Evolution of the Chicago Classification: Bridging Physiology and Mechanics

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%.

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.