RCT of Gastric ESD With or Without Epineprhine Added Solution

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

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.

Study Overview

• Status: Completed
• Conditions: Early Gastric Cancer; Gastric Neoplasm
• Intervention / Treatment: Procedure: Endoscopic submucosal dissection; Drug: Epinephrine

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 800
• Phase: Phase 3

Contacts and Locations

Study Locations

• Hong Kong
  • Hong Kong, Hong Kong
    • The Chinese University of Hong Kong
• Japan
  • Ishikawa, Japan
    • Ishikawa Prefecture Central Hospital
  • Kyoto, Japan
    • Kyoto 2nd Red Cross Hospital
  • Osaka, Japan
    • Osaka International Cancer Institute
  • Shizuoka, Japan
    • Shizuoka Cancer Center
• Korea, Republic of
  • Busan, Korea, Republic of
    • Kosin university gospel hospital
• Singapore
  • Singapore, Singapore
    • Changi General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Chinese University of Hong Kong
• Collaborators: Changi General Hospital; Kosin University Gospel Hospital; Fukuoka University; Osaka International Cancer Institute; Kyoto 2nd Red Cross Hospital; Ishikawa Prefectural Central Hospital; Machida General Hospital; Nara City Hospital; Wakayama Red Cross Hospital; JCHO Osaka Hospital; Sapporo Kinentou hospital; Japan Community Healthcare Organization Osaka Hospital
• Investigators: Principal Investigator: Hon Chi Yip, MBChB, FRCSEd, Chinese University of Hong Kong

Study record dates

Study Major Dates

• Study Start (Actual): January 10, 2020
• Primary Completion (Actual): December 31, 2022
• Study Completion (Actual): January 31, 2023

Study Registration Dates

• First Submitted: July 23, 2019
• First Submitted That Met QC Criteria: July 24, 2019
• First Posted (Actual): July 25, 2019

Study Record Updates

• Last Update Posted (Actual): May 4, 2025
• Last Update Submitted That Met QC Criteria: April 30, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: Epinephrine; Gastric Endoscopic submucosal dissection
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases; Stomach Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Neurotransmitter Agents; Adrenergic alpha-Agonists; Adrenergic Agonists; Adrenergic Agents; Respiratory System Agents; Anti-Asthmatic Agents; Bronchodilator Agents; Adrenergic beta-Agonists; Sympathomimetics; Vasoconstrictor Agents; Mydriatics; Epinephrine
• Other Study ID Numbers: EPI-ESD RCT01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No