POEM-F for Achalasia International Study

• ClinicalTrials.gov Identifier: NCT06042127
• Recruitment Status: Not yet recruiting
• First Posted: September 18, 2023
• Last Update Posted: September 22, 2023
• Sponsor: Chinese University of Hong Kong
• Collaborators: Deenanath Mangeshkar Hospital and Research Centre; Johns Hopkins University; Northwestern University Feinberg School of Medicine; Nanfang Hospital, Southern Medical University; Asian Institute of Gastroenterology, India; Post Graduate Institute of Medical Education and Research, Chandigarh
• Information provided by (Responsible Party): Hon Chi Yip, Chinese University of Hong Kong

Study Description

Brief Summary:

Per-oral endoscopic myotomy (POEM) has emerged as the endoscopic treatment of choice for achalasia, offering comparable symptom relief with laparoscopic Heller's cardiomyotomy. The main concern with POEM is the higher incidence of post-procedure gastroesophageal reflux disease (GERD), occurring in up to 50-60% of patients. In order to reduce the risk of GERD, endoscopic fundoplication has been developed as a novel procedure mimicking surgical anterior partial fundoplication that can be performed in the same session as POEM (POEM-F). Case series of POEM-F in patients with achalasia reported encouraging outcomes of low GERD rate of ~12% at 1 year. Prospective comparative data between POEM-F and conventional POEM on post-procedure GERD is current lacking. The investigators therefore designed an international multicenter prospective randomized study to investigate the efficacy of POEM-F. The investigators postulate that POEM-F could reduce the incidence of post-procedure GERD when compared with conventional POEM.

This is an international multicenter randomized controlled trial conducted between high volume expert centers from Hong Kong SAR, China, India and United States of America. Adult patients with manometry confirmed achalasia would be randomised to undergo POEM-F or POEM. The procedure would be performed by experts with vast experience in POEM. The primary outcome is the incidence of post-procedure GERD at 1 year, defined by the updated Lyon consensus. Secondary outcomes include technical and clinical success rates, adverse events, post-POEM endoscopic and manometry findings as well as patients' symptom scores.

Sample size calculation Based on existing pilot comparative data on POEM-F and POEM, it is estimated that 84 patients would be required to demonstrate a difference in post-procedure GERD of 47.6% to 18.2%, with 80% power and false positive rate of 0.05, accounting for 10% loss to follow-up.

Purpose and potential The current study proposal could demonstrate the superiority of POEM-F over POEM in reducing post-procedural GERD. It would also demonstrate the safety and reproducibility of the technique in expert centers across the globe. It could potentially replace conventional POEM as the preferred minimally invasive endoscopic treatment for achalasia.

Condition or disease	Intervention/treatment	Phase
Achalasia	Procedure: POEM-F; Procedure: Conventional POEM	Not Applicable

Detailed Description:

Achalasia is the most common esophageal motility disorder worldwide, with an annual incidence of 1.6 per 100'000 individual and prevalence of 10 per 100'000 population. The incidence of achalasia has been dramatically rising over the past decade. A study conducted in Chicago suggested that over the 10 years from 2004 to 2014, the incidence and prevalence of achalasia were two- to threefold greater than estimates would have predicted. The likely explanation to the rise in incidence is an increased awareness of this condition and widespread availability of accurate diagnostic test with high resolution manometry. The cardinal features of achalasia include failed relaxation of lower esophageal sphincter and absent esophageal peristalsis. Owing to the benign nature of the disease, patients suffering from it would experience longstanding debilitating symptoms of dysphagia, chest pain, regurgitation, resulting in poor quality of life. In the past, laparoscopic Heller's cardiomyotomy with partial fundoplication and endoscopic pneumatic dilatation were considered as treatment options for achalasia.

