Clinical trial NCT06883175: Evolution of the Chicago Classification: Bridging Physiology and Mechanics
Official title: Evolution of the Chicago Classification: Bridging Physiology and Mechanics
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Dysphagia
Achalasia, Esophageal
Ineffective Esophageal Motility
Keywords: dysphagia
swallowing
Lead sponsor: Northwestern University
Sponsor class: OTHER
Collaborators: name: The California Medical Innovations Institute, Inc.
First posted: 2025-03-19
Enrollment: 575
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: DIAGNOSTIC

Brief summary: Swallowing difficulties are extremely common and result in substantial morbidity, reduction in the quality of life, and mortality related to malnutrition and complications from regurgitation and aspiration. Unfortunately, our understanding regarding the pathophysiology of dysphagia and GERD has been hampered by focusing predominantly on circular muscle activity and ignoring the essential biomechanical properties of the esophageal wall that promote normal emptying. Our initial work explored the relationship between intrabolus pressure (IBP) and esophagogastric junction (EGJ) compliance as a metric for outflow resistance. This work highlighted the direct relationship between IBP and EGJ opening and was the foundation for the development of the classification scheme utilized around the world to diagnose esophageal motor disorders: "the Chicago Classification" (CC). Despite this improved understanding focused on bolus transit dynamics, there are still significant gaps in our scientific understanding centered on the lack of a true correlate for symptoms, reliable predictive models and effective treatments for Functional dysphagia, IEM and EGJOO. Given these limitations, we have developed novel approaches that combine assessments of primary and secondary peristalsis (a NeuroMyogenic Model of esophageal function). These will leverage our recent findings supporting the importance of the esophageal response to distension in bolus clearance, noting that this response of the esophageal wall to bolus retention or reflux is one of the most essential functions of the esophagus in preventing complications of aspiration, or reflux injury. We will also include an assessment of esophageal geometry and wall biomechanics (elasticity/dilatation) as these carry essential interactions with esophageal function that are overlooked in the current diagnostic paradigms.

In order to test our hypothesis that wall mechanics are a major determinant of esophageal diseases, we had to develop new approaches and new technology to directly measure mechanical wall state, descending inhibition and LES opening. Using impedance techniques combined with manometry, we are now capable of assessing IBP and diameter changes across a space-time continuum (4D HRM). We also developed physics-based hybrid diagnostics that include a FLIP technique to assess esophageal work and power during volumetric distention (FLIP-MECH) and a fluoroscopy approach that simultaneously assesses esophageal diameter-pressure relationships (Fluoro-MECH). We also developed a new approach, Interactive FLIP Panometry, which facilitates an assessment of descending inhibition and the mechanism behind impaired LES opening. These tools will allow us to expand our models to combine an assessment of neuromyogenic function simultaneously with geometry. Our overarching goal will be to study well-defined patient populations (Functional Dysphagia, IEM/GERD, EGJOO and Achalasia) before and after targeted interventions to test the NeuroMyogenic and MechanoGeometric Model. This work will build upon the previous success of the CC and help advance the evolution of the CC by defining new, relevant biomechanical physiomarkers of disease activity that can identify new targets for therapeutic intervention and facilitate prediction of clinical outcomes.

Detailed description: The proposed experiments in this application will utilize both standard of care diagnostic testing and treatment as well as research procedures in small subsets of participants as required for each Specific Aim. No randomization will be utilized in any aim. The source of the study population will be male and female subjects aged 18-85 years old inclusive and mentally capable to provide informed consent who present to the Northwestern Medicine Digestive Health Center with the chief complaint of dysphagia, regurgitation, chest pain or food impaction, or referral for treatment of achalasia, GERD, or endoscopy negative dysphagia. These subjects will be approached by the study team and provide informed consent prior to study involvement.

In Aim 1, 375 subjects (300 with FD, IEM, or EGJOO and 75 with GERD) will participate. For Aim 1a, standard of care procedural results and questionnaires will be used to develop the best thresholds that will stage the NeuroMyogenic Model. Sixty of these subjects will undergo open-label treatment with prucalopride (2mg qD (oral) for 2 weeks) with completion of questionnaires (research) after the 2 week time period. Fifteen of these (5 each stage of the Neuromyogenic model- I, II, and III) will complete a post-treatment procedure visit where they will undergo sedated FLIP with manometry and esophagram evaluation with questionnaires on the last day of medication. Sample sizes for this experiment are based on our previous results, where patients with HRM of normal motility, IEM, or AC will yield NeuroMyogenic classification of stage I in 15%, stage II in 15%, and stage III in 10% (with 60% of patients being "normal function dysphagia"), thus sample sizes of n=20 for each group will be feasible for recruitment.

For Aim 1b, we will recruit 50 subjects with IEM/FD with impaired LES Opening on FLIP and 50 with EGJOO and assess the ability of EUS-guided Botox to relieve symptoms as measured by EGJ opening before and after treatment. Additionally, a comparison group of type II achalasia (n=15) without significant dilatation (esophageal width \<3cm) will be tested with Interactive FLIP Panometry (Comparison from Aim 2a). Based on our data, we anticipate 20% of 250 patients with HRM of normal motility, IEM, or AC will have abnormal EGJ opening. The response rate to distension and botulinum toxin are not a priori known for EGJOO or FD patients, thus, considering rates from 15-90%, our planned sample size of n=50 per group would provide 80% power to detect absolute differences between groups of 13-27%, which correspond to odds ratios of 3.0-6.9.

