A U.S. Pilot Human Investigation of RadiofrEquency Vapor Ablation System to Evaluate Safety, TOleRability, and Effectiveness for Proximal Intestinal Mucosal Ablation in Patients With Type 2 Diabetes Mellitus (RESTORE-1 Study)

The main aims of the study are :

Evaluate the safety of the device and procedure based on the reported adverse events that occur.

Evaluate device tolerability based on pain scores reported by patients. Evaluate the effectiveness of the device and procedure by comparing change in HbA1c from baseline to 168 days post procedure.

The subject population for this study are adults (22-65 years of age) with type-2 diabetes mellitus. Study participation is 6 months for each patient.

The study is comprised of 5 phases: Screening, Run-in, Pre-procedure tests, RF Vapor ablation procedure, and Post-vapor ablation follow-up (up to 168 days).

Inclusion criteria

• Men and non-pregnant women 22-65 years of age
• Diagnosed with T2DM for at least 1 year and less than or equal to 15 years
• HbA1C of 7.5 - 10% (58-86 mmol/mol)
• BMI ≥ 24 and ≤ 40 kg/m2
• On one or more non-insulin glucose-lowering medications, with no therapeutic changes in medication regimen for at least 12 weeks prior to the screening visit, to ensure stable glycemic control.

Note 1: Exception for sulfonylureas (SU): For safety reasons, subjects taking sulfonylureas (limited to glipizide or glimepiride only) will be required to undergo a protocol-mandated reduction to ≤50% of the maximum labeled dose during the run-in phase. This adjustment is intended solely to minimize the risk of hypoglycemia during intensive monitoring and dietary standardization and will not be considered a therapeutic change for purposes of eligibility. Subjects unwilling to comply with this dose reduction will be excluded.

Note 2: GLP-1s are considered non-insulin glucose lowering medications.

• Agrees to use an additional glucose-lowering treatment (e.g., liraglutide, other OAD except for glyburide), if recommended by the study Investigator in case of persistent hyperglycemia.
• Weight stability (defined as a < 5% change in body weight) in the 12 weeks prior to the screening visit. Participants should agree to refrain from using over the counter or herbal supplements intended for weight loss. Participants already on a prescribed weight loss drug should agree to not further titrate their medications during the study.
• Women of childbearing potential must be using at least one acceptable method of contraception throughout the study
• Willing and able to use CGM for the duration of the study and comply with study visits and study tasks as required per protocol.
• Able to comply with study requirements and understand and sign the Informed Consent Form