In the past 10 years, per-oral endoscopic myotomy (POEM) has emerged as the incisionless minimally invasive endoscopic treatment of choice for achalasia. This Natural Orifice Transluminal Endoscopic Surgical (NOTES) technique involves mucosal incision and creation of a submucosal tunnel in the distal esophagus down to gastric cardia, followed by esophageal and gastric myotomy. Since the procedure was first reported by Inoue H, et al in 2010, it has seen worldwide acceptance as first-line therapy. POEM has been associated with excellent relief of dysphagia and achalasia-related symptoms with a low and acceptable adverse event rate of 0.5%. In a previous randomised controlled trial, POEM had a higher treatment success rate than pneumatic dilatation. When compared with laparoscopic Heller's cardiomyotomy, POEM was associated with at least similar treatment efficacy and a trend towards reduced short term adverse event. POEM could perform even better than surgical myotomy in patients with type III achalasia.

The main limitation of POEM is the incidence of gastroesophageal reflux disease (GERD) post-POEM. Kumbhari et al. looked at rates of GERD after POEM on patients who underwent subsequent objective pH testing. A total of 282 patients were included in this analysis from multiple centers in America, Asia, and Europe. About 58% of patients had objective evidence of abnormal acid exposure, with 23% showing evidence of esophagitis. More concerning, however, was that 60% of the patients with GERD were completely asymptomatic. This highlights an important issue at hand that many patients, either related to the propensity of GERD to be silent or the nature of achalasia to develop and insensate esophagus, do not report symptoms while showing high rates of GERD. POEM has been found to be consistently associated with higher rate of GERD than conventional Heller's cardiomyotomy or pneumatic dilatation across multiple studies.

Supported by evidence demonstrating the efficacy of partial fundoplication during Heller's operation, there has been a significant interest in performing fundoplication after POEM during the same session to prevent the development of post-POEM GERD. Inoue et al. pioneered the technique of POEM-F that mimics the surgical Dor (anterior partial fundoplication) procedure. In the pilot study, technical success was achieved in all 21 patients, and all but one had an intact fundoplication wrap on upper endoscopy at a 1-month follow-up. Four more studies conducted in Japan and India have reported good early outcomes with POEM-F (Technical success of 85-100%) for achalasia. No severe adverse event has been reported in these studies which reiterates the safety of this procedure. In the longest follow-up study on POEM-F, GERD diagnosed by an abnormal esophageal acid exposure was seen in 11.1% of the 21 cases at one-year follow-up: comparable (8.8%) to a large meta-analysis of 4871 Heller's cardiomyotomy with fundoplication procedures.

To date, no prospective multicenter randomised study has been conducted to compare the efficacy of POEM-F with conventional POEM in reducing post-procedure GERD. Therefore, in this study, the investigators aim to evaluate the of POEM-F in patients with achalasia through an international multicenter randomized controlled trial.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 81 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Randomised controlled trial
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Per-oral Endoscopic Myotomy With Fundoplication for Achalasia - an International Multicenter Randomized Controlled Trial
• Estimated Study Start Date: November 1, 2023
• Estimated Primary Completion Date: October 31, 2025
• Estimated Study Completion Date: October 31, 2026

Arms and Interventions

Arm	Intervention/treatment
Experimental: Per-oral endoscopic myotomy with fundoplication; The detail of the procedure has been reported in the literature. After completion of myotomy as per conventional anterior POEM, a serosal incision would be made at the level of the GE junction below the diaphragmatic crus. The peritoneal cavity would then be entered and the anterior gastric wall could be identified. A detachable endoloop would be introduced alongside the endoscope with the guidance of endoscopic clip. Three to four clips would be applied to the anterior gastric fundus while additional 3-4 clips would be applied to the edge of the submucosal tunnel, all anchoring to the endoloop. Upon tightening of the endoloop the anterior fundus would be approximated to the esophagogastric junction and thus completing the partial anterior fundoplication. Abdominal paracentesis to treat capnoperitoneum would be performed as required based on patient's clinical condition.	Procedure: POEM-F; POEM-F would be performed as described in the arms section
Active Comparator: Conventional POEM; Conventional per-oral endoscopic myotomy An anterior POEM would be performed per usual manner described in the literature. The procedure would be performed under general anaesthesia by expert endoscopists with at least 50 case experience of conventional POEM and 5 cases experience of POEM-F. The requirement of POEM experience is based on a recent multicenter study of learning curve by Fujiyoshi Y, et al. The procedure would follow the current recommendations from expert panel in reducing GER, including avoidance of excessive gastric myotomy and preservation of the sling fibers are the gastric cardia. The length of the esophageal and gastric myotomy is standardized at 5cm and 2cm respectively	Procedure: Conventional POEM; Anterior POEM performed as described in the arms section

