Endovascular Denervation for the Treatment of Type 2 Diabetes Mellitus

Endovascular Denervation for the Treatment of Type 2 Diabetes Mellitus - a Feasible Clinical Trial Protocol

This is a prospective, multicenter, single group feasibility clinical trial to evaluate the safety and efficacy of Endovascular denervation for the treatment of type 2 diabetes mellitus (T2DM) using the Endovascular denervation system (Generator and Catheter).

Study Overview

• Status: Active, not recruiting
• Conditions: Type 2 Diabetes Mellitus (T2DM)
• Intervention / Treatment: Device: Endovascular denervation System (Generator and Catheter )

Detailed Description

This is a prospective, multicenter, single group feasibility clinical trial. Patients with T2DM with poor glycemic control, glycated hemoglobin A1c (Hba1c) between 7.5% and 10.5% treatment with at least one to three oral antidiabetic drugs and/or insulin on the basis of metformin. All eligible patients will accept EDN treatment and were evaluated at 7, 30, 60, 90, 180, 365, 730 days post procedure. The primary safety endpoint is the number of composite major adverse events (MAE) * related to the study device and/or the denervation procedure during procedure and within 30 days after the procedure, the primary efficacy is Hba1c changes from baseline to 6 months post procedure.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Jiangsu
    • Nanjing, Jiangsu, China, 210009
      • Zhongda Hospital, Southeast University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Subject with age of >18 years old and<65 years old (both ends included)
2. Subjects understood the requirements and treatments of the trial, agreed to and were able to complete all follow-up assessments required for the trial, and signed informed consent before any special trial-related tests and treatments were performed
3. Diagnosed with T2DM for 1-15 years (according to WHO criteria)
4. Metformin (daily dose ≥1000mg) was combined with 1-3 Oads for more than 3 months and/or insulin (no dose limit). Specific Oads were: insulin secretagogues (sulfonylureas/glinides), thiazolidinediones (TZDS) and α-glucosidase inhibitors (see Note), and the combined Oads were at least half of the maximum approved dose in the package insert
5. The above OAD treatment is not effective for more than 3 months, and the glycosylated hemoglobin (HbA1c) level is between 7.5% and 10.5% (based on baseline examination)
6. Body mass index (BMI) between 18 and 40kg/m2 (both ends included)

Exclusion Criteria:

