RCT of Gastric ESD With or Without Epineprhine Added Solution

Study Overview
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Brief Summary
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This is an international multi-center randomised controlled study comparing outcomes of gastric endoscopic submucosal dissection (ESD) with or without addition of epinephrine in the submucosal injection solution.

Detailed Description
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Endoscopic submucosal dissection (ESD) is an endoscopic technique aiming to achieve en-bloc resection of mucosal neoplastic lesion in the gastrointestinal tract. It is now considered as the standard of treatment for early gastric cancer confined to the mucosa, achieving an excellent overall survival comparable to that of surgical resection. Important adverse events associated with gastric ESD include hemorrhage (intraoperative or delayed) and perforation. The reported incidence of intraprocedural and delayed hemorrhage of gastric ESD is generally higher than that of esophageal or colorectal ESD5. This is likely due to the rich blood supply of the stomach penetrating from the muscularis to the submucosal layer. Bleeding during ESD would result in difficulty in visualizing the correct plane of dissection from blood clots obscuring view of the endoscope. As a result, prolonged procedural time may be required to achieve hemostasis and obtain adequate view for dissection. There are currently different options of the solution for submucosal injection during gastric ESD. Epineprhine has often been added into these solutions with the aim of causing vasoconstrictive effect and potentially reduce bleeding during the procedure. The use of epinephrine has been recommended when removing larger pedunculated polyps with endoscopic mucosal resection (EMR)6. However the exact clinical benefit of adding epinephrine during gastric ESD has not been proven in the literature. On the other hand, when larger dose of epinephrine is absorbed systemically it may rarely cause significant tachycardia and generalized vasoconstriction, putting patients at risk of myocardial infarction or cerebrovascular accident. A retrospective propensity score analysis was previously performed in one of our Japanese center (Presented at JGCA 2019, Shizuoka). After adjustment of important confounding factors including age, sex, tumor location, specimen size, depth of tumor invasion, presence of histological ulcer or scar and operators' experience, the addition of epinephrine into submucosal solution was associated with a significantly shorter procedural time upon multivariate analysis. The mean procedural time was 72±54 minutes versus 93±62 minutes with and without epinephrine respectively. (p<0.001) With the encouraging result from a single center retrospective study, we plan to conduct a prospective multicenter randomized controlled study to confirm the benefit of adding epinephrine into the submucosal solution during gastric ESD.

Official Title
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Multicenter Randomized Controlled Trial of Gastric Endoscopic Submucosal Dissection With or Without Epineprhine Added Solution

Conditions
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Gastric Neoplasm, Early Gastric Cancer

Intervention / Treatment
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* Procedure: Endoscopic submucosal dissection
* Drug: Epinephrine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Selection criteria: Presence of intramucosal neoplastic lesions in the stomach planning for endoscopic submucosal dissection (Vienna Classification Category 3 and 4 lesion) Target subjects receiving sufficient briefing from the attending physician regarding the content of this study and providing informed consent for participation Exclusion Criteria: Recurrent / remnant lesion after previous endoscopic resection Lesions arising from surgical anastomotic site, such as gastrojejunostomy / gastroduodenostomy. Marked electrolyte abnormalities Hemostatic or coagulative abnormalities Patient on anti-coagulant agents, including warfarin and other direct oral anti-coagulants (those on antiplatelet can be included) Failure of vital organ (heart, lungs, liver, or kidneys) function Allergic to components of injection solutions: Epinephrine, hyaluronic acid etc Other cases deemed by the examining physician as unsuitable for safe treatment

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Epinephrine<br>0.2ml 1:10000 epinephrine diluted into each 20ml of the original solution for submucosal injection | Procedure: Endoscopic submucosal dissection<br>* Endoscopic submucosal dissection<br>Drug: Epinephrine<br>* Epinephrine<br>|
| Active Comparator: Non-epinephrine<br>No epinephrine would be added into the solution | Procedure: Endoscopic submucosal dissection<br>* Endoscopic submucosal dissection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall procedural time | From the beginning of mucosal incision till the end of submucosal dissection, excluding time for prophylactic homeostasis | During the endoscopic procedure | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of intra-procedural hemorrhage events | The number of oozing or spurting bleeding events during a procedure, requiring hemostasis with coagulating forceps | During the endoscopic procedure | 
| Maximum systolic blood pressure | Maximum systolic blood pressure during ESD | During the endoscopic procedure | 
| Maximum heart rate | Maximum heart rate during ESD | During the endoscopic procedure | 
| Adverse event - Delayed hemorrhage | Delayed hemorrhage (Based on CTCAE definition) | 30 days | 
| Adverse event - Perforation | Perforation (Based on CTCAE definition) | 30 days | 
| Adverse event - Cardiovascular event | Cardiovascular event (Based on CTCAE definition) | 30 days | 
| Adverse event - Cerebrovascular event | Cerebrovascular event (Based on CTCAE definition) | 30 days | 
| Other adverse event | Based on CTCAE definition | 30 days | 
| Pathology | Final histology based on Vienna Classification | During the endoscopic procedure | 
| Size of lesion | Size of lesion | During the endoscopic procedure | 
| Depth of invasion | Depth of tumor invasion | During the endoscopic procedure | 
| Vertical margin | Vertical margin involvement | During the endoscopic procedure | 
| Horizontal margin | Horizontal margin involvement | During the endoscopic procedure | 
| Differentiation | Degree of differentiation for cancer of stomach | During the endoscopic procedure | 
| Lymphovascular invasion | Lymphovascular invasion on pathology | During the endoscopic procedure | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gastric Endoscopic submucosal dissection, Epinephrine