DUODENAL MUCOSAL REGENERATION INDUCED BY ENDOSCOPIC PULSED ELECTRIC FIELD TREATMENT IMPROVES GLYCEMIC CONTROL IN PATIENTS WITH TYPE II DIABETES - INTERIM RESULTS FROM A FIRST-IN-HUMAN STUDY

Background: Gastric sleeve stenosis (GSS) is an increasingly common adverse event following sleeve gastrectomy (SG) and thought to result from progressive rotation and/or scarring of the sleeve. Objective diagnostic criteria for this condition are lacking. Given the increasing prevalence of SG procedures being performed and the rising incidence of GSS, the diagnosis of GSS is critical to expedite management and reduce patient suffering. Endoluminal impedance planimetry measurements including diameter and distensibility indices (DI) show promise in characterizing GSS, though normal and abnormal benchmark values have never been established.
Aims: To (1) establish benchmark values for the distribution of diameter and DI for normal gastric sleeve anatomy and across GSS severity, and (2) determine if impedance planimetry measurements can be used to characterize the severity of GSS.
Methods: This was a retrospective analysis of a prospective database of patients who underwent upper endoscopy with impedance planimetry for suspected GSS between 8/2018 and 11/2022. All upper endoscopies were performed by a single trained bariatric endoscopist who assessed the presence and severity of luminal narrowing and was blinded to impedance planimetry measurements. Endoscopist description of endoluminal narrowing was reported as normal [0], mild [1], moderate [2], or severe [3]. Impedance planimetry measurements were obtained by advancing the catheter across the GSS. Measurements were monitored for 60 seconds with 3 different balloon volumes (30ml, 40ml, and 50ml) and diameter and distensibility index (DI) were recorded. Primary outcome included luminal diameter and DI. Secondary outcomes included presence and severity of GSS on endoscopy.
Results: A total of 110 endoscopic procedures were included. No luminal narrowing was seen in 19 (17%). Luminal narrowing was graded as mild, moderate, and severe in 27 (25%), 34 (30%), and 30 (27%) of procedures, respectively. When stratified by severity, there was significant difference between impedance planimetry measurements of diameter and DI in all four categories using all 3 balloon volumes (Figure 1). In the group without luminal narrowing, mean (±SD) diameter and DI measurements using consecutive balloon volumes ranged from 19.1 (±5.5) to 23.2 (±1.7) and 16.8 (±4.9) to 23.1 (±10.9), respectively. Comparatively, in severe narrowing, mean (±SD) diameter and DI measurements ranged from 10.3 (±3.0) to 16.6 (±2.1) and 7.5 (±7.1) to 7.7 (±4.3), respectively. Representative images of impedance planimetry for no luminal narrowing and mild, moderate, and severe stenosis are shown in Figure 2.
Conclusion: Impedance planimetry measurements provide objective assessment in the diagnosis of GSS and correlate with luminal narrowing. This study provides new benchmark values for the diagnosis and severity of GSS.

Background
Type 2 diabetes (T2D) affects 462 million people worldwide. Non-pharmacological interventions that can improve glycemic control in patients inadequately controlled with glucose-lowering medications (GLMs) have a potential to delay insulin initiation and modify disease progression. Duodenal mucosal regeneration (DMR) induced by thermal ablation has been associated with improved glycemic control in T2D patients.

Pulsed electric field (PEF) is a unique non-thermal modality that can selectively affect cells via electroporation. This first-in-human study evaluates the safety, feasibility and preliminary efficacy of endoscopic application of PEF to elicit DMR in T2D patients inadequately controlled on GLMs and is the first PEF application in gastrointestinal tract.

Method
This is an ongoing multicenter, open-label, treatment-only study. Key eligibility criteria are 18-70 years of age, history of T2D for ≤10 years, HbA1c of 7.5%-11.0%, BMI of 24 – 40 kg/m2, C-peptide ≥ 333 pmol/l, and on 1-4 non-insulin GLMs. The primary endpoint is the incidence of device- or procedure-related serious adverse events (SAEs) at 12 wks. Secondary endpoints include technical success and changes in glycemic control at 24 wks. The procedure is performed endoscopically using the ReCET™ device (Endogenex Inc.). Patients are followed for 48 wks, with endoscopic follow up at 4 wks. The GLMs are maintained stable for ≥12 wks before and ≥24 wks after the procedure.

Results
To date, 30 patients have been enrolled (Table 1). Technical success was 100%, with a mean treated length of 11.0 ± 1.9 cm, and median procedure time of 59 min (IQR 42 – 78). No device/procedure-related SAEs occurred. Forty-five device/procedure-related adverse events (AEs) were reported in 23/30 patients. Most reported AEs were sore throat (17/30) and transient diarrhea (9/30). AEs were mild (80%) or moderate (20%) in severity. At 4 wks, the treated areas showed complete healing, mostly unidentifiable endoscopically, with no signs of stricture, ulceration, or other significant findings.

The first 12 patients were treated with single energy application (single Tx). The subsequent 18 patients received double energy application (double Tx) and 14 have reached 24 wks. Clinically significant improvements in glycemic control were observed in these 14 patients. At 24 wks, mean HbA1c was 7.5% ± 1.1% vs. 8.4% ± 1.0% at baseline (p<0.01), FPG 7.5 ± 1.7 mmol/l vs. 9.8 ± 2.2 mmol/l (P<0.01), and HOMA-IR 4.5 ± 3.6 vs. 7.4 ± 3.3 (p<0.01). Weight loss was 5.1% ± 4.1% (p<0.01) at 24 wks. An energy dose-response relationship was observed between the single Tx and double Tx dose levels (P < 0.05) (Figure 1).

Conclusions
This first GI application of PEF in human demonstrated that the technology is feasible, safe, well tolerated by patients, and is associated with clinically meaningful improvement in glycemic control.