Outcome Measures

Primary Outcome Measures :

1. Post-procedure rate of gastroesophageal reflux [ Time Frame: 1 year ]

   Defined by updated Lyon 2.0 consensus as fulfilling one or more of the criteria:

   1. Endoscopic erosive esophagitis, LA grade B or above
   2. Long segment Barrett's esophagus
   3. Peptic esophageal stricture
   4. 24-hour pH study with acid exposure time >6% Both endoscopy and pH study to be performed with proton pump inhibitor stopped for 4 weeks

Secondary Outcome Measures :

1. Clinical success rate of procedure [ Time Frame: 1 year ]
   Post-treatment Eckhardt score <=3
2. Adverse event of procedure [ Time Frame: 30 day ]
   frequency of severe adverse events with probable or definite attribution to the procedure based on the American Society of Gastrointestinal Endoscopy (ASGE) lexicon as well as Clavien Dindo classification
3. Technical success rate of procedure [ Time Frame: 1 day ]
   Completing all steps of the intended procedure successfully in the same session
4. Procedure time [ Time Frame: 1 day ]
   Procedure time of the intended procedure in minutes
5. Erosive esophagitis on post-procedure endoscopy [ Time Frame: 1 year ]
   The presence of erosive esophagitis as well as the grading on post-procedure endoscopy
6. Fundoplication wrap integrity on post-procedure endoscopy [ Time Frame: 1 year ]

   Endoscopic appearance of fundoplication wrap on retroflexion in the stomach.

   1. Intact - wrap is completely visualised
   2. Indistinct - wrap is visualised but appears to be loosened
   3. Absent - the wrap is completely not visible
7. Distensibility index on EndoFLIP, premyotomy [ Time Frame: During index procedure, before myotomy ]
   Distensibility index (mm2/mmHg) using EndoFLIP
8. Distensibility index on EndoFLIP, post myotomy [ Time Frame: During index procedure, after myotomy ]
   Distensibility index (mm2/mmHg) using EndoFLIP
9. Distensibility index on EndoFLIP, post fundoplication [ Time Frame: During index procedure, after fundoplication ]
   Distensibility index (mm2/mmHg) using EndoFLIP
10. Distensibility index on EndoFLIP, on follow-up [ Time Frame: 1 year ]
    Distensibility index (mm2/mmHg) using EndoFLIP, at follow-up endoscopy
11. Maximum diameter on EndoFLIP, premyotomy [ Time Frame: During index procedure, before myotomy ]
    Maximum diameter (mm) on EndoFLIP
12. Maximum diameter on EndoFLIP, post-myotomy [ Time Frame: During index procedure, after myotomy ]
    Maximum diameter (mm) on EndoFLIP
13. Maximum diameter on EndoFLIP, post-fundoplication [ Time Frame: During index procedure, after fundoplication ]
    Maximum diameter (mm) on EndoFLIP
14. Maximum diameter on EndoFLIP, on follow-up [ Time Frame: 1 year ]
    Maximum diameter (mm) on EndoFLIP, at follow-up endoscopy
15. GERD-HRQL score [ Time Frame: 1 month, 3 month, 6 month and 1 year ]
    Symptom and quality of life score relating to GERD The score ranged from 0-50 with higher score signifying more severe GERD symptom / worse quality of life
16. GERD-RSI score [ Time Frame: 1 month, 3 month, 6 month and 1 year ]
    Symptom and quality of life score relating to GERD The score ranged from 0-45 with higher score signifying more severe GERD symptom
17. GERD-Q score [ Time Frame: 1 month, 3 month, 6 month and 1 year ]
    Symptom and quality of life score relating to GERD The score is ranged from 0-18 with the higher score signifying more symptom of GERD
18. Use of proton pump inhibitor post-procedure [ Time Frame: 1 month, 3 month, 6 month, and 1 year ]
    Number of participants who are on regular / as required / not on PPI

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion criteria:

1. Adult patient (age ≥18 and ≤65 years-old) and with symptomatic achalasia type I or II.
2. Capability of understanding and complying with the study requirements, including filling the Eckardt Score, GERD-HRQL and RSI questionnaire and signing the informed consent form.