1. Type 1 diabetes or late-onset autoimmune diabetes in adults (LADA), or any secondary diabetes
2. Previous aortic disease (e.g., aortic aneurysm or dissection) or aortic surgery (including celiac artery denervation)
3. Baseline CTA showed aortic aneurysm or dissection, or anatomical abnormalities of the hepatic artery and its branches, or other abnormal vascular structure/status (e.g., severe tortuosity or stenosis of the artery, intraval thrombus, or unstable plaque) deemed by the investigator to be unsuitable for vascular ablation.
4. More than 2 self-reported or documented episodes of severe hypoglycemia in the past 6 months (defined as hypoglycemia with severe cognitive impairment requiring assistance from another person)
5. Have had more than one documented episode of hyperglycemia requiring hospitalization in the past 6 months, including diabetic ketoacidosis, hyperosmolar coma, etc
6. Severe diabetic complications, such as retinal, renal, vascular, neuropathy, and diabetic foot, were considered by the investigator to be ineligible for enrollment in this trial
7. Major cardiovascular and cerebrovascular events (MACCE) within the past 6 months, including cerebrovascular accident (CVA), transient cerebral ischemia (TIA), heart failure (NYHA class III-IV), acute myocardial infarction, or unstable angina requiring hospitalization (including previous coronary artery bypass grafting or coronary stent implantation); And uncontrolled or severe arrhythmias
8. Severe autonomic neuropathy (orthostatic hypotension, gastroparesis syndrome, etc.)
9. Untreated or uncontrolled high blood pressure (SBP≥160mmHg or DBP≥100mmHg), or low blood pressure (BP < 90/50 MMHG)
10. A history of renal insufficiency or failure with a baseline estimated glomerular filtration rate (eGFR) < 60mL/min/1.73m2 (see Note c of the Clinical Data collection Table in Table 5-2 for the eGFR formula)
11. Chronic active hepatitis, severe hepatobiliary disease (including cirrhosis), or hepatic insufficiency (alanine and/or aspartate aminotransferase > 3 times the upper limit of normal or serum total bilirubin > 2 times the upper limit of normal)
12. Acute and chronic pancreatitis during screening and baseline periods
13. Acute systemic infections during the screening and baseline periods
14. Bleeding tendency or coagulopathy (PT, APTT, or INR > 2 times the upper limit of normal; Platelet count < 80×109/L or ≥ 700×109/L)
15. Active GI ulcer or GI bleeding within 3 months before baseline
16. Symptomatic cholelithiasis (including cholecystolithiasis, extrahepatic bile duct stones, and intrahepatic bile duct stones) but without effective treatment such as cholecystectomy, choledocholithotomy, internal drainage or external drainage
17. Hyperthyroidism, hypothyroidism, acromegaly, Cushing's syndrome and other endocrine and metabolic diseases
18. Autoimmune diseases
19. Diagnosed with a high risk of malignancy or cancer development/recurrence, or expected life expectancy < 12 months
20. History of major surgical procedures within the past 3 months
21. A condition or concomitant medical condition, such as hemoglobinopathy or hemolytic anemia, that could have prevented the primary end point from being assessed
22. Patients with mental illness who are unable to cooperate
23. Received treatment with a GLP-1 receptor agonist, DPP-4 inhibitor, or SGLT-2 inhibitor within 3 months before the screening period
24. Received systemic or intra-articular glucocorticoids (other than topical, inhaled, or eye drops) within 3 months before the screening period
25. Use of weight-loss medications such as orlistat or other possible treatments for weight loss (weight-loss tea/herbal medicine/acupuncture, etc.) within 3 months before the screening period
26. Prior or anticipated bariatric surgery such as subtotal gastrectomy/liposuction
27. Receipt of central sympathetic inhibitors or anticonvulsants within 3 months prior to or anticipated during the screening period
28. Long-term anticoagulation therapy is required but preoperative heparin bridging anticoagulation is not possible
29. Weight gain of more than 10% in the past 3 months
30. Allergy to or contraindication to contrast media, and inadequate pretreatment, as judged by the investigator
31. A known history of allergy to the study device (containing polytetrafluoroethylene or Nitinol) or to medications associated with the trial protocol
32. Were participating in other clinical studies or were participating in clinical studies within 3 months before enrollment
33. Expect to participate in a clinical trial of another drug or medical device within 24 months after baseline surgery
34. Pregnant or lactating women, or those planning to become pregnant within the next 2 years (all women of childbearing age must undergo a pregnancy test within 7 days before baseline surgery)
35. Drastic changes in diet and exercise habits are expected during the study (due to religious/work needs/weight loss, etc.)
36. Irregular day and night work (night shift workers)
37. History of alcohol/drug/substance abuse
38. Scheduled periodic blood product therapy or severe blood loss during the previous 3 months/study period
39. According to the investigator's judgment, there is any situation that affects the safety of the subjects or interferes with the evaluation of the test results
40. Subjects had aortic aneurysm or aortic dissection confirmed on angiography before EDN
41. The subject's vascular structure and conditions were considered by the investigator to be unsuitable for ablation (e.g., severe tortuosity or stenosis of the artery, abnormal vascular anatomy, intracavinal thrombus, or unstable plaque).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: The endovascular denervation (EDN) group; Receive endovascular denervation (EDN)	Device: Endovascular denervation System (Generator and Catheter ); All patients receive endovascular denervation (EDN) treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the composite of major adverse events (MAE)* related to the study device and/or the EDN procedure during procedure and within 30 days post procedure	The primary safety endpoint is the composite of major adverse events (MAE)* related to the study device and/or the EDN procedure during procedure and within 30 days post procedure	From index procedure to 30 days post procedure
The changes of Hba1c from baseline at 6 months post procedure	The primary efficacy is the changes of Hba1c from baseline at 6 months post procedure.	From baseline to 6 months post procedure