Exclusion criteria

• Diagnosis of Type-1 Diabetes
• History of diabetic ketoacidosis or hyperosmolar nonketotic coma.
• Probable insulin production failure, defined as serum C-peptide of 0.3-0.6 nmol/l.
• Current or previous use of any types of insulin for >1 month (at any time, except for treatment of gestational diabetes) in the last 2 years.
• Hypoglycemia unawareness as defined by a score of 4 or higher on a Gold score questionnaire suggestive of impaired awareness of hypoglycemia (IAH).
• History of severe hypoglycemia (2 or more severe hypoglycemic event, as defined by need for third-party assistance, in the last 6 months from the screening visit).
• Subjects with untreated or unstable microvascular complications of diabetes such as retinopathy, nephropathy, and neuropathy. Subjects who have been appropriately treated/monitored and stable for the prior 3 months before study participation can be included as determined as safe and reasonable by the study PI.
• Known systemic autoimmune disease that is uncontrolled or requiring steroids or biologics, including a positive anti-glutamic acid decarboxylase (GAD) test. Systemic autoimmune diseases include but not limited to celiac disease, duodenal Crohn disease or pre-existing symptoms of systemic lupus erythematosus, scleroderma or other systemic autoimmune connective tissue disorder. (Participants with adequately controlled primary hypothyroidism or with mild to moderate psoriasis managed with topical therapy-affecting less than 10% of body surface area and not involving special areas (e.g., face, palms)-may be included).
• Previous GI surgery that could limit access to the duodenum such as Billroth 2, Roux-en-Y gastric bypass, or other similar procedures or conditions. (Patients who have undergone a laparoscopic sleeve gastrectomy (LSG) or an endoscopic sleeve gastrectomy (ESG) procedure more than one year prior to enrollment will not be excluded from participation in this study.)
• History of chronic pancreatitis or a diagnosis of idiopathic acute pancreatitis within the past 12 months.
• Documented history of diabetic gastroparesis confirmed by gastric emptying study.
• Known active hepatitis or liver disease, excluding nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD).
• Symptomatic gallstones, or acute gastrointestinal illness in the previous 7 days.
• Known history of severe irritable bowel syndrome, radiation enteritis or other inflammatory bowel syndrome, such as Crohn's disease and Celiac disease.
• Alcoholic liver disease, as indicated by ANI>-0.66 and AUDIT-C questionnaire
• Known history of a structural or functional esophageal disorder that could impede endoscope passage or elevate the risk of esophageal injury during an endoscopic procedure, including but not limited to moderate-severe (Los Angeles Grade C or D) esophagitis, dysphagia due to achalasia or stricture/stenosis, esophageal varices greater than Grade 2, history of esophageal perforation, or any other clinically significant esophageal condition.
• Presence of upper gastrointestinal conditions, including active ulcers, varices, strictures, congenital or acquired proximal intestinal telangiectasia, active H. pylori infection.
• Current use of anticoagulation therapy (vitamin K antagonists, such as warfarin, or current use of direct-action oral anticoagulants (DOACs) that cannot be safely discontinued peri procedurally
• Current use of P2Y12 inhibitors (clopidogrel, prasugrel, ticagrelor) that cannot be discontinued for 7 days before and 7 days after the procedure.
• Unable to discontinue high-dose non-steroidal anti-inflammatory drugs (NSAIDs) during treatment through 4 weeks following the procedure. Use of acetaminophen and low dose aspirin, PRN over the counter NSAIDs is allowed.
• Use of systemic glucocorticoids (excluding topical or ophthalmic application or inhaled forms) for more than 10 consecutive days within 12 weeks prior to the baseline visit.
• Persistent anemia, defined as hemoglobin <10 g/dl on two consecutive measurements >6 weeks apart.
• Known history of hemoglobinopathy.
• Known history of blood donation or transfusion within 3 months prior or screening or anticipated blood donation during the study period.
• Significant cardiovascular disease, including known history of valvular heart disease, or myocardial infarction, heart failure, transient ischemic attack, or stroke within 12 months prior to the Screening Visit.
• Mean of 3 separate blood pressure measurements >180 mmHg (systolic) or >100 mmHg (diastolic).
• Estimated glomerular filtration rate (eGFR) ≤ 45 ml/min/1.73m2 (estimated by MDRD).
• Known immunocompromised status, including but not limited to: individuals who have undergone organ transplantation, receipt of chemotherapy, or radiotherapy within the past 12 months, clinically significant leukopenia, confirmed human immunodeficiency virus (HIV) infection, or any other condition impacting immune function that, in the opinion of the investigator, renders the participant unsuitable for trial participation.
• History of secondary hypothyroidism or inadequately controlled primary hypothyroidism (TSH value >1.5x of the upper limit of normal range at screening)
• In the opinion of the Investigator, the participant is not an appropriate candidate for upper GI endoscopy or general anesthesia.
• Active illicit substance abuse or Alcohol Use Disorder (AUD) (consuming more than 14 drinks per week for men or more than seven drinks per week for women)
• Active malignancy within the last 5 years (excluding non-melanoma skin cancers)
• Women who are currently breastfeeding
• Participating in another ongoing clinical trial of an investigational drug or device.
• Any other physical or mental condition that, in the opinion of the investigator, would make the participant an unsuitable candidate for clinical trial participation.
• Critically ill or has a life expectancy <3 years.
• Use of a cardiac pacemaker, implantable cardioverter-defibrillator (AICD), duodenal metallic implants, or any other implanted electronic medical devices.
• General contraindications to deep or conscious sedation, general anesthesia, or upper gastrointestinal (GI) endoscopy, including individuals deemed high-risk by an anesthesiologist (e.g., ASA Physical Status Classification of IV or higher).