3. Patients with achalasia type I, II or III who are one of the following:

   • Treatment naïve, or
   • Failed prior through-the-scope balloon dilation, Savary or pneumatic dilation

Exclusion criteria:

1. Patients unable or unwilling to provide consent.
2. Previous esophageal or gastric surgery.
3. Prior achalasia treatment including Heller myotomy, POEM.
4. Sigmoid achalasia, or significant esophageal dilatation >6cm in lower esophagus
5. Disrupted mucosal integrity at the distal esophagus, eg. Ulcer, fibrotic scars etc
6. Patients with large hiatal hernias (axial length > 2 cm and Hill grade >2).
7. Patients with significant cardiorespiratory comorbidities which may limit their ability to undertake general anesthesia for the procedure, including ASA grade III or above.
8. Patients with obesity (Body Mass Index (BMI) ≥ 30).
9. Pregnant women or those planning pregnancy or breastfeeding women.
10. Uncorrectable coagulopathy defined by international normalized ratio (INR) > 1.5 or platelet count < 50000/µl.

Contacts and Locations

Contacts

Contact: Hon Chi Yip, FRCSEd; 35052627; hcyip@surgery.cuhk.edu.hk

Locations

United States, Maryland

Johns Hopkins Hospital

Baltimore, Maryland, United States, 21287

Contact: Mouen Khashab mkhasha1@jhmi.edu

Sub-Investigator: Farimah Fayyaz

Principal Investigator: Mouen Khashab

China

Nanfang Hospital, Southern Medical University

Guangzhou, China

Contact: Xiaobei Luo luoxiaobei63@126.com

Principal Investigator: Xiaobei Luo

Hong Kong

The Chinese University of Hong Kong

Hong Kong, Hong Kong

India

Post Graduate Institute of Medical Education and Research

Chandigarh, India

Contact: Jayanta Samanta dj_samanta@yahoo.co.in

Principal Investigator: Jayanta Samanta

Asian Institute of Gastroenterology

Hyderabad, India

Contact: Mohan Ramchandani ramchandanimohan@gmail.com

Principal Investigator: Mohan Ramchandani

Sub-Investigator: Nabi Zaheer

Baldota Institute of Digestive Sciences

Mumbai, India

Contact: Amit Maydeo amitmaydeo@gmail.com

Principal Investigator: Amit Maydeo

Sub-Investigator: Gaurav Patil

Sub-Investigator: Amat Nagesh

Deenanath Mangeshkar Hospital & Research Center

Pune, India

Contact: Amol Bapaye amolbapaye@gmail.com

Principal Investigator: Amol Bapaye

Sponsors and Collaborators

Chinese University of Hong Kong

Deenanath Mangeshkar Hospital and Research Centre

Johns Hopkins University

Northwestern University Feinberg School of Medicine

Nanfang Hospital, Southern Medical University

Asian Institute of Gastroenterology, India

Post Graduate Institute of Medical Education and Research, Chandigarh

Investigators

• Principal Investigator: Hon Chi Yip, FRCSEd; Chinese University of Hong Kong

More Information

• Responsible Party: Hon Chi Yip, Assistant Professor, Chinese University of Hong Kong
• ClinicalTrials.gov Identifier: NCT06042127
• Other Study ID Numbers: 2023 145-T
• First Posted: September 18, 2023
• Last Update Posted: September 22, 2023
• Last Verified: September 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Keywords provided by Hon Chi Yip, Chinese University of Hong Kong:

POEM; Fundoplication; GERD

Additional relevant MeSH terms:

Esophageal Achalasia; Esophageal Motility Disorders; Deglutition Disorders; Esophageal Diseases; Gastrointestinal Diseases; Digestive System Diseases