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients achieving target HbA1c (< 7.0% and ≤6.5%) at 1, 3, 6, 12 and 24 months post procedure	Proportion of patients achieving target HbA1c (< 7.0% and ≤6.5%) at 1, 3, 6, 12 and 24 months post procedure	From baseline to 1, 3, 6, 12 and 24 months post procedure
Proportion of patients with HbA1c < 7% without hypoglycemia/severe hypoglycemia or weight gain at 1, 3, 6, 12 and 24 months post procedure	Proportion of patients with HbA1c < 7% without hypoglycemia/severe hypoglycemia or weight gain at 1, 3, 6, 12 and 24 months post procedure	From baseline to 1, 3, 6, 12 and 24 months post procedure
Incidence of hypoglycemia and severe hypoglycemia (blood glucose level < 3.9 mmol/L) at 1, 3, 6, 12 and 24 months post procedure	Incidence of hypoglycemia and severe hypoglycemia (blood glucose level < 3.9 mmol/L) at 1, 3, 6, 12 and 24 months post procedure	From baseline to 1, 3, 6, 12 and 24 months post procedure
Incidence of cardiovascular and cerebrovascular complications (3MACE, defined as cardiovascular death, myocardial infarction and ischemic stroke) at 12 and 24 months post procedure	Incidence of cardiovascular and cerebrovascular complications (3MACE, defined as cardiovascular death, myocardial infarction and ischemic stroke) at 12 and 24 months post procedure	From baseline to 12 and 24 months post procedure
The changes of Hba1c from baseline at 1, 3, 12 and 24 months post procedure	The changes of Hba1c from baseline at 1, 3, 12 and 24 months post procedure	From baseline to 1, 3, 12 and 24 months post procedure
The changes of assessment of islet function and insulin resistance at 1, 3, 6, 12 and 24 months post procedure	The change of islet function and insulin resistance (HOMA-β and HOMA-IR) from baseline at 1, 3, 6, 12 and 24 months post procedure	From baseline to 1, 3, 6, 12 and 24 months post procedure
The changes of mean glucose, postprandial glucose increase, nocturnal glucose increase and time in target range (TIR) by 14-day ambulatory glucose monitoring (with non-invasive ambulatory glucose meter) at 1, 3, 6, 12 and 24 months post procedure	The changes of mean glucose, postprandial glucose increase, nocturnal glucose increase and time in target range (TIR) by 14-day ambulatory glucose monitoring (with non-invasive ambulatory glucose meter) at 1, 3, 6, 12 and 24 months post procedure	From baseline to 1, 3, 6, 12 and 24 months post procedure
The changes of blood lipids at 1, 3, 6, 12 and 24 months post procedure	The changes of blood lipids (triglycerides, total cholesterol, HDL and LDL) from baseline to 1, 3, 6, 12 and 24 months post procedure	From baseline to 1, 3, 6, 12 and 24 months post procedure
The changes of liver function at 1, 3, 6, 12 and 24 months post procedure	The changes of blood liver function (ALT, AST, ALP and GGT) from baseline at 1, 3, 6, 12 and 24 months post procedure	From baseline to 1, 3, 6, 12 and 24 months post procedure
The changes of renal function to 1, 3, 6, 12 and 24 months post procedure	The changes of blood renal function (urea nitrogen, blood creatinine and eGFR) from baseline at 1, 3, 6, 12 and 24 months post procedure	From baseline to 1, 3, 6, 12 and 24 months post procedure
The changes of glucose in oral glucose tolerance test (OGTT) and insulin and C-peptide release tests from baseline to 6, 12, and 24 months post procedure	The changes of glucose in oral glucose tolerance test (OGTT) and insulin and C-peptide release tests from baseline to 6, 12, and 24 months post procedure	From baseline to 1, 3, 6, 12 and 24 months post procedure
Proportion of patients with the changes of in type/dose of antidiabetic drugs at 1, 3, 6, 12 and 24 months post procedure	Proportion of patients with the changes of in type/dose of antidiabetic drugs at 1, 3, 6, 12 and 24 months post procedure	From baseline to 1, 3, 6, 12 and 24 months post procedure
The occurrence of new significant celiac or hepatic artery stenosis at 6 months post procedure (stenosis >50% as assessed by CTA and confirmed by DSA when CTA assessment shows abnormal)	The occurrence of new significant celiac or hepatic artery stenosis at 6 months post procedure (stenosis >50% as assessed by CTA and confirmed by DSA when CTA assessment shows abnormal)	From baseline to 7days, 1, 3, 6, 12 and 24 months post procedure
The occurrence of device and/or procedure-related AEs and SAEs during procedure and 7 days, 1, 3, 6, 12 and 24 months post procedure	The occurrence of device and/or procedure-related AEs and SAEs during procedure and 7 days, 1, 3, 6, 12 and 24 months post procedure	From baseline to 12 and 24 months post procedure
Quality of life assessment (EQ-5D-5L) at pre-procedure and 6 months post procedure	Quality of life assessment (EQ-5D-5L) at pre-procedure and 6 months post procedure	Before procedure to 6 months post procedure

Collaborators and Investigators

• Sponsor: Shanghai Golden Leaf MedTec Co. Ltd
• Investigators: Principal Investigator: Gao-Jun Teng, MD, Zhongda Hospital

Study record dates

Study Major Dates

• Study Start (Actual): December 27, 2022
• Primary Completion (Actual): April 1, 2024
• Study Completion (Estimated): February 28, 2025

Study Registration Dates

• First Submitted: November 13, 2022
• First Submitted That Met QC Criteria: November 20, 2022
• First Posted (Actual): November 30, 2022

Study Record Updates

• Last Update Posted (Actual): April 9, 2024
• Last Update Submitted That Met QC Criteria: April 6, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Type 2 Diabetes Mellitus; Endovascular denervation
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2
• Other Study ID Numbers: MLWY-S220501

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No