For Aim 1c, 75 subjects with GERD will undergo pH-impedance testing, HRM, FLIP and complete PROs as part of their standard of care before and after treatment (fundoplication or MSA). HRM is performed prior to the placement of the pH-Impedance catheter and the HRM procedural data along with FLIP data will be used in this experiment to attempt to predict the likelihood of dysphagia (as measured by BEDQ) after MSA or fundoplication. Assuming 25-50% of patients develop dysphagia and abnormal bolus transit occurs in 13-31% of these patients, our model would have 80% power to detect effects on the order of odds ratios of 2.6-3.3.

Aim 2 experiments focus on achalasia as the disease of interest and explore the role of abnormal geometry and esophageal wall state in determining clinical outcomes of treatment and esophageal emptying. Subjects will be studied using our clinical physiomechanical protocol (EGD, FLIP, HRM, TBE) as part of their standard of care before and 6 months after short tailored POEM. Two hundred subjects will be studied. The primary outcomes will be esophageal clearance and recoil (elasticity) in 100 subjects for experiment 2a. These data will be subject to a supervised learning method to define thresholds for defining the stages of achalasia. The planned cohort sizes (n=100) have traditionally been sufficient for fitting and evaluating SVM.

In experiment 2b, the SOC information will be collected from all 200 subjects and used to measure the primary outcome of treatment success defined as Eckart Score \<3 and TBE 5-min column height \<5cm (without re-intervention). We will study the success of POEM when the EGJ-Distensibility threshold is set at 3.0. Patients who fail will undergo repeat POEM to a target EGJ-DI of 6.0. We theorize that the higher stages will require a higher target for EGJ-DI. Assuming up to 10% attrition, GLM using all n=200 patients would have 80% power to detect differences in treatment response rates across up to 5 stages consistent with those rates ranging from 60-90%.

Eligibility criteria: Inclusion Criteria:

* The source of the study population will be male and female subjects aged 18-85 years old inclusive (females of childbearing potential should be on highly effective contraceptive methods) and mentally capable to provide informed consent who present to the Northwestern Medicine Digestive Health Center with the chief complaint of dysphagia, regurgitation, chest pain or food impaction, or referral for treatment of achalasia, GERD, scleroderma, or endoscopy negative dysphagia. All subjects must be able to undergo endoscopy with functional lumen imaging probe (FLIP) and transnasal intubation for 4 dimensional-High Resolution Manometry (4D HRM) and 24-hour pH impedance probe.

Exclusion Criteria:

* Currently participating in a concurrent clinical trial or completed another trial within past 8 weeks.

  * Active severe esophagitis (Los Angeles esophagitis Grade C and above), Patients may be eligible once esophagitis is healed if they continue to have dysphagia in the context of healed esophagitis.

Contact PD/PI: Pandolfino, John Erik Protection of Human Subjects Page 131

* Evidence of mechanical obstruction due to stricture (e.g., peptic/GERD patients, EoE, or other) or previous small bowel or colonic obstruction.
* Long-segment Barrett's metaplasia.
* Unstable medical illness with ongoing diagnostic work-up and treatment. Patients with well-controlled hypertension, diabetes and a remote history of ischemic heart disease that is deemed stable, as judged by the physician-investigator can be included. EKG will be performed before prucalopride in the 60 patients undergoing Experiment 1a.
* Current drug or alcohol abuse or dependency.
* Current neurologic or cognitive impairment which would make the patient an unsuitable candidate for a research trial.
* Severe mental illness, e.g., uncontrolled major depression with suicidal ideation, active psychosis, diagnosis of schizophrenia-spectrum disorder.
* Pregnant patients.
* Bleeding diathesis or need for anticoagulation that cannot be stopped for endoscopy.

Primary outcomes:
measure: Brief Esophageal Dysphagia Questionnaire (BEDQ)
timeFrame: baseline
measure: Brief Esophageal Dysphagia Questionnaire (BEDQ)
timeFrame: 6 months post-treatment
measure: Esophagogastric Junction (EGJ) diameter
timeFrame: baseline
measure: Esophagogastric Junction (EGJ) diameter
timeFrame: 6 months post-treatment
measure: Esophageal Clearance
timeFrame: baseline
measure: Esophageal Clearance
timeFrame: 6 months post-treatment
measure: recoil
timeFrame: baseline
measure: recoil
timeFrame: 6 months post-treatment
measure: Timed Barium Esophagram (TBE) Column Height
timeFrame: baseline
measure: Timed Barium Esophagram (TBE) Column Height
timeFrame: 6 months post-treatment
measure: Integrated Relaxation Pressure (IRP)
timeFrame: baseline
measure: Integrated Relaxation Pressure (IRP)
timeFrame: 6 months post-treatment
measure: Esophagogastric Junction Distensibility Index
timeFrame: baseline
measure: Esophagogastric Junction Distensibility Index
timeFrame: 6 months post-treatment
Secondary outcomes:
measure: Bolus Retention
timeFrame: baseline
measure: Bolus Retention
timeFrame: 6 months post-treatment
measure: Eckhart Score
timeFrame: baseline
measure: Eckhart Score
timeFrame: 6 months post-treatment
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
Study officials:
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