory
gastroparesis is often accompanied by psychological or even psychiatric disturbances and
hence a placebo" effect of G-POEM cannot be ruled out. Therefore, the real clinical efficacy
of G-POEM can only be demonstrated in a clinical randomized sham-controlled trial.

To assess the severity of gastroparesis-related symptoms, the Gastroparesis Cardinal Symptom
Index (GCSI) has been developed for this item. The GCSI is part of a larger questionnaire
PAGI-SYM (Patient Assessment of Upper Gastrointestinal Symptom severity index) established
for assessment of patient-reported symptoms in gastroparesis (dyspepsia and gastroesophageal
reflux). PAGI-SYM as well as GCSI subscale scores varied significantly by global disease
severity, with higher (worse) scores observed in those subjects who rated their gastroparesis
as moderate to severe.

The aim of this prospective, sham-controlled, cross-over study (cross-over for patients
randomized to the sham arm) is to compare short and long-term efficacy and safety of G-POEM
in patients with refractory gastroparesis. Symptoms and objective parameters of gastric
emptying will be the main outcome criteria. The reason of using a sham protocol is to control
for the potential confounders (therapeutic effects of touch and belief, which are components
of the placebo effect).

Investigators plan to randomize 86 patients (43 in the active arm, ratio 1:1 active vs.
sham). Sample size is calculated based on expected therapeutic success of G-POEM in 50% of
patients vs. 20% in the sham group; significance level 0,05; study power 0,8; beta error 0,2;
adjustment for 15% expected drop out.

Patients will be randomised in blocks of 6, stratified according to the etiologies:
(idiopathic, diabetic, and post-surgical; patients after esophagectomy with gastric
pull-through will not be included). Control visits will be scheduled at 3, 6, 12, 24, and 36
months. The primary outcome will be the proportion of patients with treatment success in the
active group vs. sham group at 6 months after the procedure. Several secondary outcomes will
also be assessed, including procedure-related parameters and safety parameters and change in
Gastric Emptying Study (GET) after G-POEM vs. sham. After 6 months, patients randomized to
the sham group will be offered G-POEM procedure and further followed up (cross-over part of
the study) providing that they did not have a therapeutic effect of the sham procedure.

Inclusion Criteria:

- Refractory (> 6 months) and severe (based on a validated total GSCI = Gastroparesis
Cardinal Symptom Index) gastroparesis, with confirmed gastric emptying based on a
gastric emptying study: standardized protocol of scintigraphy in all patients
(performed less than 4 months prior to enrolment), or confirmed by a validated gastric
emptying breath test [27]. The total GSCI score must be >2.3 [28].

- Abnormal gastric emptying is defined as retention of Tc-99 m >60% at 2 h and/or ≥10%
of residual activity at 4 h on a standardized sulphur colloid solid-phase gastric
emptying study.

- Radiolabelled liquids emptying study will be reserved as alternative technique for
patients with poor tolerance of solids during scintigraphy. Abnormal gastric emptying
will represent >50% retention of radiolabelled content (e.g. In-111) at 1 hour.

- Abnormal gastric empyting breath test based on a solid normal range determination for
the test used (e.g. T1/2 > 109 min)

Exclusion Criteria:

- Age less than 18 years

- No previous attempt with at least one prokinetic drug

- No previous attempt to withdraw anticholinergic agents and glucagon like peptide -1
(GLP-1) and amylin analogues* in patients treated with these substances

- Active treatment with opioids or a history of treatment with opioids within 12 months
before enrolment.

- Previous gastric surgery BI or II, esophagectomy, gastric pull-through

- Previous pyloromyotomy or pyloroplasty

- Known eosinophilic gastroenteritis

- Organic pyloric (or intestinal) obstruction (fibrotic stricture, etc.)

- Severe coagulopathy

- Esophageal or gastric varices and /or portal hypertensive gastropathy

- Advanced liver cirrhosis (Child B or Child C)

- Active peptic ulcer disease

- Pregnancy or puerperium

- Malignant or pre-malignant gastric diseases (dysplasia, gastric cancer, GIST)

- Any other condition, which in the opinion of the investigator would interfere with
study requirements

- Uncontrolled diabetes mellitus

- Diagnosis of rumination syndrome or "eating" disorder (mental anorexia, bulimia
nervosa) **

- Severe constipation without using laxatives

- Inability to obtain informed consent