Precision medicine in achalasia – premedia

The National Institute of Diabetes and Digestive and Kidney Diseases awarded Northwestern University $4.764 million through Cooperative Agreement U01DK142700 on September 18, 2025, to conduct a multicenter randomized controlled trial testing precision medicine approaches to peroral endoscopic myotomy (POEM) in achalasia treatment under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847). The award funds research on optimizing POEM myotomy parameters—position, length, and depth—to reduce complications including gastroesophageal reflux disease and blown-out myotomy formation, comparing a short, tailored precision approach against standard myotomy methodology across multiple clinical sites through August 31, 2030. Work is performed in Chicago, Illinois.

Northwestern University administers the award as prime recipient, with sub-awards to 18 clinical and research partner sites including Massachusetts General Hospital, Vanderbilt University Medical Center, Mayo Clinic Arizona, Emory University, Case Western Reserve University, Wake Forest University Health Sciences, Weill Medical College of Cornell University, University of Florida, University of California San Diego, Baylor Research Institute, AdventHealth Orlando, The Johns Hopkins University, University of Colorado Denver, Indiana University, and Washington University. Sub-award funding began flowing between December 22, 2025, and June 18, 2026, with documented obligations to individual sites including Vanderbilt University Medical Center (sub-awarded May 22, 2026), Mayo Clinic Arizona (March 11, 2026), Case Western Reserve University / University Hospitals Cleveland (February 17 and April 7, 2026), and Emory University (January 29, 2026). The multicenter structure enables enrollment and clinical assessment across geographically distributed sites, with each sub-recipient providing patient recruitment, endoscopic procedure delivery, outcomes assessment, and biospecimen or data collection aligned with the trial protocol.

Abstract

An interruption in the normal swallowing mechanism due to abnormal neuromuscular function in the esophageal body or the lower esophageal sphincter (LES) is associated with significant morbidity and quality of life impact, as well as increased mortality related to malnutrition, aspiration and cancer. Achalasia is the prototypical esophageal motility disorder and has an incidence of 1-5 per 100,000 and a prevalence of 10-20 per 100,000. Unfortunately, the cause of achalasia is unknown and the current therapies are primarily compensatory in nature and focus on disrupting the LES to improve emptying using either endoscopic dilation or surgical myotomy. Over the last 5 years, there has been an evolution away from dilation and surgery toward peroral endoscopic myotomy (poem) due to its less invasive approach compared to surgery and its superior efficacy compared to dilation. However, important questions regarding the effectiveness and risks of poem remain and the impact of the myotomy approach (position, length, depth) on outcomes is also unclear. The standard poem myotomy is typically 8-10 CM in length, extending 2-3 CM into the cardia and approximately 6-7 CM above the squamocolumnar junction and IT is performed with either a transmural or superficial approach targeting only the circular muscle. We recently reported that blown out myotomy (BOM) is a common mechanism of achalasia treatment failure related to focal dilatation along the myotomy site that profoundly impairs emptying. The scientific premise of this study is that the current arbitrary approach to myotomy in poem is associated with a predilection to increased gerd and BOM formation through its effects on the distal esophagus. We hypothesize that an innovative precision approach with poem can improve outcomes and reduce complications. Thus, we are proposing a multicenter randomized trial (aim 1) to test the hypothesis that a short, tailored poem will be non-inferior to the standard poem and associated with less reflux disease and a reduction in BOM formation. Additionally, we will also aim to better understand outcomes in jackhammer esophagus and spastic motility disorders through a rigorous prospective study (aim 2) assessing response to a long tailored myotomy. Using data and samples from study participants, we also aim to refine and validate a new achalasia patient reported outcome (apro) measure (aim 3) and establish a repository of biological specimens to help elucidate the pathophysiology of achalasia. This study will reshape the management of esophageal motility disorders and improve our understanding of the pathogenesis of these disorders by sharing specimens with translational scientists focused on neurogastroenterology.